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Sample records for acquired neuroprotection induced

  1. Superior neuroprotective effects of cerebrolysin in nanoparticle-induced exacerbation of hyperthermia-induced brain pathology.

    PubMed

    Sharma, Aruna; Muresanu, Dafin Fior; Mössler, Herbert; Sharma, Hari Shanker

    2012-02-01

    In recent years, the incidence of heat stroke and associated brain pathology are increasing Worldwide. More than half of the world's population are living in areas associated with high environmental heat especially during the summer seasons. Thus, new research is needed using novel drug targets to achieve neuroprotection in heat-induced brain pathology. Previous research from our laboratory showed that the pathophysiology of brain injuries following heat stroke are exacerbated by chronic intoxication of engineered nanoparticles of small sizes (50-60 nm) following identical heat exposure in rats. Interestingly, in nanoparticle-intoxicated animals the known neuroprotective agents in standard doses failed to induce effective neuroprotection. This suggests that the dose-response of the drugs either requires modification or new therapeutic agents are needed to provide better neuroprotection in nanoparticle-intoxicated animals after heat stroke. This review is focused on the use of cerebrolysin, a mixture of several neurotrophic factors and active peptide fragments, in relation to other neuroprotective agents normally used to treat ischemic stroke in clinics in nanoparticle-induced exacerbation of brain damage in heat stroke. It appears that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal rats. Interestingly, to induce effective neuroprotection in nanoparticle-induced exacerbation of brain pathology a double dose of cerebrolysin is needed. On the other hand, double doses of the other drugs were quite ineffective in reducing brain damage. These observations suggest that the drug type and doses are important factors in attenuating nanoparticle-induced exacerbation of brain pathology in heat stroke. The functional significance and possible mechanisms of drug-induced neuroprotection in nanoparticle-treated, heat-stressed rats are discussed. PMID:22229316

  2. Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity.

    PubMed

    Zou, L; Jankovic, J; Rowe, D B; Xie, W; Appel, S H; Le, W

    1999-01-01

    Pramipexole, a novel non-ergoline dopamine (DA) agonist, has been applied successfully for treatment of Parkinson's disease (PD). We report here that pramipexole can protect dopaminergic cell line Mes23.5 against dopamine- and levodopa-induced cytotoxicity possibly through a mechanism related to antioxidant activity. In the MES 23.5 cultures, DA and L-DOPA induce a dose- and time-dependent cytotoxicity, as determined by tetrazolium salt and trypan blue assays. Furthermore, an in situ terminal deoxynucleotidyl transferase assay demonstrates that DA-induced cell death is apoptotic. Pretreatment with pramipexole in a concentration range (4-100 microM) significantly attenuates DA- or L-DOPA-induced cytotoxicity and apoptosis, an action which is not blocked by D3 antagonist U-99194 A or D2 antagonist raclopride. Pramipexole also protects MES 23.5 cells from hydrogen peroxide-induced cytotoxicity in a dose-dependent manner. In cell-free system, pramipexole can effectively inhibit the formation of melanin, an end product resulting from DA or L-DOPA oxidation. These results indicate that pramipexole exerts its neuroprotective effect possibly through a mechanism, which is independent of DA receptors but related to antioxidation or scavenging of free radicals (e.g. hydrogen peroxide). As a direct DA agonist and potentially neuroprotective agent, pramipexole remains attractive in the treatment of PD. PMID:10227583

  3. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity.

    PubMed

    Zhu, Jing; Carozzi, Valentina Alda; Reed, Nicole; Mi, Ruifa; Marmiroli, Paola; Cavaletti, Guido; Hoke, Ahmet

    2016-01-01

    Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin's ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols. PMID:27350330

  4. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity

    PubMed Central

    Zhu, Jing; Carozzi, Valentina Alda; Reed, Nicole; Mi, Ruifa; Marmiroli, Paola; Cavaletti, Guido; Hoke, Ahmet

    2016-01-01

    Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin’s ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols. PMID:27350330

  5. Neuroprotective therapy for argon-laser-induced retinal injury

    NASA Astrophysics Data System (ADS)

    Belkin, Michael; Rosner, Mordechai; Solberg, Yoram; Turetz, Yosef

    1999-06-01

    Laser photocoagulation treatment of the central retina is often complicated by an immediate side effect of visual impairment, caused by the unavoidable laser-induced destruction of the normal tissue lying adjacent to the lesion and not affected directly by the laser beam. Furthermore, accidental laser injuries are at present untreatable. A neuroprotective therapy for salvaging the normal tissue might enhance the benefit obtained from treatment and allow safe perifoveal photocoagulation. We have developed a rat model for studying the efficacy of putative neuroprotective compounds in ameliorating laser-induced retinal damage. Four compounds were evaluated: the corticosteroid methylprednisolone, the glutamate-receptor blocker MK-801, the anti-oxidant enzyme superoxide dismutase, and the calcim-overload antagonist flunarizine. The study was carried out in two steps: in the first, the histopathological development of retinal laser injuries was studied. Argon laser lesions were inflicted in the retinas of 18 pigmented rats. The animals were sacrificed after 3, 20 or 60 days and their retinal lesions were evaluated under the light microscope. The laser injury mainly involved the outer layers of the retina, where it destroyed significant numbers of photoreceptor cells. Over time, evidence of two major histopathological processes was observed: traction of adjacent nomral retinal cells into the central area of the lesion forming an internal retinal bulging, and a retinal pigmented epithelial proliferative reaction associated with subretinal neovascularization and invations of the retinal lesion site by phagocytes. The neuroprotective effects of each of the four compounds were verified in a second step of the study. For each drug tested, 12 rats were irradiated wtih argon laser inflictions: six of them received the tested agent while the other six were treated with the corresponding vehicle. Twenty days after laser expsoure, the rats were sacrificed and their lesions were

  6. Treatment of laser-induced retinal injuries by neuroprotection

    NASA Astrophysics Data System (ADS)

    Solberg, Yoram; Rosner, Mordechai; Belkin, Michael

    1997-05-01

    Retinal laser photocoagulation treatments are often complicated with immediate side-effect of visual impairment. To determine whether glutamate-receptor blockers can serve as adjuvant neuroprotective therapy, we examined the effect of MK-801, an NMDA-receptor antagonist, on laser-induced retinal injury in a rat model. Argon laser retinal lesions were created in the retina of 36 DA rats. Treatment with intraperitoneal injections of MK-801 or saline was started immediately after the laser photocoagulation. The animals were sacrificed after 3, 20 or 60 days and the retinal lesions were evaluated histologically and morphometrically. Photoreceptor-cell loss was significantly smaller in MK-801-treated rats than controls. The proliferative membrane composed of retinal pigment epithelial cells which was seen at the base of the lesion in control retinas, was smaller in the MK-801-treated retinas. MK-801 exhibited neuroprotective and anti-proliferative properties in the retina. Glutamate-receptor blockers should be further investigated for serving as adjuvant therapy to retinal photocoagulation treatments.

  7. Signals mediating Klotho-induced neuroprotection in hippocampal neuronal cells.

    PubMed

    Cheng, Meng-Fu; Chen, Li-Jen; Niu, Ho-Shan; Yang, Ting-Ting; Lin, Kao-Chang; Cheng, Juei-Tang

    2015-01-01

    The erythropoietin (Epo) receptor (EpoR) is expressed in the brain and was shown to have neuroprotective effects against brain damage in animal models. A recent study indicated that EpoR and its activity are the downstream effectors of Klotho for cytoprotection in the kidney. Thus, we propose that Klotho can stimulate the expression of EpoR in neuronal cells to enhance Epo-mediated protection. H19-7 hippocampal neuronal cells were treated with recombinant Klotho. In H19-7 cells, Klotho increased the expression of both the EpoR protein and mRNA. Klotho also enhanced the transcription activity of the EpoR promoter in H19-7 cells. Moreover, Klotho augmented the Epo-triggered phosphorylation of Jak2 and Stat5 and protected H19-7 cells from hydrogen peroxide cytotoxicity. The silencing of EpoR abolished the protective effect of Klotho against peroxide-induced cytotoxicity. Finally, the silencing of GATA1 diminished the Klotho-induced increase in EpoR protein and mRNA expression as well as its promoter activity. In conclusion, Klotho increased EpoR expression in neuronal cells through GATA1, thereby enabling EpoR to function as a cytoprotective protein against oxidative injury. PMID:25856523

  8. Acquired Localized Hypertrichosis Induced by Rivastigmine

    PubMed Central

    Imbernón-Moya, Adrian; Podlipnik, Sebastian; Burgos, Fernando; Vargas-Laguna, Elena; Aguilar-Martínez, Antonio; Fernández-Cogolludo, Eva; Gallego-Valdes, Miguel Angel

    2016-01-01

    Hypertrichosis is the excessive hair growth in any area of the skin surface. Acquired localized hypertrichosis may be secondary to multiple causes and there is a secondary form due to several drugs, which is usually reversible with discontinuation of the causative agent. Rivastigmine is a reversible and competitive inhibitor of acetylcholinesterase and butyrylcholinesterase used for symptomatic treatment of Alzheimer dementia and Parkinson's disease. It has an adequate safety profile and cutaneous side effects are unusual. Irritant contact dermatitis, allergic dermatitis, baboon syndrome, and cutaneous rash due to rivastigmine have been reported. We report on a Caucasian 80-year-old male with personal history of Alzheimer's disease. The patient started therapy with oral rivastigmine one month prior to clinical presentation of localized hypertrichosis on both forearms. Norgalanthamine has been shown to promote hair growth activity via the proliferation of dermal papilla. Acetylcholinesterase inhibitors can induce hair growth. PMID:27073702

  9. Neuroprotection of pramipexole in UPS impairment induced animal model of Parkinson's disease.

    PubMed

    Li, Chao; Guo, Yuan; Xie, Wenjie; Li, Xingang; Janokovic, Joseph; Le, Weidong

    2010-10-01

    Pramipexole (PPX), a dopamine (DA) receptor D3 preferring agonist, has been used as monotherapy or adjunct therapy to treat Parkinson's disease (PD) for many years. Several in vitro and in vivo studies in neurotoxin-induced DA neuron injury models have reported that PPX may possess neuroprotective properties. The present study is to evaluate the neuroprotection of PPX in a sustained DA neuron degeneration model of PD induced by ubiquitin-proteasome system (UPS) impairment. Adult C57BL/6 mice were treated with PPX (low dose 0.1 mg/kg or high dose 0.5 mg/kg, i.p, twice a day) started 7 days before, and continued after microinjection of proteasome inhibitor lactacystin in the medial forebrain bundle for a total 4 weeks. Animal behavior observation, and pathological and biochemical assays were conducted to determine the neuroprotective effects of PPX. We report here that PPX treatment significantly improves rotarod performance, attenuates DA neuron loss and striatal DA reduction, and alleviates proteasomal inhibition and microglial activation in the substantia nigra of lactacystin-lesioned mice. PPX can increase the levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor and induce an activation of autophagy. Furthermore, pretreatment with D3 receptor antagonist U99194 can significantly block the PPX-mediated neuroprotection. These results suggest that multiple molecular pathways may be attributed to the neuroprotective effects of PPX in the UPS impairment model of PD. PMID:20635141

  10. Neuroprotective effects of ginkgetin against neuroinjury in Parkinson's disease model induced by MPTP via chelating iron.

    PubMed

    Wang, Y-Q; Wang, M-Y; Fu, X-R; Peng-Yu; Gao, G-F; Fan, Y-M; Duan, X-L; Zhao, B-L; Chang, Y-Z; Shi, Z-H

    2015-01-01

    Disruption of neuronal iron homeostasis and oxidative stress are closely related to the pathogenesis of Parkinson's disease (PD). Ginkgetin, a natural biflavonoid isolated from leaves of Ginkgo biloba L, has many known effects, including anti-inflammatory, anti-influenza virus, and anti-fungal activities, but its underlying mechanism of the neuroprotective effects in PD remains unclear. The present study utilized PD models induced by 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to explore the neuroprotective ability of ginkgetin in vivo and in vitro. Our results showed that ginkgetin could provide significant protection from MPP(+)-induced cell damage in vitro by decreasing the levels of intracellular reactive oxygen species and maintaining mitochondrial membrane potential. Meanwhile, ginkgetin dramatically inhibited cell apoptosis induced by MPP+ through the caspase-3 and Bcl2/Bax pathway. Moreover, ginkgetin significantly improved sensorimotor coordination in a mouse PD model induced by MPTP by dramatically inhibiting the decrease of tyrosine hydroxylase expression in the substantia nigra and superoxide dismutase activity in the striatum. Interestingly, ginkgetin could strongly chelate ferrous ion and thereby inhibit the increase of the intracellular labile iron pool through downregulating L-ferritin and upregulating transferrin receptor 1. These results indicate that the neuroprotective mechanism of ginkgetin against neurological injury induced by MPTP occurs via regulating iron homeostasis. Therefore, ginkgetin may provide neuroprotective therapy for PD and iron metabolism disorder related diseases. PMID:25968939

  11. Neuroprotective effects of constituents of Eragrostis ferruginea against Aβ-induced toxicity in PC12 cells.

    PubMed

    Na, Chae Sun; Hong, Seong Su; Choi, Yun-Hyeok; Lee, Yong Ho; Hong, Sun Hee; Lim, Ji-Youn; Kang, Byeong Hoa; Park, So-Young; Lee, Dongho

    2010-07-01

    A new flavonoid, 7-demethylageconyflavone A (1), and five known compounds, tricin (2), ageconyflavone A (3), corylin (4), nectandrin B (5), and 4-ketopinoresinol (6) were isolated from the aerial parts of Eragrostis ferruginea. Their structures were determined using spectroscopic techniques, including 1D- and 2D-NMR. All compounds were tested for the neuroprotective effects against amyloid beta peptide (Abeta) using PC12 cells, a major cause of the pathology of Alzheimer's disease. Tricin (2) was found to have a neuroprotective effect with an ED(50) value of 20.3 microM against Abeta-induced toxicity in PC12 cells. Ageconyflavone A (3), nectandrin B (5) and 4-ketopinoresinol (6) demonstrated moderate neuroprotective effects with ED(50) values of 58.7, 44.1, and 54.8 microM, respectively. PMID:20661708

  12. The neuroprotective effect of hyperbaric oxygen treatment on laser-induced retinal damage in rats

    NASA Astrophysics Data System (ADS)

    Vishnevskia-Dai, Victoria; Belokopytov, Mark; Dubinsky, Galina; Nachum, Gal; Avni, Isaac; Belkin, Michael; Rosner, Mordechai

    2005-04-01

    Retinal damage induced by mechanical trauma, ischemia or laser photocoagulation increases considerably by secondary degeneration processes. The spread of damage may be ameliorated by neuroprotection that is aimed at reducing the extent of the secondary degeneration and promote healing processes. Hyperbaric oxygen (HBO) treatment consists of inspiration of oxygen at higher than one absolute atmospheric pressure. Improved neural function was observed in patients with acute brain trauma or ischemia treated with HBO. This study was designed to evaluate the neuroprotective effect of hyperbaric oxygen (HBO) on laser induced retinal damage in a rat model. Standard argon laser lesions were created in 25 pigmented rats divided into three groups: Ten rats were treated immediately after the irradiation with HBO three times during the first 24 hr followed by 12 consecutive daily treatments. Five rats received a shorter treatment regimen of 10 consecutive HBO treatments. The control group (10 rats) underwent the laser damage with no additional treatment. The retinal lesions were evaluated 20 days after the injury. All outcome measures were improved by the longer HBO treatment (P<0.01). The shorter HBO treatment was less effective, showing an increase only in nuclei density at the central area of lesion (P< 0.01). Hyperbaric oxygen seems to exert a neuroprotective effect on laser-induced retinal damage in a rat model. In the range of HBO exposures studied, longer exposure provides more neuroprotection. These results encourage further evaluation of the potential therapeutic use of hyperbaric oxygen in diseases and injuries of the retina.

  13. Neuroprotective effects of pramipexole against tunicamycin-induced cell death in PC12 cells.

    PubMed

    Nakayama, Hitoshi; Zhao, Jing; Ei-Fakhrany, Amany; Isosaki, Minoru; Satoh, Hiroyasu; Kyotani, Yoji; Yoshizumi, Masanori

    2009-12-01

    1. Pramipexole (PPX), a dopamine D2 and D3 receptor agonist, exerts neuroprotective effects via both dopamine receptor-mediated and non-dopaminergic mechanisms. In the present study, we demonstrate that PPX reduces the toxicity of tunicamycin, a typical endoplasmic reticulum (ER) stressor, in PC12h cells, a subline of PC12 cells. 2. The PC12h cells were treated with 300 micromol / L PPX in the presence of 0.5 micromol / L tunicamycin for 24 h. The neuroprotective effects of PPX against tunicamycin-induced cell death were evaluated using 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays, Hoechst 33258 staining and western blot analysis. 3. Tunicamycin (0.2, 0.3 and 0.5 microg / mL) dose-dependently decreased MTT activity and increased LDH release from PC12h cells. Treatment with 300 micromol / L PPX rescued the tunicamycin-induced decrease in cell viability. 4. Spiperone (10 micromol / L), a dopamine D2 and D4 receptor antagonist, had no effect on PPX neuroprotection against tunicamycin in these cells. Marker proteins of ER stress and apoptosis are known to be upregulated by tunicamycin, but we detected no significant effects of PPX on these factors. 5. In conclusion, we speculate that a combination of several mechanisms may be involved in PPX-induced neuroprotection. PMID:19515063

  14. BCG Vaccine-Induced Neuroprotection in a Mouse Model of Parkinson's Disease

    PubMed Central

    Yong, Jing; Lacan, Goran; Dang, Hoa; Hsieh, Terry; Middleton, Blake; Wasserfall, Clive; Tian, Jide; Melega, William P.; Kaufman, Daniel L.

    2011-01-01

    There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxone® in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guérin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions. PMID:21304945

  15. BCG vaccine-induced neuroprotection in a mouse model of Parkinson's disease.

    PubMed

    Yong, Jing; Lacan, Goran; Dang, Hoa; Hsieh, Terry; Middleton, Blake; Wasserfall, Clive; Tian, Jide; Melega, William P; Kaufman, Daniel L

    2011-01-01

    There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxone® in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guérin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions. PMID:21304945

  16. Neuroprotective effect of Allium cepa L. in aluminium chloride induced neurotoxicity.

    PubMed

    Singh, Tanveer; Goel, Rajesh Kumar

    2015-07-01

    The present study was envisaged to investigate the neuroprotective potential of Allium cepa (A. cepa) in aluminium chloride induced neurotoxicity. Aluminium chloride (50 mg/kg/day) was administered orally in mice supplemented with different doses of A. cepa hydroethanolic extract for a period of 60 days. Various behavioural, biochemical and histopathological parameters were estimated in aluminium exposed animals. Chronic aluminium administration resulted in significant motor incoordination and memory deficits, which were also endorsed biochemically as there was increased oxidative stress as well as elevated acetylcholinesterase (AChE) and aluminium levels in the brain. Supplementation with A. cepa in aluminium exposed animals significantly improved muscle coordination and memory deficits as well as reduced oxidative stress, AChE and decreased abnormal aluminium deposition in the brain. Histopathologically, there was marked deterioration visualized as decreased vacuolated cytoplasm as well as decreased pyramidal cells in the hippocampal area of mice brain which were found to be reversed with A. cepa supplementation. Administration of BADGE (PPARγ antagonist) in aluminium exposed animals reversed the neuroprotective potential of A. cepa as assessed with various behavioural, biochemical, neurochemical and histopathological estimations. In conclusion, finding of this study suggested significant neuroprotective potential of A. cepa in aluminium induced neurotoxicity. Further, the role of PPARγ receptor agonism has also been suggested as a putative neuroprotective mechanism of A. cepa, which needs further studies for confirmation. PMID:25940660

  17. Exogenous agmatine has neuroprotective effects against restraint-induced structural changes in the rat brain

    PubMed Central

    Zhu, Meng-Yang; Wang, Wei-Ping; Cai, Zheng-Wei; Regunathan, Soundar; Ordway, Gregory

    2009-01-01

    Agmatine is an endogenous amine derived from decarboxylation of arginine catalysed by arginine decarboxylase. Agmatine is considered a novel neuromodulator and possesses neuroprotective properties in the central nervous system. The present study examined whether agmatine has neuroprotective effects against repeated restraint stress-induced morphological changes in rat medial prefrontal cortex and hippocampus. Sprague-Dawley rats were subjected to 6 h of restraint stress daily for 21 days. Immunohistochemical staining with β-tubulin III showed that repeated restraint stress caused marked morphological alterations in the medial prefrontal cortex and hippocampus. Stress-induced alterations were prevented by simultaneous treatment with agmatine (50 mg/kg/day, i.p.). Interestingly, endogenous agmatine levels, as measured by high-performance liquid chromatography, in the prefrontal cortex and hippocampus as well as in the striatum and hypothalamus of repeated restraint rats were significantly reduced as compared with the controls. Reduced endogenous agmatine levels in repeated restraint animals were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. Moreover, administration of exogenous agmatine to restrained rats abolished increases of arginine decarboxylase protein levels. Taken together, these results demonstrate that exogenously administered agmatine has neuroprotective effects against repeated restraint-induced structural changes in the medial prefrontal cortex and hippocampus. These findings indicate that stress-induced reductions in endogenous agmatine levels in the rat brain may play a permissive role in neuronal pathology induced by repeated restraint stress. PMID:18364017

  18. Retinal ganglion cell neuroprotection induced by activation of alpha7 nicotinic acetylcholine receptors.

    PubMed

    Mata, David; Linn, David M; Linn, Cindy L

    2015-12-01

    The α7nAChR agonist, PNU-282987, has previously been shown to have a neuroprotective effect against loss of retinal ganglion cells (RGCs) in an in vivo glaucoma model when the agent was injected into the vitreous chamber of adult Long Evans rat eyes. Here, we characterized the neuroprotective effect of PNU-282987 at the nerve fiber and retinal ganglion cell layer, determined that neuroprotection occurred when the agonist was applied as eye drops and verified detection of the agonist in the retina, using LC/MS/MS. To induce glaucoma-like conditions in adult Long Evans rats, hypertonic saline was injected into the episcleral veins to induce scar tissue and increase intraocular pressure. Within one month, this procedure produced significant loss of RGCs compared to untreated conditions. RGCs were quantified after immunostaining with an antibody against Thy 1.1 and imaged using a confocal microscope. In dose-response studies, concentrations of PNU-282987 were applied to the animal's right eye two times each day, while the left eye acted as an internal control. Eye drops of PNU-282987 resulted in neuroprotection against RGC loss in a dose-dependent manner using concentrations between 100 μM and 2 mM PNU-282987. LC/MS/MS results demonstrated that PNU-282987 was detected in the retina when applied as eye drops, relatively small amounts of PNU-282987 were measured in blood plasma and no PNU-282987 was detected in cardiac tissue. These results support the hypothesis that eye drop application of PNU-282987 can prevent loss of RGCs associated with glaucoma, which can lead to neuroprotective treatments for diseases that involve α7nAChRs. PMID:26239818

  19. Neuroprotective effect of curcumin-loaded lactoferrin nano particles against rotenone induced neurotoxicity.

    PubMed

    Bollimpelli, V Satish; Kumar, Prashant; Kumari, Sonali; Kondapi, Anand K

    2016-05-01

    Curcumin is known to have neuroprotective role and possess antioxidant, anti-inflammatory activities. Rotenone, a flavonoid induced neurotoxicity in dopaminergic cells is being widely studied in Parkinson's Disease (PD) research. In the present study, curcumin loaded lactoferrin nano particles prepared by sol-oil chemistry were used to protect dopaminergic cell line SK-N-SH against rotenone induced neurotoxicity. These curcumin loaded nano particles were of 43-60 nm diameter size and around 100 nm hydrodynamic size as assessed by transmission electron microscopy, atomic force microscopy and dynamic light scattering analysis respectively. The encapsulation efficiency was 61.3% ± 2.4%. Cellular uptake of curcumin through these nano particles was confirmed by confocal imaging and spectrofluorimetric analysis. The curcumin loaded lactoferrin nanoparticles showed greater intracellular drug uptake, sustained retention and greater neuroprotection than soluble counterpart. Neuroprotective activity was characterized through viability assays and by estimating ROS levels. Furthermore rotenone induced PD like features were characterized by decrease in tyrosine hydroxylase expression and increase in α-synuclein expression. Taken together curcumin loaded lactoferrin nanoparticles could be a promising drug delivery strategy against neurotoxicity in dopaminergic neurons. PMID:26826319

  20. Meclizine-induced enhanced glycolysis is neuroprotective in Parkinson disease cell models

    PubMed Central

    Hong, Chien Tai; Chau, Kai-Yin; Schapira, Anthony H. V.

    2016-01-01

    Meclizine is a well-tolerated drug routinely used as an anti-histamine agent in the management of disequilibrium. Recently, meclizine has been assessed for its neuroprotective properties in ischemic stroke and Huntington disease models. We found that meclizine protected against 6-hydroxydopamine-induced apoptosis and cell death in both SH-SY5Y cells and rat primary cortical cultures. Meclizine increases the level of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which activates phosphofructokinase, a rate-determining enzyme of glycolysis. This protection is therefore mediated by meclizine’s ability to enhance glycolysis and increase mitochondrial hyperpolarization. Meclizine represents an interesting candidate for further investigation to re-purpose for its potential to be neuroprotective in Parkinson disease. PMID:27145922

  1. Meclizine-induced enhanced glycolysis is neuroprotective in Parkinson disease cell models.

    PubMed

    Hong, Chien Tai; Chau, Kai-Yin; Schapira, Anthony H V

    2016-01-01

    Meclizine is a well-tolerated drug routinely used as an anti-histamine agent in the management of disequilibrium. Recently, meclizine has been assessed for its neuroprotective properties in ischemic stroke and Huntington disease models. We found that meclizine protected against 6-hydroxydopamine-induced apoptosis and cell death in both SH-SY5Y cells and rat primary cortical cultures. Meclizine increases the level of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which activates phosphofructokinase, a rate-determining enzyme of glycolysis. This protection is therefore mediated by meclizine's ability to enhance glycolysis and increase mitochondrial hyperpolarization. Meclizine represents an interesting candidate for further investigation to re-purpose for its potential to be neuroprotective in Parkinson disease. PMID:27145922

  2. Neuroprotective effects of bis(7)-tacrine against glutamate-induced retinal ganglion cells damage

    PubMed Central

    2010-01-01

    Background Glutamate-mediated excitotoxicity, primarily through N-methyl-D-aspartate (NMDA) receptors, may be an important cause of retinal ganglion cells (RGCs) death in glaucoma and several other retinal diseases. Bis(7)-tacrine is a noncompetitive NMDA receptors antagonist that can prevent glutamate-induced hippocampal neurons damage. We tested the effects of bis(7)-tacrine against glutamate-induced rat RGCs damage in vitro and in vivo. Results In cultured neonatal rats RGCs, the MTT assay showed that glutamate induced a concentration- and time-dependent toxicity. Bis(7)-tacrine and memantine prevented glutamate-induced cell death in a concentration-dependent manner with IC50 values of 0.028 μM and 0.834 μM, respectively. The anti-apoptosis effects of bis(7)-tacrine were confirmed by annexin V-FITC/PI staining. In vivo, TUNEL analysis and retrograde labeling analysis found that pretreatment with bis(7)-tacrine(0.2 mg/kg) induced a significant neuroprotective effect against glutamate-induced RGCs damage. Conclusions Our results showed that bis(7)-tacrine had neuroprotective effects against glutamate-induced RGCs damage in vitro and in vivo, possibly through the drug's anti-NMDA receptor effects. These findings make bis(7)-tacrine potentially useful for treating a variety of ischemic or traumatic retinopathies inclusive of glaucoma. PMID:20199668

  3. Neuroprotective effect of Tinospora cordifolia ethanol extract on 6-hydroxy dopamine induced Parkinsonism

    PubMed Central

    Kosaraju, Jayasankar; Chinni, Santhivardhan; Roy, Partha Deb; Kannan, Elango; Antony, A. Shanish; Kumar, M. N. Satish

    2014-01-01

    Objective: The present study investigates the neuroprotective activity of ethanol extract of Tinospora cordifolia aerial parts against 6-hydroxy dopamine (6-OHDA) lesion rat model of Parkinson's disease (PD). Materials and Methods: T. cordifolia ethanol extract (TCEE) was standardized with high performance thin layer chromatography using berberine. Experimental PD was induced by intracerebral injection of 6-OHDA (8 μg). Animals were divided into five groups: sham operated, negative control, positive control (levodopa 6 mg/kg) and two experimental groups (n = 6/group). Experimental groups received 200 and 400 mg/kg of TCEE once daily for 30 days by oral gavage. Biochemical parameters including dopamine level, oxidative stress, complex I activity and brain iron asymmetry ratio and locomotor activity including skeletal muscle co-ordination and degree of catatonia were assessed. Results: TCEE exhibited significant neuroprotection by increasing the dopamine levels (1.96 ± 0.20 and 2.45 ± 0.40 ng/mg of protein) and complex I activity (77.14 ± 0.89 and 78.50 ± 0.96 nmol/min/mg of protein) at 200 and 400 mg/kg respectively when compared with negative control group. Iron asymmetry ratio was also significantly attenuated by TCEE at 200 (1.57 ± 0.18) and 400 mg/kg (1.11 ± 0.15) when compared with negative control group. Neuroprotection by TCEE was further supported by reduced oxidative stress and restored locomotor activity in treatment groups. Conclusion: Results show that TCEE possess significant neuroprotection in 6-OHDA induced PD by protecting dopaminergic neurons and reducing the iron accumulation. PMID:24741189

  4. Neuroprotective effects of (-)-linalool against oxygen-glucose deprivation-induced neuronal injury.

    PubMed

    Park, Hyeon; Seol, Geun Hee; Ryu, Sangwoo; Choi, In-Young

    2016-04-01

    (-)-Linalool, a major component of many essential oils, is widely used in cosmetics and flavoring ingredients as well as in traditional medicines. Although various in vitro and in vivo studies have shown that (-)-linalool has anti-convulsant, anti-nociceptive, anti-inflammatory and anti-oxidative properties, its anti-ischemic/hypoxic effects have yet to be determined. This study assessed the neuroprotective effects of (-)-linalool against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cortical neuronal injury, an in vitro model of ischemic stroke. (-)-Linalool significantly attenuated OGD/R-evoked cortical neuronal injury/death, although it did not inhibit N-methyl-D-aspartate (NMDA)-induced excitotoxicity. (-)-Linalool significantly reduced intracellular oxidative stress during OGD/R-induced injury, as well as scavenging peroxyl radicals (Trolox equivalents or TE = 3.8). This anti-oxidant effect was found to correlate with the restoration of OGD/R-induced decreases in the activities of SOD and catalase. In addition, (-)-linalool inhibited microglial migration induced by monocyte-chemoattractant protein-1 (MCP-1), a chemokine released by OGD/R. These findings show that (-)-linalool has neuroprotective effects against OGD/R-induced neuronal injury, which may be due to its anti-oxidant and anti-inflammatory activities. Detailed examination of the anti-ischemic mechanisms of (-)-linalool may indicate strategies for the development of drugs to treat cerebral ischemic injury. PMID:26832326

  5. Neuroprotection by GH against excitotoxic-induced cell death in retinal ganglion cells.

    PubMed

    Martínez-Moreno, Carlos G; Ávila-Mendoza, José; Wu, Yilun; Arellanes-Licea, Elvira Del Carmen; Louie, Marcela; Luna, Maricela; Arámburo, Carlos; Harvey, Steve

    2016-08-01

    Retinal growth hormone (GH) has been shown to promote cell survival in retinal ganglion cells (RGCs) during developmental waves of apoptosis during chicken embryonic development. The possibility that it might also against excitotoxicity-induced cell death was therefore examined in the present study, which utilized quail-derived QNR/D cells as an in vitro RGC model. QNR/D cell death was induced by glutamate in the presence of BSO (buthionine sulfoxamide) (an enhancer of oxidative stress), but this was significantly reduced (P<0.01) in the presence of exogenous recombinant chicken GH (rcGH). Similarly, QNR/D cells that had been prior transfected with a GH plasmid to overexpress secreted and non-secreted GH. This treatment reduced the number of TUNEL-labeled cells and blocked their release of lactate dehydrogenase (LDH). In a further experiment with dissected neuroretinal explants from ED (embryonic day) 10 embryos, rcGH treatment of the explants also reduced (P<0.01) the number of glutamate-BSO-induced apoptotic cells and blocked the explant release of LDH. This neuroprotective action was likely mediated by increased STAT5 phosphorylation and increased bcl-2 production, as induced by exogenous rcGH treatment and the media from GH-overexpressing QNR/D cells. As rcGH treatment and GH-overexpression cells also increased the content of IGF-1 and IGF-1 mRNA this neuroprotective action of GH is likely to be mediated, at least partially, through an IGF-1 mechanism. This possibility is supported by the fact that the siRNA knockdown of GH or IGF-1 significantly reduced QNR/D cell viability, as did the immunoneutralization of IGF-1. GH is therefore neuroprotective against excitotoxicity-induced RGC cell death by anti-apoptotic actions involving IGF-1 stimulation. PMID:27129619

  6. Paracrine Neuroprotective Effects of Neural Stem Cells on Glutamate-Induced Cortical Neuronal Cell Excitotoxicity

    PubMed Central

    Geranmayeh, Mohammad Hossein; Baghbanzadeh, Ali; Barin, Abbas; Salar-Amoli, Jamileh; Dehghan, Mohammad Mehdi; Rahbarghazi, Reza; Azari, Hassan

    2015-01-01

    Purpose: Glutamate is a major excitatory neurotransmitter in mammalian central nervous system. Excessive glutamate releasing overactivates its receptors and changes calcium homeostasis that in turn leads to a cascade of intracellular events causing neuronal degeneration. In current study, we used neural stem cells conditioned medium (NSCs-CM) to investigate its neuroprotective effects on glutamate-treated primary cortical neurons. Methods: Embryonic rat primary cortical cultures were exposed to different concentrations of glutamate for 1 hour and then they incubated with NSCs-CM. Subsequently, the amount of cell survival in different glutamate excitotoxic groups were measured after 24 h of incubation by trypan blue exclusion assay and MTT assay. Hoechst and propidium iodide were used for determining apoptotic and necrotic cell death pathways proportion and then the effect of NSCs-CM was investigated on this proportion. Results: NSCs conditioned medium increased viability rate of the primary cortical neurons after glutamate-induced excitotoxicity. Also we found that NSCs-CM provides its neuroprotective effects mainly by decreasing apoptotic cell death rate rather than necrotic cell death rate. Conclusion: The current study shows that adult neural stem cells could exert paracrine neuroprotective effects on cortical neurons following a glutamate neurotoxic insult. PMID:26819924

  7. Neuroprotective effects of ginsenoside Rg3 against homocysteine-induced excitotoxicity in rat hippocampus.

    PubMed

    Kim, Jong-Hoon; Cho, Soo Yeun; Lee, Jun-Ho; Jeong, Sang Min; Yoon, In-Soo; Lee, Byung-Hwan; Lee, Joon-Hee; Pyo, Mi Kyung; Lee, Sang-Mok; Chung, Jun-Mo; Kim, Sunoh; Rhim, Hyewhon; Oh, Jae-Wook; Nah, Seung-Yeol

    2007-03-01

    We previously demonstrated that ginsenoside Rg(3) (Rg(3)), one of the active ingredients in Panax ginseng, attenuates NMDA receptor-mediated currents and NMDA-induced neurotoxicity (Kim, S., Kim, T., Ahn, K., Park, W.K., Nah, S.Y., Rhim, H., 2004. Ginsenoside Rg(3) antagonizes NMDA receptors through a glycine modulatory site in rat cultured hippocampal neurons. Biochem. Biophys. Res. Commun. 323, 416-424). Accumulating evidence suggests that homocysteine (HC), a metabolite of methionine, exerts its excitotoxicity through NMDA receptor activation. In the present study, we examined the neuroprotective effects of Rg(3) on HC-induced hippocampal excitotoxicity in vitro and in vivo. Our in vitro studies using rat cultured hippocampal neurons revealed that Rg(3) treatment significantly and dose-dependently inhibited HC-induced hippocampal cell death, with an EC(50) value of 28.7+/-7.5 muM. Rg(3) treatment not only significantly reduced HC-induced DNA damage, but also dose-dependently attenuated HC-induced caspase-3 activity in vitro. Our in vivo studies revealed that intracerebroventricular (i.c.v.) pre-administration of Rg(3) significantly and dose-dependently reduced i.c.v. HC-induced hippocampal damage in rats. To examine the mechanisms underlying the in vitro and in vivo neuroprotective effects of Rg(3) against HC-induced hippocampal excitotoxicity, we examined the effect of Rg(3) on HC-induced intracellular Ca(2+) elevations in cultured hippocampal cells and found that Rg(3) treatment dose-dependently inhibited HC-induced intracellular Ca(2+) elevation, with an IC(50) value of 41.5+/-17.5 muM. In addition, Rg(3) treatment dose-dependently inhibited HC-induced currents in Xenopus oocytes expressing the NMDA receptor, with an IC(50) of 47.3+/-14.2 muM. These results collectively indicate that Rg(3)-induced neuroprotection against HC in rat hippocampus might be achieved via inhibition of HC-mediated NMDA receptor activation. PMID:17239831

  8. Neuroprotective Effect of Lutein on NMDA-Induced Retinal Ganglion Cell Injury in Rat Retina.

    PubMed

    Zhang, Chanjuan; Wang, Zhen; Zhao, Jiayi; Li, Qin; Huang, Cuiqin; Zhu, Lihong; Lu, Daxiang

    2016-05-01

    Lutein injection is a possible therapeutic approach for retinal diseases, but the molecular mechanism of its neuroprotective effect remains to be elucidated. The aim of this study was to investigate its protective effects in retinal ganglion cells (RGCs) against N-methyl-D-aspartate (NMDA)-induced retinal damage in vivo. Retinal damage was induced by intravitreal NMDA injection in rats. Each animal was given five daily intraperitoneal injections of Lutein or vehicle along with intravitreal NMDA injections. Electroretinograms were recorded. The number of viable RGCs was quantified using the retinal whole-mount method by immunofluorescence. Proteins were measured by Western blot assays. Lutein reduced the retinal damage and improved the response to light, as shown by an animal behavior assay (the black-and-white box method) in rats. Furthermore, Lutein treatment prevented the NMDA-induced reduction in phNR wave amplitude. Lutein increased RGC number after NMDA-induced retina damage. Most importantly, Bax, cytochrome c, p-p38 MAPK, and p-c-Jun were all upregulated in rats injected with NMDA, but these expression patterns were reversed by continuous Lutein uptake. Bcl-2, p-GSK-3β, and p-Akt in the Lutein-treated eyes were increased compared with the NMDA group. Lutein has neuroprotective effects against retinal damage, its protective effects may be partly mediated by its anti-excitability neurotoxicity, through MAPKs and PI3K/Akt signaling, suggesting a potential approach for suppressing retinal neural damage. PMID:26119305

  9. Bleomycin Containing Chemotherapeutic Regimen Induced Acquired Partial Lipodystrophy

    PubMed Central

    Tandon, Vishal R; Gupte, Novy; Mahajan, Vivek; Sharma, Rahul; Langer, Cheena; Khajuria, Vijay; Mahajan, Annil

    2016-01-01

    Bleomycin toxicity predominantly affects the skin and lungs. Cutaneous toxicity classically known to present with bleomycin are flagellate erythema and drug rash. We hereby report an isolated case of (bleomyicn)-induced acquired partial (lipodytrophy) having potential cosmetic implications in a young women prescribed postoperatively following a case of germ cell carcinoma of ovary (endodermal sinus tumor). PMID:26955139

  10. p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing

    PubMed Central

    Posada-Duque, Rafael Andres; López-Tobón, Alejandro; Piedrahita, Diego; González-Billault, Christian; Cardona-Gomez, Gloria Patricia

    2015-01-01

    CDK5 plays an important role in neurotransmission and synaptic plasticity in the normal function of the adult brain, and dysregulation can lead to Tau hyperphosphorylation and cognitive impairment. In a previous study, we demonstrated that RNAi knock down of CDK5 reduced the formation of neurofibrillary tangles and prevented neuronal loss in triple transgenic Alzheimer’s mice. Here, we report that CDK5 RNAi protected against glutamate-mediated excitotoxicity using primary hippocampal neurons transduced with AAV2.5 viral vector eGFP-tagged SCR or CDK5 shRNA-miR during 12 days. Protection was dependent on a concomitant increase in p35 and was reversed using p35 RNAi, which affected the down-stream Rho GTPase activity. Furthermore, p35 overexpression and constitutively active Rac1 mimicked CDK5 silencing-induced neuroprotection. In addition, 3xTg-AD mice (24 months old) were injected in the hippocampus with SCR or CDK5 shRNA-miR, and spatial learning and memory were performed three weeks post injection using “Morris” water maze test. Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer’s mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi. PMID:25864429

  11. p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing.

    PubMed

    Posada-Duque, Rafael Andres; López-Tobón, Alejandro; Piedrahita, Diego; González-Billault, Christian; Cardona-Gomez, Gloria Patricia

    2015-07-01

    CDK5 plays an important role in neurotransmission and synaptic plasticity in the normal function of the adult brain, and dysregulation can lead to Tau hyperphosphorylation and cognitive impairment. In a previous study, we demonstrated that RNAi knock down of CDK5 reduced the formation of neurofibrillary tangles (NFT) and prevented neuronal loss in triple transgenic Alzheimer's mice. Here, we report that CDK5 RNAi protected against glutamate-mediated excitotoxicity using primary hippocampal neurons transduced with adeno-associated virus 2.5 viral vector eGFP-tagged scrambled or CDK5 shRNA-miR during 12 days. Protection was dependent on a concomitant increase in p35 and was reversed using p35 RNAi, which affected the down-stream Rho GTPase activity. Furthermore, p35 over-expression and constitutively active Rac1 mimicked CDK5 silencing-induced neuroprotection. In addition, 3xTg-Alzheimer's disease mice (24 months old) were injected in the hippocampus with scrambled or CDK5 shRNA-miR, and spatial learning and memory were performed 3 weeks post-injection using 'Morris' water maze test. Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi. PMID:25864429

  12. Gender difference in the neuroprotective effect of rat bone marrow mesenchymal cells against hypoxia-induced apoptosis of retinal ganglion cells

    PubMed Central

    Yuan, Jing; Yu, Jian-xiong

    2016-01-01

    Bone marrow mesenchymal stem cells can reduce retinal ganglion cell death and effectively prevent vision loss. Previously, we found that during differentiation, female rhesus monkey bone marrow mesenchymal stem cells acquire a higher neurogenic potential compared with male rhesus monkey bone marrow mesenchymal stem cells. This suggests that female bone marrow mesenchymal stem cells have a stronger neuroprotective effect than male bone marrow mesenchymal stem cells. Here, we first isolated and cultured bone marrow mesenchymal stem cells from female and male rats by density gradient centrifugation. Retinal tissue from newborn rats was prepared by enzymatic digestion to obtain primary retinal ganglion cells. Using the transwell system, retinal ganglion cells were co-cultured with bone marrow mesenchymal stem cells under hypoxia. Cell apoptosis was detected by flow cytometry and caspase-3 activity assay. We found a marked increase in apoptotic rate and caspase-3 activity of retinal ganglion cells after 24 hours of hypoxia compared with normoxia. Moreover, apoptotic rate and caspase-3 activity of retinal ganglion cells significantly decreased with both female and male bone marrow mesenchymal stem cell co-culture under hypoxia compared with culture alone, with more significant effects from female bone marrow mesenchymal stem cells. Our results indicate that bone marrow mesenchymal stem cells exert a neuroprotective effect against hypoxia-induced apoptosis of retinal ganglion cells, and also that female cells have greater neuroprotective ability compared with male cells. PMID:27335573

  13. Gender difference in the neuroprotective effect of rat bone marrow mesenchymal cells against hypoxia-induced apoptosis of retinal ganglion cells.

    PubMed

    Yuan, Jing; Yu, Jian-Xiong

    2016-05-01

    Bone marrow mesenchymal stem cells can reduce retinal ganglion cell death and effectively prevent vision loss. Previously, we found that during differentiation, female rhesus monkey bone marrow mesenchymal stem cells acquire a higher neurogenic potential compared with male rhesus monkey bone marrow mesenchymal stem cells. This suggests that female bone marrow mesenchymal stem cells have a stronger neuroprotective effect than male bone marrow mesenchymal stem cells. Here, we first isolated and cultured bone marrow mesenchymal stem cells from female and male rats by density gradient centrifugation. Retinal tissue from newborn rats was prepared by enzymatic digestion to obtain primary retinal ganglion cells. Using the transwell system, retinal ganglion cells were co-cultured with bone marrow mesenchymal stem cells under hypoxia. Cell apoptosis was detected by flow cytometry and caspase-3 activity assay. We found a marked increase in apoptotic rate and caspase-3 activity of retinal ganglion cells after 24 hours of hypoxia compared with normoxia. Moreover, apoptotic rate and caspase-3 activity of retinal ganglion cells significantly decreased with both female and male bone marrow mesenchymal stem cell co-culture under hypoxia compared with culture alone, with more significant effects from female bone marrow mesenchymal stem cells. Our results indicate that bone marrow mesenchymal stem cells exert a neuroprotective effect against hypoxia-induced apoptosis of retinal ganglion cells, and also that female cells have greater neuroprotective ability compared with male cells. PMID:27335573

  14. TLR9 bone marrow chimeric mice define a role for cerebral TNF in neuroprotection induced by CpG preconditioning.

    PubMed

    Packard, Amy E B; Leung, Philberta Y; Vartanian, Keri B; Stevens, Susan L; Bahjat, Frances R; Stenzel-Poore, Mary P

    2012-12-01

    Systemic preconditioning with the TLR9 ligand CpG induces neuroprotection against brain ischemic injury through a tumor necrosis factor (TNF)-dependent mechanism. It is unclear how systemic administration of CpG engages the brain to induce the protective phenotype. To address this, we created TLR9-deficient reciprocal bone marrow chimeric mice lacking TLR9 on either hematopoietic cells or radiation-resistant cells of nonhematopoietic origin. We report that wild-type mice reconstituted with TLR9-deficient hematopoietic cells failed to show neuroprotection after systemic CpG preconditioning. Further, while hematopoietic expression of TLR9 is required for CpG-induced neuroprotection it is not sufficient to restore protection to TLR9-deficient mice that are reconstituted with hematopoietic cells bearing TLR9. To determine whether the absence of protection was associated with TNF, we examined TNF levels in the systemic circulation and the brain. We found that although TNF is required for CpG preconditioning, systemic TNF levels did not correlate with the protective phenotype. However, induction of cerebral TNF mRNA required expression of TLR9 on both hematopoietic and nonhematopoietic cells and correlated with neuroprotection. In accordance with these results, we show the therapeutic potential of intranasal CpG preconditioning, which induces brain TNF mRNA and robust neuroprotection with no concomitant increase in systemic levels of TNF. PMID:23010947

  15. Acquired inducible antimicrobial resistance in Gram-positive bacteria

    PubMed Central

    Chancey, Scott T; Zähner, Dorothea; Stephens, David S

    2012-01-01

    A major contributor to the emergence of antibiotic resistance in Gram-positive bacterial pathogens is the expansion of acquired, inducible genetic elements. Although acquired, inducible antibiotic resistance is not new, the interest in its molecular basis has been accelerated by the widening distribution and often ‘silent’ spread of the elements responsible, the diagnostic challenges of such resistance and the mounting limitations of available agents to treat Gram-positive infections. Acquired, inducible antibiotic resistance elements belong to the accessory genome of a species and are horizontally acquired by transformation/recombination or through the transfer of mobile DNA elements. The two key, but mechanistically very different, induction mechanisms are: ribosome-sensed induction, characteristic of the macrolide–lincosamide–streptogramin B antibiotics and tetracycline resistance, leading to ribosomal modifications or efflux pump activation; and resistance by cell surface-associated sensing of β-lactams (e.g., oxacillin), glycopeptides (e.g., vancomycin) and the polypeptide bacitracin, leading to drug inactivation or resistance due to cell wall alterations. PMID:22913355

  16. Autoregulation of Inducible Nitric Oxide Synthase Expression by RNA Interference Provides Neuroprotection in Neonatal Rats

    PubMed Central

    Wang, Zhi; Feng, Chenzhuo; Zhao, Huijuan; Ren, Xiaoyan; Peng, Shuling; Zuo, Zhiyi

    2015-01-01

    We have shown that autoregulation of gene expression by RNA interference is achievable in cell cultures. To determine whether this novel concept could be used to produce neuroprotection under in vivo condition, postnatal day (PND) 3 rats received intracerebroventricular injection of lentivirus that carried or did not carry code for short hairpin RNA (shRNA) of inducible nitric oxide synthase (iNOS). The expression of this shRNA was controlled by an iNOS promoter (piNOS-shRNA) or cytomegalovirus promoter (pCMV-shRNA). The rats were subjected to brain hypoxia-ischemia at PND7. Ischemic brain tissues had increased iNOS expression. This increase was attenuated by virus carrying piNOS-shRNA. Virus carrying pCMV-shRNA reduced iNOS to a level that was lower than control. Brain tissue loss and functional impairment after the hypoxia-ischemia were attenuated by the virus carrying piNOS-shRNA but not by pCMV-shRNA. Our results provide proof-of-concept evidence that autoregulation of iNOS expression by RNA interference induces neuroprotection in vivo and that appropriate regulation of gene expression is important. PMID:25767617

  17. Epsilon Aminocaproic Acid Pretreatment Provides Neuroprotection Following Surgically Induced Brain Injury in a Rat Model.

    PubMed

    Komanapalli, Esther S; Sherchan, Prativa; Rolland, William; Khatibi, Nikan; Martin, Robert D; Applegate, Richard L; Tang, Jiping; Zhang, John H

    2016-01-01

    Neurosurgical procedures can damage viable brain tissue unintentionally by a wide range of mechanisms. This surgically induced brain injury (SBI) can be a result of direct incision, electrocauterization, or tissue retraction. Plasmin, a serine protease that dissolves fibrin blood clots, has been shown to enhance cerebral edema and hemorrhage accumulation in the brain through disruption of the blood brain barrier. Epsilon aminocaproic acid (EAA), a recognized antifibrinolytic lysine analogue, can reduce the levels of active plasmin and, in doing so, potentially can preserve the neurovascular unit of the brain. We investigated the role of EAA as a pretreatment neuroprotective modality in a SBI rat model, hypothesizing that EAA therapy would protect brain tissue integrity, translating into preserved neurobehavioral function. Male Sprague-Dawley rats were randomly assigned to one of four groups: sham (n = 7), SBI (n = 7), SBI with low-dose EAA, 150 mg/kg (n = 7), and SBI with high-dose EAA, 450 mg/kg (n = 7). SBI was induced by partial right frontal lobe resection through a frontal craniotomy. Postoperative assessment at 24 h included neurobehavioral testing and measurement of brain water content. Results at 24 h showed both low- and high-dose EAA reduced brain water content and improved neurobehavioral function compared with the SBI groups. This suggests that EAA may be a useful pretherapeutic modality for SBI. Further studies are needed to clarify optimal therapeutic dosing and to identify mechanisms of neuroprotection in rat SBI models. PMID:26463967

  18. Pharmacological blockade of the calcium plateau provides neuroprotection following organophosphate paraoxon induced status epilepticus in rats.

    PubMed

    Deshpande, Laxmikant S; Blair, Robert E; Huang, Beverly A; Phillips, Kristin F; DeLorenzo, Robert J

    2016-01-01

    Organophosphate (OP) compounds which include nerve agents and pesticides are considered chemical threat agents. Currently approved antidotes are crucial in limiting OP mediated acute mortality. However, survivors of lethal OP exposure exhibit delayed neuronal injury and chronic behavioral morbidities. In this study, we investigated neuroprotective capabilities of dantrolene and carisbamate in a rat survival model of paraoxon (POX) induced status epilepticus (SE). Significant elevations in hippocampal calcium levels were observed 48-h post POX SE survival, and treatment with dantrolene (10mg/kg, i.m.) and carisbamate (90mg/kg, i.m.) lowered these protracted calcium elevations. POX SE induced delayed neuronal injury as characterized by Fluoro Jade C labeling was observed in critical brain areas including the dentate gyrus, parietal cortex, amygdala, and thalamus. Dantrolene and carisbamate treatment provided significant neuroprotection against delayed neuronal damage in these brain regions when administered one-hour after POX-SE. These results indicate that dantrolene or carisbamate could be effective adjuvant therapies to the existing countermeasures to reduce neuronal injury and behavioral morbidities post OP SE survival. PMID:27224207

  19. The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination

    PubMed Central

    Slowik, A; Schmidt, T; Beyer, C; Amor, S; Clarner, T; Kipp, M

    2015-01-01

    BACKGROUND AND PURPOSE Modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection. EXPERIMENTAL APPROACH In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin-induced experimental demyelination. We used histological, immunohistochemical and gene expression methods. KEY RESULTS The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone-induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this compound alleviated ongoing axonal damage. CONCLUSIONS AND IMPLICATIONS We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined. PMID:25220526

  20. Low Doses of Camptothecin Induced Hormetic and Neuroprotective Effects in PC12 Cells

    PubMed Central

    Zhang, Chao; Chen, Shenghui; Bao, Jiaolin; Zhang, Yulin; Huang, Borong; Jia, Xuejing; Chen, Meiwan; Wan, Jian-Bo; Su, Huanxing; Wang, Yitao

    2015-01-01

    Hormetic response is an adaptive mechanism for a cell or organism surviving in an unfavorable environment. It has been an intriguing subject of researches covering a broad range of biological and medical disciplines, in which the underlying significance and molecular mechanisms are under intensive investigation. In the present study, we demonstrated that topoisomerase I inhibitor camptothecin (CPT), a potent anticancer agent, induced an obvious hormetic response in rat pheochromocytoma PC12 cells. Camptothecin inhibited PC12 cell growth at relative high doses as generally acknowledged while stimulated the cell growth by as much as 39% at low doses. Moreover, low doses of CPT protected the cells from hydrogen peroxide (H2O2)-induced cell death. Phosphoinositide 3-kinase (PI3K)/Akt and nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathways were reported playing pivotal roles in protecting cells from oxidative stress. We observed that these 2 pathways were upregulated by low doses of CPT, as evidenced by increased levels of phosphorylated PI3K, phosphorylated Akt, phosphorylated mammalian target of rapamycin, Nrf2, and HO-1; and abolishment of the growth-promoting and neuroprotective effects of CPT by LY294002, a PI3K inhibitor. These results suggest that the hormetic and neuroprotective effects of CPT at low doses on PC12 cells were attributable, at least partially, to upregulated PI3K/Akt and Nrf2/HO-1 pathways. PMID:26674066

  1. MiRNA-124 induces neuroprotection and functional improvement after focal cerebral ischemia.

    PubMed

    Hamzei Taj, Somayyeh; Kho, Widuri; Riou, Adrien; Wiedermann, Dirk; Hoehn, Mathias

    2016-06-01

    microRNA-124 (miR-124), the most abundant miRNA of the CNS, was recently shown to modulate the polarization of activated microglia and infiltrating macrophages towards the anti-inflammatory M2 phenotype and protect neurons in various ways after brain disease. In ischemic stroke, microglia and macrophages of a detrimental and persistent pro-inflammatory M1 phenotype have been shown to aggravate the secondary injury. Thus, shifting the polarization of microglia/macrophages into the beneficial, anti-inflammatory M2-like phenotype is considered neuroprotective after stroke onset. Here, we have induced 30 min transient occlusion of the right middle cerebral artery (MCAO) in 34 male, C57BL/6 mice. Lesion development was monitored with T2-weighted MRI. Liposomated miR-124 was injected in 11 animals at 48 h and in 5 animals at 10 days after MCAO. Arg-1, a marker for M2 phenotype, was co-stained with Iba-1, NeuN or GFAP. The distribution of astrocytes, neurons and microglia/macrophages and their expression of Arg-1 were quantified. Early miR-124 injection resulted in a significantly increased neuronal survival and a significantly increased number of M2-like polarized microglia/macrophages. Moreover, the lesion core, delineated by reactive astrocytes, was significantly reduced over time upon early miR-124 injection. These neuroprotective and anti-inflammatory effects of the early miR-124 treatment were pronounced during the first week with Arg-1. Number of Arg-1+ microglia/macrophages correlated with neuronal protection and with functional improvement during the first week. Thus, our present results demonstrate that miR-124 may serve as a novel therapeutic strategy for neuroprotection and functional recovery upon stroke onset. PMID:27031810

  2. Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats.

    PubMed

    Kushwah, Neetu; Jain, Vishal; Deep, Satayanarayan; Prasad, Dipti; Singh, Shashi Bala; Khan, Nilofar

    2016-01-01

    Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state. PMID:26901349

  3. Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats

    PubMed Central

    Deep, Satayanarayan; Prasad, Dipti; Singh, Shashi Bala; Khan, Nilofar

    2016-01-01

    Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state. PMID:26901349

  4. Neuregulin-1 is Neuroprotective in a Rat Model of Organophosphate-Induced Delayed Neuronal Injury

    PubMed Central

    Li, Yonggang; Lein, Pamela J.; Liu, Cuimei; Bruun, Donald A.; Giulivi, Cecilia; Ford, Gregory; Tewolde, Teclemichael; Ross-Inta, Catherine; Ford, Byron D.

    2012-01-01

    Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatment with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. PMID:22583949

  5. Neuroprotection of microglial conditioned medium on 6-hydroxydopamine-induced neuronal death: role of transforming growth factor beta-2.

    PubMed

    Polazzi, Elisabetta; Altamira, Luis Emiliano Peña; Eleuteri, Simona; Barbaro, Raffaella; Casadio, Chiara; Contestabile, Antonio; Monti, Barbara

    2009-07-01

    Microglia, the immune cells of the CNS, play essential roles in both physiological and pathological brain states. Here we have used an in vitro model to demonstrate neuroprotection of a 48 h-microglial conditioned medium (MCM) towards cerebellar granule neurons (CGNs) challenged with the neurotoxin 6-hydroxydopamine, which induces a Parkinson-like neurodegeneration, and to identify the protective factor(s). MCM nearly completely protects CGNs from 6-hydroxydopamine neurotoxicity and at least some of the protective factor(s) are peptidic in nature. While the fraction of the medium containing molecules < 30 kDa completely protects CGNs, fractions containing molecules < 10 kDa or > 10 kDa are not neuroprotective. We further demonstrate that microglia release high amounts of transforming growth factor-beta2 (TGF-beta2) and that its exogenous addition to the fraction of the medium not containing it (< 10 kDa) fully restores the neuroprotective action. Moreover, MCM neuroprotection is significantly counteracted by an inhibitor of TGF-beta2 transduction pathway. Our results identify TGF-beta2 as an essential neuroprotective factor released by microglia in its culture medium that requires to be fully effective the concomitant presence of other factor(s) of low molecular weight. PMID:19457129

  6. Repeated preconditioning with hyperbaric oxygen induces neuroprotection against forebrain ischemia via suppression of p38 mitogen activated protein kinase.

    PubMed

    Yamashita, Satoshi; Hirata, Takao; Mizukami, Yoichi; Cui, Ying Jun; Fukuda, Shiro; Ishida, Kazuyoshi; Matsumoto, Mishiya; Sakabe, Takefumi

    2009-12-01

    We previously reported in rats that preconditioning with hyperbaric oxygen (HBO; 100% O(2) 3.5-atomsphere absolute (ATA), 1 h/day for 5 days) provided neuroprotection against transient (8 min) forebrain ischemia possibly through protein synthesis relevant to neurotrophin receptor and inflammatory-immune system. A recent report suggested that HBO-induced neuroprotection is relevant to brain derived neurotrophic factor and its downstream event involving suppression of p38 mitogen activated protein kinase (p38) activation. In the present study, we first performed a dose comparison (1, 2, and 3.5 ATA) of HBO-induced neuroprotection and then investigated pharmacological modification by 10 mg/kg anisomycin (a protein synthesis inhibitor and potent activator for p38) and 200 microg/kg SB203580 (a p38 inhibitor), which were given intraperitoneally 60 and 30 min before every 3.5 ATA-HBO treatment, respectively. Most prominent protective effect on hippocampal CA1 neurons was observed with 3.5 ATA-HBO (survived neurons: 69% [62-73%] vs. untreated: 3.9% [2-8%], 1 ATA: 8.8% [0-26%], 2 ATA-HBO: 46% [22-62%] (median [range]) (7 days after ischemia). Anisomycin abolished a neuroprotective effect (survived neuron: 1.2% [0-7%]). SB203580, when given between administration of anisomycin and HBO treatment, resumed a neuroprotective effect (survived neuron: 52% [37-62%]). The level of phosphorylated p38 at 10-min reperfusion was significantly decreased in 3.5 ATA-HBO group (32% [12-53%] of sham). Single pretreatment with 100 and 200 microg/kg of SB203580 exerted a similar neuroprotective effect (39% [25-51%] and 59% [50-72%]) to 2 and 3.5 ATA-HBO preconditioning, respectively. It is concluded that suppression of p38 phosphorylation plays a key role in HBO-induced neuroprotection and that pretreatment with a p38 inhibitor (SB203580) can provide similar neuroprotection. PMID:19747454

  7. Neuroprotective effect of osmotin against ethanol-induced apoptotic neurodegeneration in the developing rat brain.

    PubMed

    Naseer, M I; Ullah, I; Narasimhan, M L; Lee, H Y; Bressan, R A; Yoon, G H; Yun, D J; Kim, M O

    2014-01-01

    Fetal alcohol syndrome is a neurological and developmental disorder caused by exposure of developing brain to ethanol. Administration of osmotin to rat pups reduced ethanol-induced apoptosis in cortical and hippocampal neurons. Osmotin, a plant protein, mitigated the ethanol-induced increases in cytochrome c, cleaved caspase-3, and PARP-1. Osmotin and ethanol reduced ethanol neurotoxicity both in vivo and in vitro by reducing the protein levels of cleaved caspase-3, intracellular [Ca(2+)]cyt, and mitochondrial transmembrane potential collapse, and also upregulated antiapoptotic Bcl-2 protein. Osmotin is a homolog of adiponectin, and it controls energy metabolism via phosphorylation. Adiponectin can protect hippocampal neurons against ethanol-induced apoptosis. Abrogation of signaling via receptors AdipoR1 or AdipoR2, by transfection with siRNAs, reduced the ability of osmotin and adiponectin to protect neurons against ethanol-induced neurodegeneration. Metformin, an activator of AMPK (adenosine monophosphate-activated protein kinase), increased whereas Compound C, an inhibitor of AMPK pathway, reduced the ability of osmotin and adiponectin to protect against ethanol-induced apoptosis. Osmotin exerted its neuroprotection via Bcl-2 family proteins and activation of AMPK signaling pathway. Modulation of AMPK pathways by osmotin, adiponectin, and metformin hold promise as a preventive therapy for fetal alcohol syndrome. PMID:24675468

  8. Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury

    SciTech Connect

    Li, Yonggang; Lein, Pamela J.; Liu, Cuimei; Bruun, Donald A.; Giulivi, Cecilia; Ford, Gregory D.; Tewolde, Teclemichael; Ross-Inta, Catherine; Ford, Byron D.

    2012-07-15

    Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylflurophosphate (DFP). Adult male Sprague–Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatment with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. -- Highlights: ► NRG-1 blocked DFP induced neuronal injury. ► NRG-1 did not protect against seizures in rats exposed to DFP. ► NRG-1 blocked apoptosis and oxidative stress in the brains of DFP-intoxicated rats. ► Administration of NRG-1 at 1 h after DFP injection prevented delayed neuronal injury.

  9. Neuroprotection by taurine in ethanol-induced apoptosis in the developing cerebellum

    PubMed Central

    2010-01-01

    Background Acute ethanol administration leads to massive apoptotic neurodegeneration in the developing central nervous system. We studied whether taurine is neuroprotective in ethanol-induced apoptosis in the mouse cerebellum during the postnatal period. Methods The mice were divided into three groups: ethanol-treated, ethanol+taurine-treated and controls. Ethanol (20% solution) was administered subcutaneously at a total dose of 5 g/kg (2.5 g/kg at time 1 h and 2.5 g/kg at 3 h) to the ethanol and ethanol+taurine groups. The ethanol+taurine group also received two injections of taurine (1 g/kg each, at time zero and at 4 h). To estimate apoptosis, immunostaining for activated caspase-3 and TUNEL staining were made in the mid-sagittal sections containing lobules I-X of the cerebellar vermis at 12 or 8 hours after the first taurine injection. Changes in the blood taurine level were monitored at each hour by reverse-phase high-performance liquid chromatography (HPLC). Results Ethanol administration induced apoptosis of Purkinje cells on P4 in all cerebellar lobules, most extensively in lobules IX and X, and on P7 increased the number of activated caspase-3-immunoreactive and TUNEL-positive cells in the internal layer of the cerebellum. Administration of taurine significantly decreased the number of activated caspase-3-immunoreactive and TUNEL-positive cells in the internal layer of the cerebellum on P7, but had no effect on Purkinje cells in P4 mice. The high initial taurine concentration in blood of the ethanol+taurine group diminished dramatically during the experiment, not being different at 13 h from that in the controls. Conclusions We conclude that the neuroprotective action of taurine is not straightforward and seems to be different in different types of neurons and/or requires prolonged maintenance of the high taurine concentration in blood plasma. PMID:20804586

  10. Neuroprotective effects of bee venom acupuncture therapy against rotenone-induced oxidative stress and apoptosis.

    PubMed

    Khalil, Wagdy K B; Assaf, Naglaa; ElShebiney, Shaimaa A; Salem, Neveen A

    2015-01-01

    Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic neurodegeneration, mitochondrial impairment, and oxidative stress. Exposure of animals to rotenone induces a range of responses characteristic of PD, including reactive oxygen species production and dopaminergic cell death. Although l-dopa is the drug of choice for improving core symptoms of PD, it is associated with involuntary movements. The current study was directed to evaluate the neuroprotective effect of bee venom acupuncture therapy (BVA) against rotenone-induced oxidative stress, neuroinflammation, and apoptosis in PD mouse model. Forty male Swiss mice were divided into four groups: (1) received saline solution orally and served as normal control, (2) received rotenone (1.5 mg/kg, s.c. every other day for 6 doses), (3) received rotenone concomitantly with l-dopa (25 mg/kg, daily, p.o. for 6 days), and finally (4) received rotenone concomitantly with BVA (0.02 ml once every 3 days for two weeks). Rotenone-treated mice showed impairment in locomotor behavior and a significant reduction in brain dopamine, serotonin, norepinephrine, GSH levels, and paraoxonase activity, whereas a significant increase was observed in brain malondialdehyde, tumor necrosis factor-α, interleukin-β levels besides DNA damage, and over-expression of caspase-3, Bax, and Bcl-2 genes. Significant improvement of the aforementioned parameters was demonstrated after BVA compared to l-dopa therapy. In conclusion, bee venom normalized all the neuroinflammatory and apoptotic markers and restored brain neurochemistry after rotenone injury. Therefore, BVA is a promising neuroprotective therapy for PD. PMID:25481089

  11. Neuroprotective effect of some plant extracts in cultured CT105-induced PC12 cells.

    PubMed

    Kim, Sang Tae; Kim, Jeong Do; Lyu, Yeoung-Su; Lee, Min-Yung; Kang, Hyung-Won

    2006-10-01

    Carboxyl-terminal fragments of APP (CT) have been found in plaques, microvessels and the neurofibrillary tangles in the brains of AD patients. These carboxyl-terminal fragments, which contain the complete Abeta sequence, appear to be toxic to neurons in culture cells. However, the possible role of other cleaved products of APP is less clear. We showed that a recombinant carboxy-terminal 105 amino acid fragment (CT105) of APP induced strong neurotoxicity in PC12 cells. We prepared alcoholic extract from Oriental herbal plants and screened their protective effects against CT105-induced cell death in PC12 cells after the treatment of these extracts. Of the 10 kinds of plant extracts, 12 kinds of extracts had considerable protective effects against CT105-induced cell death, especially, Uncariae Ramulus et Uncus (UREU), Gastrodia elata (GAE), Evodia officinalis (EO) and Panax ginseng (PAG) showed the most protective effect at the concentration of 50 microg/ml. BuOH extract of UREU and GAE possessed the strongest protective effects against neurotoxicity of CT105-induced PC12 cells and showed inhibitory effect with IC50 values of 4.8 and 8.3 microg/ml, respectively. These plants are promising candidates of neuroprotective effects and would be useful for the treatment of the neuronal degenerative diseases such as Alzheimer's diseases. PMID:17015944

  12. Bioassay-Guided Isolation of Neuroprotective Compounds from Uncaria rhynchophylla against Beta-Amyloid-Induced Neurotoxicity

    PubMed Central

    Xian, Yan-Fang; Lin, Zhi-Xiu; Mao, Qing-Qiu; Hu, Zhen; Zhao, Ming; Che, Chun-Tao; Ip, Siu-Po

    2012-01-01

    Uncaria rhynchophylla is a component herb of many Chinese herbal formulae for the treatment of neurodegenerative diseases. Previous study in our laboratory has demonstrated that an ethanol extract of Uncaria rhynchophylla ameliorated cognitive deficits in a mouse model of Alzheimer's disease induced by D-galactose. However, the active ingredients of Uncaria rhynchophylla responsible for the anti-Alzheimer's disease activity have not been identified. This study aims to identify the active ingredients of Uncaria rhynchophylla by a bioassay-guided fractionation approach and explore the acting mechanism of these active ingredients by using a well-established cellular model of Alzheimer's disease, beta-amyloid- (Aβ-) induced neurotoxicity in PC12 cells. The results showed that six alkaloids, namely, corynoxine, corynoxine B, corynoxeine, isorhynchophylline, isocorynoxeine, and rhynchophylline were isolated from the extract of Uncaria rhynchophylla. Among them, rhynchophylline and isorhynchophylline significantly decreased Aβ-induced cell death, intracellular calcium overloading, and tau protein hyperphosphorylation in PC12 cells. These results suggest that rhynchophylline and isorhynchophylline are the major active ingredients responsible for the protective action of Uncaria rhynchophylla against Aβ-induced neuronal toxicity, and their neuroprotective effect may be mediated, at least in part, by inhibiting intracellular calcium overloading and tau protein hyperphosphorylation. PMID:22778778

  13. Neuroprotective effects of Triticum aestivum L. against beta-amyloid-induced cell death and memory impairments.

    PubMed

    Jang, Jung-Hee; Kim, Chang-Yul; Lim, Sun Ha; Yang, Chae Ha; Song, Kyung-Sik; Han, Hyung Soo; Lee, Hyeong-Kyu; Lee, Jongwon

    2010-01-01

    beta-Amyloid (A beta) is a key component of senile plaques, neuropathological hallmarks of Alzheimer's disease (AD) and has been reported to induce cell death via oxidative stress. This study investigated the protective effects of Triticum aestivum L. (TAL) on A beta-induced apoptosis in SH-SY5Y cells and cognitive dysfunctions in Sprague-Dawley (SD) rats. Cells treated with A beta exhibited decreased viability and apoptotic features, such as DNA fragmentation, alterations in mitochondria and an increased Bax/Bcl-2 ratio, which were attenuated by TAL extract (TALE) pretreatment. To elucidate the neuroprotective mechanisms of TALE, the study examined A beta-induced oxidative stress and cellular defense. TALE pretreatment suppressed A beta-increased intracellular accumulation of reactive oxygen species (ROS) via up-regulation of glutathione, an essential endogenous antioxidant. To further verify the effect of TALE on memory impairments, A beta or scopolamine was injected in SD rats and a water maze task conducted as a spatial memory test. A beta or scopolamine treatment increased the time taken to find the platform during training trials, which was decreased by TALE pretreatment. Furthermore, one of the active components of TALE, total dietary fiber also effectively inhibited A beta-induced cytotoxicity and scopolamine-caused memory deficits. These results suggest that TALE may have preventive and/or therapeutic potential in the management of AD. PMID:19441012

  14. Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats

    SciTech Connect

    Srivastava, Pranay; Yadav, Rajesh S.; Chandravanshi, Lalit P.; Shukla, Rajendra K.; Dhuriya, Yogesh K.; Chauhan, Lalit K.S.; Dwivedi, Hari N.; Pant, Aditiya B.; Khanna, Vinay K.

    2014-09-15

    Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20 mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenic exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20 mg/kg body weight, p.o) and curcumin (100 mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin. - Highlights: • Neuroprotective mechanism of curcumin in arsenic induced cholinergic deficits studied • Curcumin protected arsenic induced enhanced expression of stress markers in rat brain • Arsenic compromised mitochondrial electron transport chain protected

  15. Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones.

    PubMed

    Bösel, Julian; Gandor, Florin; Harms, Christoph; Synowitz, Michael; Harms, Ulrike; Djoufack, Pierre Chryso; Megow, Dirk; Dirnagl, Ulrich; Hörtnagl, Heide; Fink, Klaus B; Endres, Matthias

    2005-03-01

    Statins [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors] exert cholesterol-independent pleiotropic effects that include anti-thrombotic, anti-inflammatory, and anti-oxidative properties. Here, we examined direct protective effects of atorvastatin on neurones in different cell damage models in vitro. Primary cortical neurones were pre-treated with atorvastatin and then exposed to (i) glutamate, (ii) oxygen-glucose deprivation or (iii) several apoptosis-inducing compounds. Atorvastatin significantly protected from glutamate-induced excitotoxicity as evidenced by propidium iodide staining, nuclear morphology, release of lactate dehydrogenase, and mitochondrial tetrazolium metabolism, but not from oxygen-glucose deprivation or apoptotic cell death. This anti-excitototoxic effect was evident with 2-4 days pre-treatment but not with daily administration or shorter-term pre-treatment. The protective properties occurred independently of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition because co-treatment with mevalonate or other isoprenoids did not reverse or attenuate neuroprotection. Atorvastatin attenuated the glutamate-induced increase of intracellular calcium, which was associated with a modulation of NMDA receptor function. Taken together, atorvastatin exerts specific anti-excitotoxic effects independent of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition, which has potential therapeutic implications. PMID:15748157

  16. Neuroprotection of luteolin against methylmercury-induced toxicity in lobster cockroach Nauphoeta cinerea.

    PubMed

    Adedara, Isaac A; Rosemberg, Denis B; Souza, Diogo O; Farombi, Ebenezer O; Aschner, Michael; Rocha, Joao B T

    2016-03-01

    Luteolin (3', 4', 5, 7-tetrahydroxyflavone) is a polyphenolic compound found in foods of plant origin and has been reported to possess antioxidant and neuroprotective properties. However, there is dearth of information on the beneficial effects of luteolin on methylmercury (MeHg), a long-established neurotoxic compound in animals and humans. This study evaluated the effect of luteolin on MeHg-induced behavioral and biochemical deficits, using lobster cockroach Nauphoeta cinerea as an alternative and complementary animal model. The insects were exposed for 35 consecutive days to either MeHg alone (0.05 mg/g feed) or in combination with luteolin at 0.25, 0.5 and 1.0 mg/g feed. Locomotor behavior was assessed using video-tracking software during a 10-min trial in a novel arena and subsequently, biochemical analyses were carried out using the cockroaches' heads. Luteolin supplementation dose-dependently reversed the MeHg-induced locomotor deficits and enhanced the exploratory profiles of MeHg-exposed cockroaches as confirmed by track and occupancy plot analyses. Luteolin reversed the MeHg-induced acetylcholinesterase activity inhibition, decreased dichlorofluorescein oxidation and lipid peroxidation levels, but increased total thiol level and catalase and glutathione S-transferase activities in the treated cockroaches. In conclusion, luteolin prevented oxidative stress indices and neurobehavioral deficits in a Nauphoeta cinerea model of MeHg toxicity. PMID:26905302

  17. Neuroprotective Effect of Dexmedetomidine on Hyperoxia-Induced Toxicity in the Neonatal Rat Brain

    PubMed Central

    Sifringer, Marco; von Haefen, Clarissa; Krain, Maria; Paeschke, Nadine; Bendix, Ivo; Bührer, Christoph; Spies, Claudia D.; Endesfelder, Stefanie

    2015-01-01

    Dexmedetomidine is a highly selective agonist of α2-receptors with sedative, anxiolytic, analgesic, and anesthetic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on neurodegeneration, oxidative stress markers, and inflammation following the induction of hyperoxia in neonatal rats. Six-day-old Wistar rats received different concentrations of dexmedetomidine (1, 5, or 10 µg/kg bodyweight) and were exposed to 80% oxygen for 24 h. Sex-matched littermates kept in room air and injected with normal saline or dexmedetomidine served as controls. Dexmedetomidine pretreatment significantly reduced hyperoxia-induced neurodegeneration in different brain regions of the neonatal rat. In addition, dexmedetomidine restored the reduced/oxidized glutathione ratio and attenuated the levels of malondialdehyde, a marker of lipid peroxidation, after exposure to high oxygen concentration. Moreover, administration of dexmedetomidine induced downregulation of IL-1β on mRNA and protein level in the developing rat brain. Dexmedetomidine provides protections against toxic oxygen induced neonatal brain injury which is likely associated with oxidative stress signaling and inflammatory cytokines. Our results suggest that dexmedetomidine may have a therapeutic potential since oxygen administration to neonates is sometimes inevitable. PMID:25653737

  18. The neuroprotective role of ferrostatin-1 under rotenone-induced oxidative stress in dopaminergic neuroblastoma cells.

    PubMed

    Kabiraj, Parijat; Valenzuela, Carlos A; Marin, Jose E; Ramirez, David A; Mendez, Lois; Hwang, Michael S; Varela-Ramirez, Armando; Fenelon, Karine; Narayan, Mahesh; Skouta, Rachid

    2015-10-01

    Endoplasmic reticulum (ER) proteins including protein disulfide isomerase (PDI) are playing crucial roles in maintaining appropriate protein folding. Under nitrosative stress, an excess of nitric oxide (NO) radical species induced the S-nitrosylation of PDI cysteines which eliminate its isomerase and oxidoreductase capabilities. In addition, the S-nitrosylation-PDI complex is the cause of aggregation especially of the α-synuclein (α-syn) protein (accumulation of Lewy-body aggregates). We recently identified a potent antioxidant small molecule, Ferrostatin-1 (Fer-1), that was able to inhibit a non-apoptotic cell death named ferroptosis. Ferroptosis cell death involved the generation of oxidative stress particularly lipid peroxide. In this work, we reported the neuroprotective role of ferrostatin-1 under rotenone-induced oxidative stress in dopaminergic neuroblastoma cells (SH-SY5Y). We first synthesized the Fer-1 and confirmed that it is not toxic toward the SH-SY5Y cells at concentrations up to 12.5 μM. Second, we showed that Fer-1 compound quenched the commercially available stable radical, the 2,2-diphenyl-1-picrylhydrazyl (DPPH), in non-cellular assay at 82 %. Third, Fer-1 inhibited the ROS/RNS generated under rotenone insult in SH-SY5Y cells. Fourth, we revealed the effective role of Fer-1 in ER stress mediated activation of apoptotic pathway. Finally, we reported that Fer-1 mitigated rotenone-induced α-syn aggregation. PMID:26385697

  19. Neuroprotective effects of bloodletting at Jing points combined with mild induced hypothermia in acute severe traumatic brain injury

    PubMed Central

    Tu, Yue; Miao, Xiao-mei; Yi, Tai-long; Chen, Xu-yi; Sun, Hong-tao; Cheng, Shi-xiang; Zhang, Sai

    2016-01-01

    Bloodletting at Jing points has been used to treat coma in traditional Chinese medicine. Mild induced hypothermia has also been shown to have neuroprotective effects. However, the therapeutic effects of bloodletting at Jing points and mild induced hypothermia alone are limited. Therefore, we investigated whether combined treatment might have clinical effectiveness for the treatment of acute severe traumatic brain injury. Using a rat model of traumatic brain injury, combined treatment substantially alleviated cerebral edema and blood-brain barrier dysfunction. Furthermore, neurological function was ameliorated, and cellular necrosis and the inflammatory response were lessened. These findings suggest that the combined effects of bloodletting at Jing points (20 μL, twice a day, for 2 days) and mild induced hypothermia (6 hours) are better than their individual effects alone. Their combined application may have marked neuroprotective effects in the clinical treatment of acute severe traumatic brain injury. PMID:27482221

  20. Nanowired drug delivery of antioxidant compound H-290/51 enhances neuroprotection in hyperthermia-induced neurotoxicity.

    PubMed

    Muresanu, Dafin F; Sharma, Aruna; Tian, Z Ryan; Smith, Mark A; Sharma, Hari Shanker

    2012-02-01

    Nanoparticles from the environment or through industrial sources can induce profound alterations in human health, often leading to brain dysfunction. However, it is still unclear whether nanoparticle intoxication could also alter the physiological or pathological responses of additional brain injury, stress response or disease processes. Military personals engaged in combat or peacekeeping operations are often exposed to nanoparticles from various environmental sources, e.g., Ag, Cu, Si, C, Al. In addition, these military personals are often exposed to high environmental heat, or gun and missle explosion injury leading to head or spinal trauma. Thus it is likely that additional CNS injury or stress-induced pathophysiological processes are influenced by nanoparticle intoxication. In this situation, when a combination of nanoparticles and central nervous system (CNS) injury or stress exist together, drug therapy needed to correct these anomalies may not work as effectively as in normal situation. Previous studies from our laboratory show that nanoparticle-intoxicated animals when subjected to hyperthermia resulted in exacerbation of brain pathology. In these animals, antioxidant compounds, e.g., H-290/51 that inhibits free radical formation and induces marked neuroprotection in normal rats after heat stress, failed to protect brain damage when a combination of nanoparticles and heat exposure was used. However, nanowired H-290/51 resulted in better neuroprotection in nanoparticles intoxicated animals after heat stress. Interestingly, high doses of the normal compound induced some neuroprotection in these nanoparticle-treated, heat-stressed rats. These observations suggest that a combination of nanoparticles and heat stress is dangerous and in such situations modification of drug dosage is needed to achieve comparable neuroprotection. In this review possible mechanisms of nanoparticle-induced exacerbation of heat induced neurotoxicity and brain protection achieved by

  1. Multimodal Neuroprotection Induced by PACAP38 in Oxygen–Glucose Deprivation and Middle Cerebral Artery Occlusion Stroke Models

    PubMed Central

    Cohen, Gadi; Arien-Zakay, Hadar; Chen, Jieli; Zhang, Chunling; Chopp, Michael; Jiang, Hao

    2014-01-01

    Pituitary adenylate cyclase activating peptide (PACAP), a potent neuropeptide which crosses the blood–brain barrier, is known to provide neuroprotection in rat stroke models of middle cerebral artery occlusion (MCAO) by mechanism(s) which deserve clarification. We confirmed that following i.v. injection of 30 ng/kg of PACAP38 in rats exposed to 2 h of MCAO focal cerebral ischemia and 48 h reoxygenation, 50 % neuroprotection was measured by reduced caspase-3 activity and volume of cerebral infarction. Similar neuroprotective effects were measured upon PACAP38 treatment of oxygen–glucose deprivation and reoxygenation of brain cortical neurons. The neuroprotection was temporally associated with increased expression of brain-derived neurotrophic factor, phosphorylation of its receptor—tropomyosin-related kinase receptor type B (trkB), activation of phosphoinositide 3-kinase and Akt, and reduction of extracellular signal-regulated kinases 1/2 phosphorylation. PACAP38 increased expression of neuronal markers beta-tubulin III, microtubule-associated protein-2, and growth-associated protein-43. PACAP38 induced stimulation of Rac and suppression of Rho GTPase activities. PACAP38 down-regulated the nerve growth factor receptor (p75NTR) and associated Nogo-(Neurite outgrowth-A) receptor. Collectively, these in vitro and in vivo results propose that PACAP exhibits neuroprotective effects in cerebral ischemia by three mechanisms: a direct one, mediated by PACAP receptors, and two indirect, induced by neurotrophin release, activation of the trkB receptors and attenuation of neuronal growth inhibitory signaling molecules p75NTR and Nogo receptor. PMID:22678884

  2. Neuroprotective effects of Rhizoma Dioscoreae polysaccharides against neuronal apoptosis induced by in vitro hypoxia

    PubMed Central

    XIANG, QIN; ZHOU, WEN-YUN; HU, WEI-XU; WEN, ZHU; HE, DAN; WU, XIAO-MU; WEI, HUI-PING; WANG, WEN-DING; HU, GUO-ZHU

    2015-01-01

    Rhizoma Dioscoreae polysaccharides (RDPS) are the primary active ingredient of Rhizoma Dioscoreae, which is a traditional Chinese medicine. RDPS have previously been shown to scavenge reactive oxygen species, and protect against D-galactose-induced mimetic aging. The present study aimed to investigate the neuroprotective effects of RDPS against hypoxia-induced neuronal cell apoptosis. Neuronal cells harvested from pregnant Sprague-Dawley rats were divided into groups, as follows: i) Normal control group; ii) hypoxia-induced apoptosis neuronal cell model; iii) 0.025 g/l RDPS-treated group; iv) 0.05 g/l RDPS-treated group; v) 0.1 g/l RDPS-treated group; and vi) 0.25 g/l RDPS treated group. Neuronal cell viability was investigated using an MTT assay, and neuronal cell apoptosis was analyzed using Annexin V-fluorescein isothiocyanate/propidium iodide double-staining, Hoechst 33342 fluorescent staining, Rhodamine 123 staining, polymerase chain reaction and immunocytochemical staining. The RDPS-treated neuronal cells exhibited improved viability, and decreased hypoxia-induced mitochondrial injury and apoptosis. In addition, the mRNA and protein expression levels of caspase-3 and B-cell lymphoma (Bcl)-2-associated X protein (Bax) were significantly downregulated, whereas the mRNA and protein expression levels of Bcl-2 were significantly upregulated, in the RDPS-treated hypoxic neurons, as compared with the apoptosis model (P<0.05). Furthermore, the ratio of Bcl-2 expression:Bax expression significantly increased following RDPS treatment, as compared with the apoptosis model (P<0.05). The results of the present study suggested that RDPS may attenuate hypoxia-induced neuronal cell apoptosis by altering the expression levels of key apoptosis-regulating proteins in hypoxic neurons. PMID:26668596

  3. Neuroprotective effect of caffeic acid phenethyl ester in 3-nitropropionic acid-induced striatal neurotoxicity.

    PubMed

    Bak, Jia; Kim, Hee Jung; Kim, Seong Yun; Choi, Yun-Sik

    2016-05-01

    Caffeic acid phenethyl ester (CAPE), derived from honeybee hives, is a bioactive compound with strong antioxidant activity. This study was designed to test the neuroprotective effect of CAPE in 3-nitropropionic acid (3NP)-induced striatal neurotoxicity, a chemical model of Huntington's disease (HD). Initially, to test CAPE's antioxidant activity, a 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) antioxidant assay was employed, and CAPE showed a strong direct radical-scavenging eff ect. In addition, CAPE provided protection from 3NP-induced neuronal cell death in cultured striatal neurons. Based on these observations, the in vivo therapeutic potential of CAPE in 3NP-induced HD was tested. For this purpose, male C57BL/6 mice were repeatedly given 3NP to induce HD-like pathogenesis, and 30 mg/kg of CAPE or vehicle (5% dimethyl sulfoxide and 95% peanut oil) was administered daily. CAPE did not cause changes in body weight, but it reduced mortality by 29%. In addition, compared to the vehicle-treated group, robustly reduced striatal damage was observed in the CAPE-treated animals, and the 3NP-induced behavioral defi cits on the rotarod test were signifi cantly rescued after the CAPE treatment. Furthermore, immunohistochemical data showed that immunoreactivity to glial fibrillary acidic protein (GFAP) and CD45, markers for astrocyte and microglia activation, respectively, were strikingly reduced. Combined, these data unequivocally indicate that CAPE has a strong antioxidant eff ect and can be used as a potential therapeutic agent against HD. PMID:27162482

  4. Neuroprotective effect of caffeic acid phenethyl ester in 3-nitropropionic acid-induced striatal neurotoxicity

    PubMed Central

    Bak, Jia; Kim, Hee Jung; Kim, Seong Yun

    2016-01-01

    Caffeic acid phenethyl ester (CAPE), derived from honeybee hives, is a bioactive compound with strong antioxidant activity. This study was designed to test the neuroprotective effect of CAPE in 3-nitropropionic acid (3NP)-induced striatal neurotoxicity, a chemical model of Huntington's disease (HD). Initially, to test CAPE's antioxidant activity, a 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) antioxidant assay was employed, and CAPE showed a strong direct radical-scavenging eff ect. In addition, CAPE provided protection from 3NP-induced neuronal cell death in cultured striatal neurons. Based on these observations, the in vivo therapeutic potential of CAPE in 3NP-induced HD was tested. For this purpose, male C57BL/6 mice were repeatedly given 3NP to induce HD-like pathogenesis, and 30 mg/kg of CAPE or vehicle (5% dimethyl sulfoxide and 95% peanut oil) was administered daily. CAPE did not cause changes in body weight, but it reduced mortality by 29%. In addition, compared to the vehicle-treated group, robustly reduced striatal damage was observed in the CAPE-treated animals, and the 3NP-induced behavioral defi cits on the rotarod test were signifi cantly rescued after the CAPE treatment. Furthermore, immunohistochemical data showed that immunoreactivity to glial fibrillary acidic protein (GFAP) and CD45, markers for astrocyte and microglia activation, respectively, were strikingly reduced. Combined, these data unequivocally indicate that CAPE has a strong antioxidant eff ect and can be used as a potential therapeutic agent against HD. PMID:27162482

  5. Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1-40).

    PubMed

    Miguel-Hidalgo, J J; Alvarez, X A; Cacabelos, R; Quack, G

    2002-12-20

    Progressive neuronal loss and cognitive decline in Alzheimer's disease (AD) might be aggravated by beta-amyloid-enhanced excitotoxicity. Memantine is an uncompetitive NMDA receptor antagonist under clinical development for the treatment of AD. Memantine has neuroprotective actions in several in vitro and in vivo models. In the present study, we determined whether memantine protected against beta-amyloid induced neurotoxicity and learning impairment in rats. Twenty Sprague-Dawley rats received vehicle or vehicle plus memantine (steady-state plasma concentrations of 2.34+/-0.23 microM, n=10) s.c. by osmotic pump for 9 days. After 2 days of treatment, 2 microl of water containing beta-amyloid 1-40 [Abeta(1-40)] were injected into the hippocampal fissure. On the ninth day of treatment, animals were sacrificed, and morphological and immunohistochemical techniques were used to determine the extent of neuronal degeneration and astrocytic and microglial activation in the hippocampus. Psychomotor activity and spatial discrimination were tested on the eighth day of treatment. Abeta(1-40), but not water, injections into hippocampus led to neuronal loss in the CA1 subfield, evidence of widespread apoptosis, and astrocytic and microglial activation and hypertrophy. Memantine treated animals had significant reductions in the amount of neuronal degeneration, pyknotic nuclei, and GFAP immunostaining as compared with vehicle treated animals. These data suggest that memantine, at therapeutically relevant concentrations, can protect against neuronal degeneration induced by beta-amyloid. PMID:12468047

  6. Neuroprotection of Grape Seed Extract and Pyridoxine against Triton-Induced Neurotoxicity.

    PubMed

    Abdou, Heba M; Wahby, Mayssaa M

    2016-01-01

    Triton WR-1339 administration causes neurotoxicity. Natural products and herbal extracts can attenuate cerebral injury. In the present study, we investigated the neuroprotective role of grape seed extract and/or vitamin B6 against triton-induced neurotoxicity. Thirty-five adult male albino rats of the Sprague-Dawley strain, weighing 140-145 g, were divided into five groups: control, triton, grape seed extract + triton, grape seed extract + triton + vitamin B6, and vitamin B6 + triton. The hematological and biochemical analyses were carried out. Alteration in iNOS mRNA gene expression was determined using reverse-transcriptase PCR analysis. In addition, qualitative DNA fragmentation was examined using agarose gel electrophoresis. Triton-treatment caused significant disturbances in the hematological parameters, the neurological functions, and the antioxidant profile. Also, triton significantly increased the iNOS mRNA expression and DNA damage. Our results showed that grape seed extract and/or vitamin B6 could attenuate all the examined parameters. These natural substances could exhibit protective effects against triton-induced neurological damage because of their antioxidative and antiapoptotic capacities. PMID:27293516

  7. Neuroprotective effect of cobalt chloride on hypobaric hypoxia-induced oxidative stress.

    PubMed

    Shrivastava, Kalpana; Shukla, Dhananjay; Bansal, Anju; Sairam, Mustoori; Banerjee, P K; Ilavazhagan, Govindaswamy

    2008-02-01

    Hypobaric hypoxia, characteristic of high altitude is known to increase the formation of reactive oxygen and nitrogen species (RONS), and decrease effectiveness of antioxidant enzymes. RONS are involved and may even play a causative role in high altitude related ailments. Brain is highly susceptible to hypoxic stress and is involved in physiological responses that follow. Exposure of rats to hypobaric hypoxia (7619 m) resulted in increased oxidation of lipids and proteins due to increased RONS and decreased reduced to oxidized glutathione (GSH/GSSG) ratio. Further, there was a significant increase in superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) levels. Increase in heme oxygenase 1 (HO-1) and heat shock protein 70 (HSP70) was also noticed along with metallothionein (MT) II and III. Administration of cobalt appreciably attenuated the RONS generation, oxidation of lipids and proteins and maintained GSH/GSSH ratio similar to that of control cells via induction of HO-1 and MT offering efficient neuroprotection. It can be concluded that cobalt reduces hypoxia oxidative stress by maintaining higher cellular HO-1 and MT levels via hypoxia inducible factor 1alpha (HIF-1alpha) signaling mechanisms. These findings provide a basis for possible use of cobalt for prevention of hypoxia-induced oxidative stress. PMID:17706837

  8. In Vitro Neuroprotective Effect of Shikimic Acid Against Hydrogen Peroxide-Induced Oxidative Stress.

    PubMed

    Rabelo, Thallita Kelly; Zeidán-Chuliá, Fares; Caregnato, Fernanda Freitas; Schnorr, Carlos Eduardo; Gasparotto, Juciano; Serafini, Mairim Russo; de Souza Araújo, Adriano Antunes; Quintans-Junior, Lucindo José; Moreira, José Cláudio Fonseca; Gelain, Daniel Pens

    2015-08-01

    Shikimic acid (SA), originally extracted from Illicium verum Hook. fil., is an indispensable starting material for the synthesis of the antiviral drug Oseltamivir (Tamiflu(®)) with very limited number of studies regarding its biological effects in vitro. Therefore, we here evaluated the thermoanalytical profile, redox properties, and in vitro effects of SA on human neuronal-like cells (SH-SY5Y). The thermoanalytical profile of SA was studied by using differential scanning calorimetry (DSC) and thermogravimetry/derivative thermogravimetry (TG/DTG) characterization. Both antioxidant potential and in vitro lipoperoxidation levels were analyzed. Cell viability and intracellular reactive species (RS) production was determined by DCF and SRB assays, respectively. Our results show in vitro antioxidant activity of SA without exerting cytotoxic effects on SH-SY5Y cells at tested concentrations of 10 nM, 10 μM, and 10 mM. In addition, SA protected the cells against H2O2-induced toxicity; effect that could be related, at least in part, with decreased intracellular RS production and its antioxidant potential. The present study shows evidence for neuroprotective actions of SA against oxidative stress-induced toxicity on SH-SY5Y cells, inviting for further investigation about its potential use in the context of oxidative stress-associated neurodegenerative diseases. PMID:25862258

  9. Neuroprotection of Grape Seed Extract and Pyridoxine against Triton-Induced Neurotoxicity

    PubMed Central

    Abdou, Heba M.

    2016-01-01

    Triton WR-1339 administration causes neurotoxicity. Natural products and herbal extracts can attenuate cerebral injury. In the present study, we investigated the neuroprotective role of grape seed extract and/or vitamin B6 against triton-induced neurotoxicity. Thirty-five adult male albino rats of the Sprague-Dawley strain, weighing 140–145 g, were divided into five groups: control, triton, grape seed extract + triton, grape seed extract + triton + vitamin B6, and vitamin B6 + triton. The hematological and biochemical analyses were carried out. Alteration in iNOS mRNA gene expression was determined using reverse-transcriptase PCR analysis. In addition, qualitative DNA fragmentation was examined using agarose gel electrophoresis. Triton-treatment caused significant disturbances in the hematological parameters, the neurological functions, and the antioxidant profile. Also, triton significantly increased the iNOS mRNA expression and DNA damage. Our results showed that grape seed extract and/or vitamin B6 could attenuate all the examined parameters. These natural substances could exhibit protective effects against triton-induced neurological damage because of their antioxidative and antiapoptotic capacities. PMID:27293516

  10. The indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis.

    PubMed

    Jaeger, Hanna M; Pehlke, Jens R; Kaltwasser, Britta; Kilic, Ertugrul; Bähr, Mathias; Hermann, Dirk M; Doeppner, Thorsten R

    2015-06-10

    N-methyl-D-aspartate receptor (NMDAR) activation induces excitotoxicity, contributing to post-stroke brain injury. Hitherto, NMDAR deactivation failed in clinical trials due to insufficient pre-clinical study designs and drug toxicity. Flupirtine is an indirect NMDAR antagonist being used as analgesic in patients. Taking into account its tolerability profile, we evaluated effects of flupirtine on post-stroke tissue survival, neurological recovery and brain remodeling.Mice were exposed to stroke and intraperitoneally treated with saline (control) or flupirtine at various doses (1-10 mg/kg) and time-points (0-12 hours). Tissue survival and cell signaling were studied on day 2, whereas neurological recovery and tissue remodeling were analyzed until day 84.Flupirtine induced sustained neuroprotection, when delivered up to 9 hours. The latter yielded enhanced neurological recovery that persisted over three months and which was accompanied by enhanced angioneurogenesis. On the molecular level, inhibition of calpain activation was noted, which was associated with increased signal-transducer-and-activator-of-transcription-6 (STAT6) abundance, reduced N-terminal-Jun-kinase and NF-κB activation, as well as reduced proteasomal activity. Consequently, blood-brain-barrier integrity was stabilized, oxidative stress was reduced and brain leukocyte infiltration was diminished.In view of its excellent tolerability, considering its sustained effects on neurological recovery, brain tissue survival and remodeling, flupirtine is an attractive candidate for stroke therapy. PMID:26050199

  11. The indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis

    PubMed Central

    Jaeger, Hanna M.; Pehlke, Jens R.; Kaltwasser, Britta; Kilic, Ertugrul; Bähr, Mathias; Hermann, Dirk M.; Doeppner, Thorsten R.

    2015-01-01

    N-methyl-D-aspartate receptor (NMDAR) activation induces excitotoxicity, contributing to post-stroke brain injury. Hitherto, NMDAR deactivation failed in clinical trials due to insufficient pre-clinical study designs and drug toxicity. Flupirtine is an indirect NMDAR antagonist being used as analgesic in patients. Taking into account its tolerability profile, we evaluated effects of flupirtine on post-stroke tissue survival, neurological recovery and brain remodeling. Mice were exposed to stroke and intraperitoneally treated with saline (control) or flupirtine at various doses (1-10 mg/kg) and time-points (0-12 hours). Tissue survival and cell signaling were studied on day 2, whereas neurological recovery and tissue remodeling were analyzed until day 84. Flupirtine induced sustained neuroprotection, when delivered up to 9 hours. The latter yielded enhanced neurological recovery that persisted over three months and which was accompanied by enhanced angioneurogenesis. On the molecular level, inhibition of calpain activation was noted, which was associated with increased signal-transducer-and-activator-of-transcription-6 (STAT6) abundance, reduced N-terminal-Jun-kinase and NF-κB activation, as well as reduced proteasomal activity. Consequently, blood-brain-barrier integrity was stabilized, oxidative stress was reduced and brain leukocyte infiltration was diminished. In view of its excellent tolerability, considering its sustained effects on neurological recovery, brain tissue survival and remodeling, flupirtine is an attractive candidate for stroke therapy. PMID:26050199

  12. Neuroprotective effects of 20(S)-protopanaxadiol against glutamate-induced mitochondrial dysfunction in PC12 cells.

    PubMed

    Bak, Dong-Ho; Kim, Hyung Don; Kim, Young Ock; Park, Chun Geun; Han, Seung-Yun; Kim, Jwa-Jin

    2016-02-01

    Ginseng (Panax ginseng C.A. Mey.) is commonly used in traditional oriental medicine for its wide spectrum of medicinal properties, including anti-inflammatory, antitumorigenic, adaptogenic and anti-aging properties. 20(S)-Protopanaxadiol (PPD), the main intestinal metabolite of ginsenosides, is one of the active ingredients in ginseng. In this study, we aimed to investigate the neuroprotective effects of PPD on PC12 cells; however, the underlying mechanisms remain elusive. We examined cell viability by MTT assay and the morphological changes of PC12 cells following glutamate‑induced cell damage and evaluated the anti‑apoptotic effects of PPD using Hoechst 33258 staining, western blot analysis and Muse™ Cell Analyzer and the antioxidant effects of PPD using FACS analysis and immunofluorescence. Furthermore, PPD exerted protective effects on PC12 cells via the inhibition of mitochondrial damage against glutamate-induced excitotoxicity using immunofluorescence, electron microscopy and FACS analysis. We demonstrate that treatment with PPD suppresses apoptosis, which contributes to the neuroprotective effects of PPD against glutamate‑induced excitotoxicity in PC12 cells. Treatment with PPD inhibited nuclear condensation and decreased the number of Annexin V-positive cells. In addition, PPD increased antioxidant activity and mitochondrial homeostasis in the glutamate-exposed cells. These antioxidant effects were responsible for the neuroprotection and enhanced mitochondrial function following treatment with PPD. Furthermore, PD inhibited the glutamate-induced morphological changes in the mitochondria and scavenged the mitochondrial and cytosolic reactive oxygen species (ROS) induced by glutamate. In addition, mitochondrial function was significantly improved in terms of mitochondrial membrane potential (MMP) and enhanced mitochondrial mass compared with the cells exposed to glutamate and not treated with PPD. Taken together, the findings of our study indicate

  13. Neuroprotective effects of 20(S)-protopanaxadiol against glutamate-induced mitochondrial dysfunction in PC12 cells

    PubMed Central

    BAK, DONG-HO; KIM, HYUNG DON; KIM, YOUNG OCK; PARK, CHUN GEUN; HAN, SEUNG-YUN; KIM, JWA-JIN

    2016-01-01

    Ginseng (Panax ginseng C.A. Mey.) is commonly used in traditional oriental medicine for its wide spectrum of medicinal properties, including anti-inflammatory, antitumorigenic, adaptogenic and anti-aging properties. 20(S)-Protopanaxadiol (PPD), the main intestinal metabolite of ginsenosides, is one of the active ingredients in ginseng. In this study, we aimed to investigate the neuroprotective effects of PPD on PC12 cells; however, the underlying mechanisms remain elusive. We examined cell viability by MTT assay and the morphological changes of PC12 cells following glutamate-induced cell damage and evaluated the anti-apoptotic effects of PPD using Hoechst 33258 staining, western blot analysis and Muse™ Cell Analyzer and the antioxidant effects of PPD using FACS analysis and immunofluorescence. Furthermore, PPD exerted protective effects on PC12 cells via the inhibition of mitochondrial damage against glutamate-induced excitotoxicity using immunofluorescence, electron microscopy and FACS analysis. We demonstrate that treatment with PPD suppresses apoptosis, which contributes to the neuroprotective effects of PPD against glutamate-induced excitotoxicity in PC12 cells. Treatment with PPD inhibited nuclear condensation and decreased the number of Annexin V-positive cells. In addition, PPD increased antioxidant activity and mitochondrial homeostasis in the glutamate-exposed cells. These antioxidant effects were responsible for the neuroprotection and enhanced mitochondrial function following treatment with PPD. Furthermore, PD inhibited the glutamate-induced morphological changes in the mitochondria and scavenged the mitochondrial and cytosolic reactive oxygen species (ROS) induced by glutamate. In addition, mitochondrial function was significantly improved in terms of mitochondrial membrane potential (MMP) and enhanced mitochondrial mass compared with the cells exposed to glutamate and not treated with PPD. Taken together, the findings of our study indicate that the

  14. Antiamnesic and neuroprotective effects of donepezil against learning impairments induced in mice by exposure to carbon monoxide gas.

    PubMed

    Meunier, Johann; Ieni, John; Maurice, Tangui

    2006-06-01

    Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the sigma1 receptor, an intracellular neuromodulatory protein. In the present study, we analyzed the antiamnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine, and galanthamine, and the reference sigma1 agonist igmesine. CO exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses. When injected 20 min before the behavioral tests, i.e., 7 to 8 days after CO, all drugs showed antiamnesic properties. Preadministration of the sigma1 receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) blocked only the igmesine and donepezil effects. The neuroprotective activity of the drugs was tested by injection 20 min before the first CO exposure (preinsult protection) or by injection 1 h after the last CO exposure (postinsult protection). All drugs alleviated the hypoxia-induced neurodegeneration and behavioral impairments when injected before CO exposure. Preadministration of BD1047 blocked both the igmesine and donepezil effects. However, when injected after CO exposure, only igmesine and donepezil induced effective neuroprotection, and the morphological and behavioral effects were BD1047-sensitive. These results showed that donepezil is a potent antiamnesic and neuroprotective compound against the neurodegeneration induced by excitotoxic insult, and its pharmacological actions as both an acetylcholinesterase inhibitor and sigma1 receptor agonist contribute to its marked efficacy. In particular, the drug is a more potent postinsult protecting agent compared with more selective cholinesterase inhibitors. PMID:16551835

  15. Neuroprotective effects of a sesquiterpene lactone and flavanones from Paulownia tomentosa Steud. against glutamate-induced neurotoxicity in primary cultured rat cortical cells.

    PubMed

    Kim, Soo-Ki; Cho, Sang-Buem; Moon, Hyung-In

    2010-12-01

    The neuroprotective effects of Paulownia tomentosa against glutamate-induced neurotoxicity were studied in primary cultured rat cortical cells. It was found that the aqueous extract of this medicinal plant significantly attenuated glutamate-induced toxicity. In order to clarify the mechanism(s) underlying this neuroprotective effect, the active fractions and components were isolated and identified. Five compounds were isolated as the methanol extracts from air-dried flowers of P. tomentosa. Isoatriplicolide tiglate exhibited significant neuroprotective activity against glutamate-induced toxicity at concentrations ranging from 1 μM to 10 μM, and exhibited cell viability of approximately 43-78%. Therefore, the neuroprotective effect of P. tomentosa might be due to the inhibition of glutamate-induced toxicity by the sesquiterpene lactone derivative it contains. PMID:20683844

  16. Chemically Bonding of Amantadine with Gardenamide A Enhances the Neuroprotective Effects against Corticosterone-Induced Insults in PC12 Cells

    PubMed Central

    Zhao, Jiaqiang; Peng, Lizhi; Zheng, Wenhua; Wang, Rikang; Zhang, Lei; Yang, Jian; Chen, Heru

    2015-01-01

    Two amantadine (ATD)-gardenamide A (GA) ligands have been designed and synthesized. The bonding of ATD with GA through a methylene carbonyl brigde (L1) enhances the neuroprotective effect against corticosterone (CORT)-induced impairments in PC12 cells; while the bonding through a succinyl brigde (L2) does not. L1 reduces the level of reactive oxygen species (ROS) and cell apoptosis generated by CORT. It restores CORT-changed cell morphology to a state that is closed to normal PC12 cells. One mechanism of L1 to attenuate CORT-induced cell apoptosis is through the adjustment of both caspase-3 and Bcl-2 proteins. Like GA, both nNOS and eNOS might be involved in the neuroprotective mechanism of L1. All the evidences suggest that L1 may be a potential agent to treat depression. PMID:26402670

  17. Inducible and Acquired Clarithromycin Resistance in the Mycobacterium abscessus Complex

    PubMed Central

    Rubio, Marc; March, Francesca; Garrigó, Montserrat; Moreno, Carmen; Español, Montserrat; Coll, Pere

    2015-01-01

    Purpose Clarithromycin was considered the cornerstone for the treatment of Mycobacterium abscessus complex infections. Genetic resistance mechanisms have been described and many experts propose amikacin as an alternative. Nevertheless, clarithromycin has several advantages; therefore, it is necessary to identify the non-functional erm(41) allele to determine the most suitable treatment. The aims of this study were to characterize the molecular mechanisms of clarithromycin resistance in a collection of Mycobacterium abscessus complex isolates and to verify the relationship between these mechanisms and the antibiogram. Materials and Methods Clinical isolates of M. abscessus complex (n = 22) from 16 patients were identified using four housekeeping genes (rpoB, secA1, sodA and hsp65), and their genetic resistance was characterized by studying erm(41) and rrl genes. Nine strains were recovered from the clinical isolates and subjected to E-test and microdilution clarithromycin susceptibility tests, with readings at 3, 7 and 14 days. Results We classified 11/16 (68.8%) M. abscessus subsp. abscessus, 4/16 (25.0%) M. abscessus subsp. bolletii, and 1/16 (6.3%) M. abscessus subsp. massiliense. T28 erm(41) allele was observed in 8 Mycobacterium abscessus subps. abscessus and 3 Mycobacterium abscessus subsp. bolletii. One strain of M. abscessus subsp. bolletii had an erm(41) gene truncated and was susceptible to clarithromycin. No mutations were observed in rrl gene first isolates. In three patients, follow-up of initial rrl wild-type strains showed acquired resistance. Conclusions Most clinical isolates of M. abscessus complex had inducible resistance to clarithromycin and total absence of constitutive resistance. Our findings showed that the acquisition of resistance mutations in rrl gene was associated with functional and non-functional erm(41) gene. Caution is needed when using erm(41) sequencing alone to identify M. abscessus subspecies. This study reports an acquired

  18. Neuroprotective effect of Decalepis hamiltonii in paraquat-induced neurotoxicity in Drosophila melanogaster: biochemical and behavioral evidences.

    PubMed

    Jahromi, Samaneh Reiszadeh; Haddadi, Mohammad; Shivanandappa, T; Ramesh, S R

    2013-12-01

    In this paper, we have demonstrated for the first time, the antioxidant and neuroprotective effects of Decalepis hamiltonii (Dh) root extract against paraquat (PQ)-induced oxidative stress and neurotoxicity in Drosophila melanogaster. Exposure of adult D. melanogaster (Oregon K) to PQ induced oxidative stress as evidenced by glutathione depletion, lipid peroxidation and enhanced activities of antioxidant enzymes such as catalase, superoxide dismutase as well as elevated levels of acetylcholine esterase. Pretreatment of flies by feeding with Dh extract (0.1, 0.5 %) for 14 days boosted the activities of antioxidant enzymes and prevented the PQ-induced oxidative stress. Dietary feeding of Dh extract prior to PQ exposure showed a lower incidence of mortality and enhanced motor activities of flies in a negative geotaxis assay; both suggesting the neuroprotective potential of Dh. Based on the results, we contemplate that the roots of Dh might prevent and ameliorate the human diseases caused by oxidative stress. The neuroprotective action of Dh can be attributed to the antioxidant constituents while the precise mechanism of its action needs further investigations. PMID:24173775

  19. Neuroprotective role of Withania somnifera root extract in maneb-paraquat induced mouse model of parkinsonism.

    PubMed

    Prakash, Jay; Yadav, Satyndra Kumar; Chouhan, Shikha; Singh, Surya Pratap

    2013-05-01

    Parkinson's disease (PD) is a neurodegenerative disorder and these days a lot of emphasis is given on the treatment of this disease using herbal medicines. The present study evaluates the neuroprotective effect of Withania somnifera (Ws) root extract on Parkinsonian mice. The mice were divided into three groups; the first group served as control, the second group was given maneb (MB) and paraquat (PQ) and the last group was administered MB-PQ along with Ws root extract for 3, 6 and 9 weeks. The behavioral studies showed a significant improvement in the motor movement patterns and gripping ability of Ws root extract exposed Parkinsonian mice. Tyrosine hydroxylase (TH) immunostaining was reduced in the substantia nigra of MB-PQ exposed mice, while Ws co-exposure restored TH immunostaining significantly. Additionally, our results also demonstrate generation of oxidative stress in the nigrostriatal region of MB-PQ exposed mice. There was a marked decline in the level of catalase and a simultaneous increase in the level of nitrite and lipid peroxidation in Parkinsonian mice. Thus, the Ws root extract have shown to counteract the pro-oxidants and their associated oxidative stress in the PD model studied here. Our results clearly indicate the usefulness of Ws root extract in providing protection against MB-PQ induced nigrostriatal dopaminergic neurodegeneration and marked improvement in the behavioral, anatomical and the biochemical deformities. PMID:23430469

  20. The Neuroprotective Effect of Gugijihwang-Tang on Trimethyltin-Induced Memory Dysfunction in the Rat

    PubMed Central

    Jung, Eun-Yee; Ahn, Chang Joon; Cho, Seung-Hun; Bae, Hyunsu; Shim, Insop

    2013-01-01

    Gugijihwang-Tang (the herbal formula PM012), a decoction consisting of several herbs including Rehmanniae Radix Preparata, has been widely used as herbal treatment for dementia. In order to investigate the neuroprotective action of this prescription, we examined the effect of Gugijihwang-Tang on learning and memory using the Morris water maze and [F-18]FDG micro PET neuroimaging technique. After injection of trimethyltin (TMT, 8.0 mg/kg, i.p.), which is a potent toxicant that selectively kills cells in the central nervous system, rats were administered Gugijihwang-Tang (100 mg/kg, p.o.) daily for two weeks, followed by the Morris water maze tasks and [F-18]FDG micro PET neuroimaging. In Gugijihwang-Tang administered TMT-treated rats, they showed improved learning and memory abilities in water maze tasks and glucose metabolism, suggesting that Gugijihwang-Tang plays effectively positive role in the improvement of brain function including learning and memory after TMT-induced neurodegeneration. Taken together, our results suggested that the Gugijihwang-Tang should be useful for developing strategies protecting nervous system and improving brain function. PMID:23861706

  1. SIRT3 Acts as a Neuroprotective Agent in Rotenone-Induced Parkinson Cell Model.

    PubMed

    Zhang, Jing-Yi; Deng, Yong-Ning; Zhang, Meng; Su, Hua; Qu, Qiu-Min

    2016-07-01

    SIRT3 is a member of Sirtuins family, which belongs to NAD(+) dependent class III histone deacetylases. Emerging evidence suggests that SIRT3 plays a pivotal role in regulating mitochondrial function. Mitochondrial dysfunction is a main pathogenesis of Parkinson's disease (PD). Here, we have investigated the protective effect of SIRT3 for PD cell model. The rotenone-induced human neuroblastoma SH-SY5Y cells damage was used as PD cell model. The lentiviral vectors were used to over-expression or knockdown SIRT3 expression. The cell viability was analyzed using MTT method. The apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were measured by flow cytometer. Superoxide dismutase (SOD) and glutathione (GSH) were detected by using automated microplate reader. The accumulation of α-synuclein was determined by immunofluorescence staining. SIRT3 knockdown significantly worsen rotenone-induced decline of cell viability (p < 0.01) and enhanced cell apoptosis (p < 0.01), exacerbated the decrease of SOD (p < 0.05) and GSH (p < 0.05), and augmented the accumulation of α-synuclein (p < 0.05). While SIRT3 overexpression dramatically increased cell viability (p < 0.01), and decreased cell apoptosis (p < 0.01), prevented the accumulation of α-synuclein (p < 0.05), suppressed the reducing of SOD (p < 0.05) and GSH (p < 0.01), decreased ROS generation (p < 0.05), and alleviated MMP collapse (p < 0.01) induced by rotenone. SIRT3 has neuroprotective effect in PD cell model and could be developed into a therapeutic agent for PD patients. PMID:27053302

  2. Neuroprotective activity of L-theanine on 3-nitropropionic acid-induced neurotoxicity in rat striatum.

    PubMed

    Thangarajan, Sumathi; Deivasigamani, Asha; Natarajan, Suganya Sarumani; Krishnan, Prasanna; Mohanan, Sandhya Koombankallil

    2014-09-01

    The present study has been designed to investigate the protective effect of L-theanine against 3-nitropropionic acid (3-NP)-induced Huntington's disease (HD)-like symptoms in rats. The present experimental protocol design includes systemic 3-NP acid (10 mg/kg intraperitonially) treatment for 14 d. L-theanine (100 and 200 mg/kg) was given orally, once a day, 1 h before 3-NP acid treatment for 14 d. Body weight and behavioral parameters (Morris water maze, open field test (OFT), forced swim test (FST) and rotarod activity) were assessed on 1st, 5th, 10th and 15th day post-3-NP acid administration. Malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels and mitochondrial enzyme complex. Succinate dehydrogenase (SDH) were measured on the 15th day in the striatum. Systemic 3-NP acid treatment significantly reduced body weight, locomotor activity and oxidative defense. The mitochondrial enzyme activity was also significantly impaired in the striatum region in 3-NP acid-treated animals. L-theanine (100 and 200 mg/kg b.wt.) treatment significantly attenuated the impairment in behavioral, biochemical and mitochondrial enzyme activities as compared to the 3-NP acid-treated group. The results of the present study suggest that pretreatment with L-theanine significantly attenuated 3-NP induced oxidative stress and restored the decreased SOD, GSH, CAT and SDH activity. It also decreased the neuronal damage as evidenced by histopathological analysis of striatum. Based on the above study, it has been proved that L-theanine has neuroprotective activity against 3-NP induced neurotoxicity. PMID:24325390

  3. Design, synthesis and biological evaluation of novel chiral oxazino-indoles as potential and selective neuroprotective agents against Aβ25-35-induced neuronal damage.

    PubMed

    Chen, Jing; Tao, Ling-Xue; Xiao, Wei; Ji, Sha-Sha; Wang, Jian-Rong; Li, Xu-Wen; Zhang, Hai-Yan; Guo, Yue-Wei

    2016-08-01

    A series of chiral oxazino-indoles have been synthesized via a key intermolecular oxa-Pictet-Spengler reaction. These compounds exhibited significant and selective neuroprotective effects against Aβ25-35-induced neuronal damage. This is the first report of evaluating the influence of chiral diversity of oxazino-indoles on their neuroprotective activities, with the structure-activity relationship been analyzed. The highly active compounds 3f, 3g, 4g, 4h, and 6b all performed over 90% cell protection, providing a new direction for the development of neuroprotective agents against Alzheimer's disease. PMID:27301369

  4. Exercise-induced neuroprotection in the spastic Han Wistar rat: the possible role of brain-derived neurotrophic factor.

    PubMed

    Van Kummer, Brooke H; Cohen, Randy W

    2015-01-01

    Moderate aerobic exercise has been shown to enhance motor skills and protect the nervous system from neurodegenerative diseases, like ataxia. Our lab uses the spastic Han Wistar rat as a model of ataxia. Mutant rats develop forelimb tremor and hind limb rigidity and have a decreased lifespan. Our lab has shown that exercise reduced Purkinje cell degeneration and delayed motor dysfunction, significantly increasing lifespan. Our study investigated how moderate exercise may mediate neuroprotection by analyzing brain-derived neurotrophic factor (BDNF) and its receptor TrkB. To link BDNF to exercise-induced neuroprotection, mutant and normal rats were infused with the TrkB antagonist K252a or vehicle into the third ventricle. During infusion, rats were subjected to moderate exercise regimens on a treadmill. Exercised mutants receiving K252a exhibited a 21.4% loss in Purkinje cells compared to their controls. Cerebellar TrkB expression was evaluated using non-drug-treated mutants subjected to various treadmill running regimens. Running animals expressed three times more TrkB than sedentary animals. BDNF was quantified via Sandwich ELISA, and cerebellar expression was found to be 26.6% greater in mutant rats on 7-day treadmill exercise regimen compared to 30 days of treadmill exercise. These results suggest that BDNF is involved in mediating exercise-induced neuroprotection. PMID:25710032

  5. Enhanced Neuroprotection of Minimally Invasive Surgery Joint Local Cooling Lavage against ICH-induced Inflammation Injury and Apoptosis in Rats.

    PubMed

    Liu, Xi-Chang; Jing, Li-Yan; Yang, Ming-Feng; Wang, Kun; Wang, Yuan; Fu, Xiao-Yan; Fang, Jie; Hou, Ya-Jun; Sun, Jing-Yi; Li, Da-Wei; Zhang, Zong-Yong; Mao, Lei-Lei; Tang, You-Mei; Fu, Xiao-Ting; Fan, Cun-Dong; Yang, Xiao-Yi; Sun, Bao-Liang

    2016-07-01

    Hypothermia treatment is one of the neuroprotective strategies that improve neurological outcomes effectively after brain damage. Minimally invasive surgery (MIS) has been an important treatment of intracerebral hemorrhage (ICH). Herein, we evaluated the neuroprotective effect and mechanism of MIS joint local cooling lavage (LCL) treatment on ICH via detecting the inflammatory responses, oxidative injury, and neuronal apoptosis around the hematoma cavity in rats. ICH model was established by type IV collagenase caudatum infusion. The rats were treated with MIS 6 h after injection, and then were lavaged by normothermic (37 °C) and hypothermic (33 °C) normal saline in brain separately. The results indicated that MIS joint LCL treatment showed enhanced therapeutic effects against ICH-induced inflammation injury and apoptosis in rats, as convinced by the decline of TUNEL-positive cells, followed by the decrease of IL-1β and LDH and increase of IL-10 and SOD. This study demonstrated that the strategy of using MIS joint LCL may achieve enhanced neuroprotection against ICH-induced inflammation injury and apoptosis in rats with potential clinic application. PMID:26224360

  6. Neuroprotective Effects of Germinated Brown Rice in Rotenone-Induced Parkinson's-Like Disease Rats.

    PubMed

    Chompoopong, Supin; Jarungjitaree, Sunit; Punbanlaem, Tideeporn; Rungruang, Thanaporn; Chongthammakun, Sukumal; Kettawan, Aikkarach; Taechowisan, Thongchai

    2016-09-01

    The effects of germinated brown rice (GBR) on the motor deficits and the dopaminergic (DA) cell death were investigated in Parkinson's-like disease (PD) rats. Reactive oxidative species generated by chronic subcutaneous injection of rotenone (RT) lead to neuronal apoptosis particularly in the nigrostriatal DA system and produce many features of PD, bradykinesis, postural instability and rigidity. In this study, 4-phenylbutyric acid (4-PBA), previously reported to inhibit RT-induced DA cell death, was used as the positive control. Results show that pretreatment with GBR as well as 4-PBA significantly enhanced the motor activity after RT injection, and GBR affected significantly in open field test, only in the ambulation but not the mobility duration, and ameliorated the time to orient down (t-turn) and total time to descend the pole (t-total) in pole test as compared to RT group, but significantly lowered both t-turn and t-total only in 4-PBA group. The percentage of apoptotic cells in brain measured by flow cytometry and the inflammatory effect measured by ELISA of TNF-α showed significant increase in RT group as compared to the control (CT) group at P < 0.05. Apoptotic cells in RT group (85.98 %) showed a significant (P < 0.05) increase versus CT group (17.50 %), and this effect was attenuated in GBR+RT group by decreasing apoptotic cells (79.32 %), whereas, increased viable cells (17.94 %) versus RT group (10.79 %). GBR in GBR + RT group could decrease TNF-α both in the serum and in brain. In summary, GBR showed a neuroprotective effect in RT-induced PD rats, and it may be useful as a value-added functional food to prevent neurodegenerative disease or PD. PMID:27430236

  7. Failure and rescue of preconditioning-induced neuroprotection in severe stroke-like insults.

    PubMed

    Tauskela, Joseph S; Aylsworth, Amy; Hewitt, Melissa; Brunette, Eric; Blondeau, Nicolas

    2016-06-01

    Preconditioning is a well established neuroprotective modality. However, the mechanism and relative efficacy of neuroprotection between diverse preconditioners is poorly defined. Cultured neurons were preconditioned by 4-aminopyridine and bicuculline (4-AP/bic), rendering neurons tolerant to normally lethal (sufficient to kill most neurons) oxygen-glucose deprivation (OGD) or a chemical OGD-mimic, ouabain/TBOA, by suppression of extracellular glutamate (glutamateex) elevations. However, subjecting preconditioned neurons to longer-duration supra-lethal insults caused neurotoxic glutamateex elevations, thereby identifying a 'ceiling' to neuroprotection. Neuroprotective 'rescue' of neurons could be obtained by administration of an NMDA receptor antagonist, MK-801, just before glutamateex rose during these supra-lethal insults. Next, we evaluated if these concepts of glutamateex suppression during lethal OGD, and a neuroprotective ceiling requiring MK-801 rescue under supra-lethal OGD, extended to the preconditioning field. In screening a panel of 42 diverse putative preconditioners, neuroprotection against normally lethal OGD was observed in 12 cases, which correlated with glutamateex suppression, both of which could be reversed, either by the inclusion of a glutamate uptake inhibitor (TBOA, to increase glutamateex levels) during OGD or by exposure to supra-lethal OGD. Administrating MK-801 during the latter stages of supra-lethal OGD again rescued neurons, although to varying degrees dependent on the preconditioning agent. Thus, 'stress-testing' against the harshest ischemic-like insults yet tested identifies the most efficacious preconditioners, which dictates how early MK-801 needs to be administered during the insult in order to maintain neuroprotection. Preconditioning delays a neurotoxic rise in glutamateex levels, thereby 'buying time' for acute anti-excitotoxic pharmacologic rescue. PMID:26867506

  8. MLC901, a Traditional Chinese Medicine induces neuroprotective and neuroregenerative benefits after traumatic brain injury in rats.

    PubMed

    Quintard, H; Lorivel, T; Gandin, C; Lazdunski, M; Heurteaux, C

    2014-09-26

    Traumatic brain injury (TBI) is a frequent and clinically highly heterogeneous neurological disorder with large socioeconomic consequences. NeuroAid (MLC601 and MLC901), a Traditional Medicine used in China for patients after stroke has been previously reported to induce neuroprotection and neuroplasticity. This study was designed to evaluate the neuroprotective and neuroregenerative effects of MLC901 in a rat model of TBI. TBI was induced by a moderate lateral fluid percussion applied to the right parietal cortex. MLC901 was injected intraperitoneally at 2h post-TBI, and then administered in drinking water at a concentration of 10mg/ml until sacrifice of the animals. The cognitive deficits induced by TBI were followed by using the "what-where-when" task, which allows the measurement of episodic-like memory. MLC901 treatment decreased brain lesions induced by TBI. It prevented the serum increase of S-100 beta (S100B) and neuron-specific enolase (NSE), which may be markers to predict the neurologic outcome in human patients with TBI. MLC901 reduced the infarct volume when injected up to 2h post-TBI, prevented edema formation and assisted its resolution, probably via the regulation of aquaporin 4. These positive MLC901 effects were associated with an upregulation of vascular endothelial growth factor (VEGF) as well as an increase of endogenous hippocampal neurogenesis and gliogenesis around the lesion. Furthermore, MLC901 reduced cognitive deficits induced by TBI. Rats subjected to TBI displayed a suppression of temporal order memory, which was restored by MLC901. This work provides evidence that MLC901 has neuroprotective and neurorestorative actions, which lead to an improvement in the recovery of cognitive functions in a model of traumatic brain injury. PMID:24993477

  9. Neuroprotective Effects of Dexmedetomidine Against Hypoxia-Induced Nervous System Injury are Related to Inhibition of NF-κB/COX-2 Pathways.

    PubMed

    Pan, Wanying; Lin, Lin; Zhang, Nan; Yuan, Fuli; Hua, Xiaoxiao; Wang, Yueting; Mo, Liqiu

    2016-10-01

    Dexmedetomidine has been reported to provide neuroprotection against hypoxia-induced damage. However, the underlying mechanisms remain unclear. We examined whether dexmedetomidine's neuroprotective effects were mediated by the NF-κB/COX-2 pathways. Adult male C57BL/6 mice were subjected to a 30-min hypoxic treatment followed by recovery to normal conditions. They received dexmedetomidine (16 or 160 μg/kg) or 25 mg/kg atipamezole, an α2-adrenoreceptor antagonist, intraperitoneally before exposure to hypoxia. The whole brain was harvested 6, 18, or 36 h after the hypoxia to determine the histopathological outcome and cleaved caspase-3, Bax/Bcl, NF-κB, and COX-2 levels. Hypoxia treatment induced significant neurotoxicity, including destruction of the tissue structure and upregulation of the protein levels of caspase-3, the ratio of Bax/Bcl-2, NF-κB, and COX-2. Dexmedetomidine pretreatment effectively improved histological outcome and restored levels of caspase-3, the Bax/Bcl-2 ratio, NF-κB, and COX-2. Atipamezole reversed the neuroprotection induced by dexmedetomidine. Neuroprotection was achieved by PDTC and NS-398, inhibitors of NF-κB and COX-2, respectively. Dexmedetomidine use before hypoxia provides neuroprotection. Inhibition of NF-κB/COX-2 pathways activation may contribute to the neuroprotection of dexmedetomidine. PMID:26683659

  10. Treatment with an activator of hypoxia-inducible factor 1, DMOG provides neuroprotection after traumatic brain injury.

    PubMed

    Sen, Tanusree; Sen, Nilkantha

    2016-08-01

    Traumatic brain injury (TBI) is one of the major cause of morbidity and mortality and it affects more than 1.7 million people in the USA. A couple of regenerative pathways including activation of hypoxia-inducible transcription factor 1 alpha (HIF-1α) are initiated to reduce cellular damage following TBI; however endogenous activation of these pathways is not enough to provide neuroprotection after TBI. Thus we aimed to see whether sustained activation of HIF-1α can provide neuroprotection and neurorepair following TBI. We found that chronic treatment with dimethyloxaloylglycine (DMOG) markedly increases the expression level of HIF-1α and mRNA levels of its downstream proteins such as Vascular endothelial growth factor (VEGF), Phosphoinositide-dependent kinase-1 and 4 (PDK1, PDK4) and Erythropoietin (EPO). Treatment of DMOG activates a major cell survival protein kinase Akt and reduces both cell death and lesion volume following TBI. Moreover, administration of DMOG augments cluster of differentiation 31 (CD31) staining in pericontusional cortex after TBI, which suggests that DMOG stimulates angiogenesis after TBI. Treatment with DMOG also improves both memory and motor functions after TBI. Taken together our results suggest that sustained activation of HIF-1α provides significant neuroprotection following TBI. PMID:26970014

  11. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer's disease.

    PubMed

    Balez, Rachelle; Steiner, Nicole; Engel, Martin; Muñoz, Sonia Sanz; Lum, Jeremy Stephen; Wu, Yizhen; Wang, Dadong; Vallotton, Pascal; Sachdev, Perminder; O'Connor, Michael; Sidhu, Kuldip; Münch, Gerald; Ooi, Lezanne

    2016-01-01

    Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, yet current therapeutic treatments are inadequate due to a complex disease pathogenesis. The plant polyphenol apigenin has been shown to have anti-inflammatory and neuroprotective properties in a number of cell and animal models; however a comprehensive assessment has not been performed in a human model of AD. Here we have used a human induced pluripotent stem cell (iPSC) model of familial and sporadic AD, in addition to healthy controls, to assess the neuroprotective activity of apigenin. The iPSC-derived AD neurons demonstrated a hyper-excitable calcium signalling phenotype, elevated levels of nitrite, increased cytotoxicity and apoptosis, reduced neurite length and increased susceptibility to inflammatory stress challenge from activated murine microglia, in comparison to control neurons. We identified that apigenin has potent anti-inflammatory properties with the ability to protect neurites and cell viability by promoting a global down-regulation of cytokine and nitric oxide (NO) release in inflammatory cells. In addition, we show that apigenin is able to protect iPSC-derived AD neurons via multiple means by reducing the frequency of spontaneous Ca(2+) signals and significantly reducing caspase-3/7 mediated apoptosis. These data demonstrate the broad neuroprotective action of apigenin against AD pathogenesis in a human disease model. PMID:27514990

  12. A single fraction from Uncaria sinensis exerts neuroprotective effects against glutamate-induced neurotoxicity in primary cultured cortical neurons.

    PubMed

    Kim, Ha Neui; Jang, Ji Yeon; Choi, Byung Tae

    2015-06-01

    We identified a neuroprotective single fraction among 62 ones of hexane extract from Uncaria sinensis (JGH43IA) and investigated its effects and mechanisms in primary cortical neurons. Pretreatment with JGH43IA showed a significantly increase cell viability in a dose-dependent manner with a decrease in the lactate dehydrogenase release. When we performed morphological assay and flow cytometry to determination of the type of cell death, pretreatment with JGH43IA showed a significant reduction of glutamate-induced apoptotic cell death. Then we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation to elucidate possible pathways of neuroprotection by JGH43IA. Pretreatment with JGH43IA exhibited a significant attenuation of NMDAR GluN2B subunit activation and a decrease in active form of calpain 1 leading to subsequent cleavage of striatal-enriched protein tyrosine phosphatase (STEP). In addition, pretreatment with JGH43IA showed a marked increase of cAMP responsive element binding protein. These results suggest that JGH43IA may have neuroprotective effects through down-regulation of NMDAR GluN2B subunit and calpain 1 activation, and subsequent alleviation of STEP cleavage. This single fraction from U. sinensis might be a useful therapeutic agent for brain disorder associated with glutamate injury. PMID:26140220

  13. A single fraction from Uncaria sinensis exerts neuroprotective effects against glutamate-induced neurotoxicity in primary cultured cortical neurons

    PubMed Central

    Kim, Ha Neui; Jang, Ji Yeon

    2015-01-01

    We identified a neuroprotective single fraction among 62 ones of hexane extract from Uncaria sinensis (JGH43IA) and investigated its effects and mechanisms in primary cortical neurons. Pretreatment with JGH43IA showed a significantly increase cell viability in a dose-dependent manner with a decrease in the lactate dehydrogenase release. When we performed morphological assay and flow cytometry to determination of the type of cell death, pretreatment with JGH43IA showed a significant reduction of glutamate-induced apoptotic cell death. Then we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation to elucidate possible pathways of neuroprotection by JGH43IA. Pretreatment with JGH43IA exhibited a significant attenuation of NMDAR GluN2B subunit activation and a decrease in active form of calpain 1 leading to subsequent cleavage of striatal-enriched protein tyrosine phosphatase (STEP). In addition, pretreatment with JGH43IA showed a marked increase of cAMP responsive element binding protein. These results suggest that JGH43IA may have neuroprotective effects through down-regulation of NMDAR GluN2B subunit and calpain 1 activation, and subsequent alleviation of STEP cleavage. This single fraction from U. sinensis might be a useful therapeutic agent for brain disorder associated with glutamate injury. PMID:26140220

  14. Neuroprotective effect of estradiol-loaded poly(lactic-co-glycolic acid) nanoparticles on glutamate-induced excitotoxic neuronal death.

    PubMed

    Kim, Jeong Hwan; Kim, Gyu Hyun; Jeong, Ji Heun; Lee, In Ho; Lee, Ye Ji; Lee, Nam Seob; Jeong, Young Gil; Lee, Je Hun; Yu, Kwang Sik; Lee, Shin Hye; Hong, Seul Ki; Kang, Seong Hee; Kang, Bo Sun; Kim, Do Kyung; Han, Seung Yun

    2014-11-01

    Different concentrations of estradiol (E2)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (E2-PLGA-NPs) were synthesized using the emulsion-diffusion method. Transmission electron microscopy results showed that the average particle size of E2-PLGA-NPs was 98 ± 1.9 nm when stabilized with polyvinyl alcohol and 103 ± 4.9 nm when stabilized with Tween-80. Fourier transform-infrared spectroscopy with diamond attenuated total reflectance was used to identify the presence or absence of E2 molecules in PLGA nanocapsules. Cell proliferation was assessed after treating SH-SY5Y neuroblastoma cells with 1 nM-1 μM of E2 and E2-PLGA-NPs. The neuroprotective efficacy against glutamate-induced excitotoxicity was also investigated in SH-SY5Y neuroblastoma cells. Neuroprotection was greater in E2-PLGA-NP-treated cells than in cells treated with the same concentration of E2. Furthermore, E2- and E2-PLGA-NP-treated cells expressed more p-ERK1/2 and p-CREB than cells treated with glutamate only. Moreover, the expression of p-ERK1/2 was higher than that of p-CREB. In this study, p-ERK1/2 had a greater influence on the neuroprotective effect of E2 and E2-PLGA-NPs than p-CREB. PMID:25958534

  15. Neuroprotective Actions of Clinoptilolite and Ethylenediaminetetraacetic Acid Against Lead-induced Toxicity in Mice Mus musculus

    PubMed Central

    Basha, Mahaboob P.; Begum, Shabana; Mir, Bilal Ahmed

    2013-01-01

    Objectives: Oxidative stress is considered as a possible molecular mechanism involved in lead (Pb2+) neurotoxicity. Very few studies have been investigated on the occurrence of oxidative stress in developing animals due to Pb2+ exposure. Considering the vulnerability of the developing brain to Pb2+, this study was carried out to investigate the effects of Pb2+ exposure in brain regions especially on antioxidant enzyme activities along with ameliorative effects of ethylenediaminetetraacetic acid (EDTA) and clinoptilolite. Methods: Three-week old developing Swiss mice Mus musculus were intraperitoneally administered with Pb2+ acetate in water (w/v) (100 mg/kg body weight/day) for 21 days and control group was given distilled water. Further Pb2+-toxicated mice were made into two subgroups and separately supplemented with EDTA and clinoptilolite (100 mg/kg body weight) for 2 weeks. Results: In Pb2+-exposed mice, in addition to increased lipid peroxidation, the activity levels of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH) found to decrease in all regions of brain indicating, existence of severe oxidative stress due to decreased antioxidant function. Treatment of Pb2+-exposed mice with EDTA and clinoptilolite lowered the lipid peroxidation (LPO) levels revealing their antioxidant potential to prevent oxidative stress. Similarly their administration led to recover the level of catalase, SOD, and GPx enzymes affected during Pb2+ toxicity in different regions of brain. Conclusions: The protection of brain tissue against Pb2+-induced toxicity by clinoptilolite and EDTA in the present experiment might be due to their ability to react faster with peroxyl radicals there by reducing the severity of biochemical variable indicative of oxidative damage. Thus, the results of present study indicate the neuroprotective potential of clinoptilolite and EDTA against Pb2+ toxicity. PMID:24403728

  16. Aquaporin-4 Inhibition Mediates Piroxicam-Induced Neuroprotection against Focal Cerebral Ischemia/Reperfusion Injury in Rodents

    PubMed Central

    Paul, Sudip; Patnaik, Ranjana

    2013-01-01

    Background and Purpose Aquaporin-4(AQP4) is an abundant water channel protein in brain that regulates water transport to maintain homeostasis. Cerebral edema resulting from AQP4 over expression is considered to be one of the major determinants for progressive neuronal insult during cerebral ischemia. Although, both upregulation and downregulation of AQP4 expression is associated with brain pathology, over expression of AQP4 is one of the chief contributors of water imbalance in brain during ischemic pathology. We have found that Piroxicam binds to AQP4 with optimal binding energy value. Thus, we hypothesized that Piroxicam is neuroprotective in the rodent cerebral ischemic model by mitigating cerebral edema via AQP4 regulation. Methods Rats were treated with Piroxicam OR placebo at 30 min prior, 2 h post and 4 h post 60 minutes of MCAO followed by 24 hour reperfusion. Rats were evaluated for neurological deficits and motor function just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, RT-PCR and western blot experiments. Results Piroxicam pretreatment thirty minutes prior to ischemia and four hour post reperfusion afforded neuroprotection as evident through significant reduction in cerebral infarct volume, improvement in motor behavior, neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde were also found to be significantly reduced in ischemic brain regions in treated animals. This neuroprotection was found to be associated with inhibition of acid mediated rise in intracellular calcium levels and also downregulated AQP4 expression. Conclusions Findings of the present study provide significant evidence that Piroxicam acts as a potent AQP4 regulator and renders neuroprotection in focal cerebral ischemia. Piroxicam could be clinically exploited for the treatment of brain stroke along with other anti-stroke therapeutics in

  17. Neuroprotective effects of Gymnema sylvestre on streptozotocin-induced diabetic neuropathy in rats

    PubMed Central

    FATANI, AMAL JAMIL; AL-REJAIE, SALIM SALIH; ABUOHASHISH, HATEM MUSTAFA; AL-ASSAF, ABDULLAH; PARMAR, MIHIR YOGESHKUMAR; OLA, MOHAMMAD SHAMSUL; AHMED, MOHAMMED MAHBOOBUDDIN

    2015-01-01

    The application of traditional medicine for diabetes and associated complications, such as diabetic neuropathy (DN), has received increasing attention. The aim of the present study was to investigate the potential ameliorative effect of Gymnema sylvestre (Gs) in a rat model of DN. Diabetes was induced via a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg). Treatment with Gs extract (50 or 100 mg/kg/day) began two weeks following the administration of STZ and was continued for five weeks. Pain threshold behavior tests were performed subsequent to the five-week Gs treatment period. In addition, the serum levels of glucose, insulin and proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, were determined. Furthermore, the sciatic tissue levels of nitric oxide, thiobarbituric acid reactive substances and reduced glutathione were determined, as well as the activity levels of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. Levels of insulin-like growth factor (IGF), nerve growth factor (NGF), TNF-α, IL-1β and IL-6 were also assessed in the sciatic tissue. In addition, the sciatic nerve tissue samples were analyzed for histopathological alterations. The diabetic rats exhibited apparent reductions in the paw-withdrawal (31%; P<0.01) and tail-flick latencies (38%; P<0.05). Furthermore, the diabetic rats demonstrated an evident elevation in serum and sciatic levels of proinflammatory cytokines. Measured oxidative stress biomarkers were significantly altered in the sciatic nerve tissue of the diabetic rats. Treatment with Gs attenuated diabetes-induced modifications with regard to the levels of serum glucose, insulin and proinflammatory cytokines. In the sciatic nerve tissue, the diabetes-induced alterations in IL levels and oxidative stress biomarkers were significantly improved in the Gs-treated rats. Furthermore, the reduction in the sciatic tissue expression levels of IGF

  18. Neuroprotective Effects of Endurance Exercise Against High-Fat Diet-Induced Hippocampal Neuroinflammation.

    PubMed

    Kang, E-B; Koo, J-H; Jang, Y-C; Yang, C-H; Lee, Y; Cosio-Lima, L M; Cho, J-Y

    2016-05-01

    Obesity contributes to systemic inflammation, which is associated with the varied pathogenesis of neurodegenerative diseases. Growing evidence has demonstrated that endurance exercise (EE) mitigates obesity-induced brain inflammation. However, exercise-mediated anti-inflammatory mechanisms remain largely unknown. We investigated how treadmill exercise (TE) reverses obesity-induced brain inflammation, mainly focusing on toll-like receptor-4 (TLR-4)-dependent neuroinflammation in the obese rat brain after 20 weeks of a high-fat diet (HFD). TE in HFD-fed rats resulted in a significant lowering in the homeostasis model assessment of insulin resistance index, the area under the curve for glucose and abdominal visceral fat, and also improved working memory ability in a passive avoidance task relative to sedentary behaviour in HFD-fed rats, with the exception of body weight. More importantly, TE revoked the increase in HFD-induced proinflammatory cytokines (tumour necrosis factor α and interleukin-1β) and cyclooxygenase-2, which is in parallel with a reduction in TLR-4 and its downstream proteins, myeloid differentiation 88 and tumour necrosis factor receptor associated factor 6, and phosphorylation of transforming growth factor β-activated kinase 1, IkBα and nuclear factor-κB. Moreover, TE reduced an indicator of microglia activation, ionised calcium-binding adapter molecule-1, and also decreased glial fibrillary acidic protein, an indicator of gliosis formed by activated astrocytes in the cerebral cortex and the hippocampal dentate gyrus, compared to HFD-fed sedentary rats. Finally, EE up-regulated the expression of anti-apoptotic protein, Bcl-2, and suppressed the expression of pro-apoptotic protein, Bax, in the hippocampus compared to HFD-fed sedentary rats. Taken together, these data suggest that TE may exert neuroprotective effects as a result of mitigating the production of proinflammatory cytokines by inhibiting the TLR4 signalling pathways. The results of

  19. Neuroprotective effects of purslane herb aquenous extracts against D-galactose induced neurotoxicity.

    PubMed

    Hongxing, Zhang; Nancai, Yu; Guofu, Huang; Jianbo, Shao; Yanxia, Wu; Hanju, Huang; Qian, Liu; Wei, Ma; Yandong, Yi; Hao, Huang

    2007-12-15

    In order to evaluate mechanisms of natural plant purslane herb aquenous extracts (PHAS) for neuroprotective, we assessed neuroprotective effects of PHAS at doses of 2.5, 5 and 10 mg/(kg day) on SD mice injected daily with D-gal (50 mg/(kg day)) by behavioral tests. PHAS-fed mice showed higher activity upon induction by new environmental stimuli, lower anxiety and higher novelty-seeking behavior in the open field tasks, and significantly improved learning and memory ability in step-through compared with D-gal-treated mice. We further examined the mechanisms involved in neuroprotective effects of PHAS on mouse brain. PHAS significantly increased superoxide dismutase (SOD) activity and decreased the malondialdehyde (MDA) level. Meanwhile, PHAS also could up-regulate telomere lengths and telomerase activity in PHAS-fed groups. Furthermore, we examined the expression of p21(waf1) and p53 mRNA and protein in mouse brain by western blot analysis and real-time RT-PCR. We found that p21(waf1)was down-regulated by PHAS without changing the expression of p53. The results of this study suggested that the PHAS might be a primary target of p21(waf1)and the neuroprotective effect of PHAS might be carried out through a p21(waf1)-dependent and p53-independent pathway. PMID:17764668

  20. p120-catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease.

    PubMed

    Uribe-Arias, Alejandro; Posada-Duque, Rafael Andrés; González-Billault, Christian; Villegas, Andrés; Lopera, Francisco; Cardona-Gómez, Gloria Patricia

    2016-08-01

    Cyclin-dependent kinase 5 (CDK5) plays important roles in synaptic function. Its unregulated over-activation has been, however, associated with neurodegeneration in Alzheimer's disease. Our previous studies revealed that CDK5 silencing ameliorates tauopathy and spatial memory impairment in the 3xTgAD mouse model. However, how CDK5 targeting affects synaptic adhesion proteins, such as those involved in the cadherin/catenin system, during learning and memory processes is not completely understood. In this study, we detected reduced expression of p120 catenin (p120 ctn), N-cadherin, and β-catenin in the brain of human Alzheimer's disease patients, in addition to a reduced PSD95 and GluN2B protein levels in a 3xTgAD mouse model. Such decrease in synaptic proteins was recovered by CDK5 silencing in mice leading to a better learning and memory performance. Additionally, CDK5 inhibition or knockout increased p120 ctn levels. Moreover, in a glutamate-induced excitotoxicity model, CDK5 silencing-induced neuroprotection depended on p120 ctn. Together, those findings suggest that p120 ctn plays an important role in the neuronal dysfunction of Alzheimer's disease models and contributes to CDK5 silencing-induced neuroprotection and improvement of memory function. p120ctn is part of the synaptic adhesion molecular complex N-cadh/p120ctn/B-ctn/PSD95, and it has a pivotal role in cell adhesion stabilization and dendritic spine modulation. Our data show that synaptic adhesion complex is affected in AD human brains and in AD models. This complex is recovered by the silencing of CDK5, preventing memory dysfunction in an AD mice model and contributing to the neuroprotection in a depend-mode of p120ctn. PMID:27273428

  1. Discovery of a novel neuroprotectant, BHDPC, that protects against MPP+/MPTP-induced neuronal death in multiple experimental models.

    PubMed

    Chong, Cheong-Meng; Ma, Dan; Zhao, Chao; Franklin, Robin J M; Zhou, Zhong-Yan; Ai, Nana; Li, Chuwen; Yu, Huidong; Hou, Tingjun; Sa, Fei; Lee, Simon Ming-Yuen

    2015-12-01

    Progressive degeneration and death of neurons are main causes of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Although some current medicines may temporarily improve their symptoms, no treatments can slow or halt the progression of neuronal death. In this study, a pyrimidine derivative, benzyl 7-(4-hydroxy-3-methoxyphenyl)-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (BHDPC), was found to attenuate dramatically the MPTP-induced death of dopaminergic neurons and improve behavior movement deficiency in zebrafish, supporting its potential neuroprotective activity in vivo. Further study in rat organotypic cerebellar cultures indicated that BHDPC was able to suppress MPP(+)-induced cell death of brain tissue slices ex vivo. The protective effect of BHDPC against MPP(+) toxicity was also effective in human neuroblastoma SH-SY5Y cells through restoring abnormal changes in mitochondrial membrane potential and numerous apoptotic regulators. Western blotting analysis indicated that BHDPC was able to activate PKA/CREB survival signaling and further up-regulate Bcl2 expression. However, BHDPC failed to suppress MPP(+)-induced cytotoxicity and the increase of caspase 3 activity in the presence of the PKA inhibitor H89. Taken together, these results suggest that BHDPC is a potential neuroprotectant with prosurvival effects in multiple models of neurodegenerative disease in vitro, ex vivo, and in vivo. PMID:26415025

  2. Transient expression of Nxf, a bHLH-PAS transactivator induced by neuronal preconditioning, confers neuroprotection in cultured cells.

    PubMed

    Hester, Ian; McKee, Sarah; Pelletier, Phillip; Thompson, Charles; Storbeck, Christopher; Mears, Alan; Schulz, Jörg B; Hakim, Antoine A; Sabourin, Luc A

    2007-03-01

    Cortical spreading depression (CSD) induces waves of neuronal depolarization that confer neuroprotection to subsequent ischemic events in the rat brain. To gain insights into the molecular mechanisms elicited by CSD, we used representational difference analysis (RDA) to identify mRNAs induced by potassium depolarization in vivo. Using this approach, we have isolated a cDNA encoding the SIM2-related bHLH-PAS protein Nxf. Our results confirm that Nxf mRNA and protein are rapidly and transiently expressed in cortical neurons following CSD. Reporter assays show that Nxf is a transcriptional activator that associates with the bHLH-PAS sub-class co-factor ARNT2. Adenovirus-mediated expression of epitope-tagged Nxf results in cell death and the direct activation of the Bax gene in cultured cells. However, RNA interference studies show that endogenous Nxf is required for optimal neuroprotection by preconditioning in cultured F-11 cells. Together, our data indicate that Nxf is a novel bHLH-PAS transactivator transiently induced by preconditioning and that its sustained expression is detrimental. The identification of Nxf may represent an important step in our understanding of the molecular mechanisms of brain preconditioning and injury. PMID:17214977

  3. Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1-42)-induced toxicity.

    PubMed

    Caraci, Filippo; Pappalardo, Giuseppe; Basile, Livia; Giuffrida, Alessandro; Copani, Agata; Tosto, Rita; Sinopoli, Alessandro; Giuffrida, Maria Laura; Pirrone, Emanuele; Drago, Filippo; Pignatello, Rosario; Guccione, Salvatore

    2015-10-01

    Monoamine oxidase (MAO) enzymes play a central role in the pathogenesis of Alzheimer's disease (AD) and MAO inhibitors (MAOIs) are antidepressant drugs currently studied for their neuroprotective properties in neurodegenerative disorders. In the present work MAOIs such as tranylcypromine [trans-(+)-2-phenylcyclopropanamine, TCP] and its amide derivatives, TCP butyramide (TCP-But) and TCP acetamide (TCP-Ac), were tested for their ability to protect cortical neurons challenged with synthetic amyloid-β (Aβ)-(1-42) oligomers (100 nM) for 48 h. TCP significantly prevented Aβ-induced neuronal death in a concentration-dependent fashion and was maximally protective only at 10 µM. TCP-But was maximally protective in mixed neuronal cultures at 1 µM, a lower concentration compared to TCP, whereas the new derivative, TCP-Ac, was more efficacious than TCP and TCP-But and significantly protected cortical neurons against Aβ toxicity at nanomolar concentrations (100 nM). Experiments carried out with the Thioflavin-T (Th-T) fluorescence assay for fibril formation showed that TCP and its amide derivatives influenced the early events of the Aβ aggregation process in a concentration-dependent manner. TCP-Ac was more effective than TCP-But and TCP in slowing down the Aβ(1-42) aggregates formation through a lengthening at the lag phase. In our experimental model co-incubation of Aβ(1-42) oligomers with TCP-Ac was able to almost completely prevent Aβ-induced neurodegeneration. These results suggest that inhibition of Aβ oligomer-mediated aggregation significantly contributes to the overall neuroprotective activity of TCP-Ac and also raise the possibility that TCP, and in particular the new compound TCP-Ac, might represent new pharmacological tools to yield neuroprotection in AD. PMID:26162702

  4. Neuroprotective Properties of Compounds Extracted from Dianthus superbus L. against Glutamate-induced Cell Death in HT22 Cells

    PubMed Central

    Yun, Bo-Ra; Yang, Hye Jin; Weon, Jin Bae; Lee, Jiwoo; Eom, Min Rye; Ma, Choong Je

    2016-01-01

    Background: Dianthus superbus L. has been used in Chinese herbal medicine as a diuretic and anti-inflammatory agent. Objective: In this study, we isolated ten bioactive compounds from D. superbus and evaluated their neuroprotective activity against glutamate-induced cell death in the hippocampal neuronal HT22 cells. Materials and Methods: New compound, (E)-methyl-4-hydroxy-4-(8a-methyl-3-oxodecahydronaphthalen-4a-yl) (1) and, nine known compounds, diosmetin-7-O (2’’,6’’-di-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (2), 4-hydroxy-3-methoxy-pentyl ester benzenepropanoic acid (3), vanillic acid (4), 4-hydroxy-benzeneacetic acid (5), 4-methoxybenzeneacetic acid (6), (E)-4-methoxycinnamic acid (7), 3-methoxy-4-hydroxyphenylethanol (8), hydroferulic acid (9), and methyl hydroferulate (10), were isolated by bioactivity-guided separation. Structures of the isolated compounds were identified on the basis of 1H nuclear magnetic resonance (NMR), 13C NMR, and two-dimensional NMR spectra, while their neuroprotective properties were evaluated by performing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: D. superbus extract had a neuroprotective effect and isolated 10 compounds. Among the compounds, compounds 5 and 6 effectively protected HT22 cells against glutamate toxicity. Conclusion: In conclusion, the extract of D. superbus and compounds isolated from it exhibited neuroprotective properties, suggesting therapeutic potential for applications in neurotoxic diseases. SUMMARY D. superbus extract significantly protected on glutamate-induced cell death in HT22 cellsNew compound, (E)-methyl-4-hydroxy-4-(8a-methyl-3-oxodecahydronaphthalen-4a-yl) (1) and, nine known compounds, diosmetin-7-O(2’’,6’’-di-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (2), 4-hydroxy-3-methoxy-pentyl ester benzenepropanoic acid (3), vanillic acid (4), 4-hydroxy-benzeneacetic acid (5), 4-methoxybenzeneacetic acid (6), (E)-4-methoxycinnamic acid (7), 3

  5. BDNF-TrkB Pathway Mediates Neuroprotection of Hydrogen Sulfide against Formaldehyde-Induced Toxicity to PC12 Cells

    PubMed Central

    Gao, Sheng-Lan; Tian, Ying; Wang, Chun-Yan; Wang, Li; Gu, Hong-Feng; Tang, Xiao-Qing

    2015-01-01

    Formaldehyde (FA) is a common environmental contaminant that has toxic effects on the central nervous system (CNS). Our previous data demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator, has protective effects against FA-induced neurotoxicity. As is known to all, Brain-derived neurotropic factor (BDNF), a member of the neurotrophin gene family, mediates its neuroprotective properties via various intracellular signaling pathways triggered by activating the tyrosine kinase receptor B (TrkB). Intriguingly, our previous data have illustrated the upregulatory role of H2S on BDNF protein expression in the hippocampus of rats. Therefore, in this study, we hypothesized that H2S provides neuroprotection against FA toxicity by regulating BDNF-TrkB pathway. In the present study, we found that NaHS, a donor of H2S, upregulated the level of BDNF protein in PC12 cells, and significantly rescued FA-induced downregulation of BDNF levels. Furthermore, we found that pretreatment of PC12 cells with K252a, an inhibitor of the BDNF receptor TrkB, markedly reversed the inhibition of NaHS on FA-induced cytotoxicity and ablated the protective effects of NaHS on FA-induced oxidative stress, including the accumulation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-trans-nonenal (4-HNE), and malondialdehyde (MDA). We also showed that K252a abolished the inhibition of NaHS on FA-induced apoptosis, as well as the activation of caspase-3 in PC12 cells. In addition, K252a reversed the protection of H2S against FA-induced downregulation of Bcl-2 protein expression and upregulation of Bax protein expression in PC12 cells. These data indicate that the BDNF-TrkB pathway mediates the neuroprotection of H2S against FA-induced cytotoxicity, oxidative stress and apoptosis in PC12 cells. These findings provide a novel mechanism underlying the protection of H2S against FA-induced neurotoxicity. PMID:25749582

  6. Cerebrolysin, a mixture of neurotrophic factors induces marked neuroprotection in spinal cord injury following intoxication of engineered nanoparticles from metals.

    PubMed

    Menon, Preeti Kumaran; Muresanu, Dafin Fior; Sharma, Aruna; Mössler, Herbert; Sharma, Hari Shanker

    2012-02-01

    Spinal cord injury (SCI) is the world's most disastrous disease for which there is no effective treatment till today. Several studies suggest that nanoparticles could adversely influence the pathology of SCI and thereby alter the efficacy of many neuroprotective agents. Thus, there is an urgent need to find suitable therapeutic agents that could minimize cord pathology following trauma upon nanoparticle intoxication. Our laboratory has been engaged for the last 7 years in finding suitable therapeutic strategies that could equally reduce cord pathology in normal and in nanoparticle-treated animal models of SCI. We observed that engineered nanoparticles from metals e.g., aluminum (Al), silver (Ag) and copper (Cu) (50-60 nm) when administered in rats daily for 7 days (50 mg/kg, i.p.) resulted in exacerbation of cord pathology after trauma that correlated well with breakdown of the blood-spinal cord barrier (BSCB) to serum proteins. The entry of plasma proteins into the cord leads to edema formation and neuronal damage. Thus, future drugs should be designed in such a way to be effective even when the SCI is influenced by nanoparticles. Previous research suggests that a suitable combination of neurotrophic factors could induce marked neuroprotection in SCI in normal animals. Thus, we examined the effects of a new drug; cerebrolysin that is a mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments to treat normal or nanoparticle-treated rats after SCI. Our observations showed that cerebrolysin (2.5 ml/kg, i.v.) before SCI resulted in good neuroprotection in normal animals, whereas nanoparticle-treated rats required a higher dose of the drug (5.0 ml/kg, i.v.) to induce comparable neuroprotection in the cord after SCI. Cerebrolysin also reduced spinal cord water content, leakage of plasma proteins

  7. Neuroprotective effects of tenuigenin in a SH-SY5Y cell model with 6-OHDA-induced injury.

    PubMed

    Liang, Zhigang; Shi, Fang; Wang, Yong; Lu, Li; Zhang, Zhanjun; Wang, Xuan; Wang, Xiaomin

    2011-06-22

    Tenuigenin, an active component of Polygala tenuifolia root extracts, has been shown to provide antioxidative and anti-aging effects in Alzheimer's disease, as well as to promote proliferation and differentiation of neural progenitor cells. However, the effects of tenuigenin on Parkinson's disease remain unclear. In the present study, SH-SY5Y cells were utilized to determine the effects of tenuigenin on 6-hydroxydopamine (6-OHDA)-induced injury. Results showed that 1.0 × 10⁻¹-10 μM tenuigenin significantly promoted cell viability and reduced cell death. In addition, tenuigenin protected mitochondrial membrane potential (MMP) against 6-OHDA damage and significantly increased glutathione and superoxide dismutase expression. At the mRNA level, tenuigenin resulted in down-regulation of caspase-3, but up-regulation of tyrosine hydroxylase expression in 6-OHDA damaged cells. These results suggested that tenuigenin provides neuroprotection to dopaminergic neurons from 6-OHDA-induced damage. The neuroprotective mechanisms might involve antioxidative effects, maintenance of mitochondrial function, and regulation of caspase-3 and tyrosine hydroxylase expression and activity. Tenuigenin could provide a novel antioxidative strategy for Parkinson's disease. PMID:21536104

  8. Neuroprotective and nootropic activity of Clitorea ternatea Linn.(Fabaceae) leaves on diabetes induced cognitive decline in experimental animals

    PubMed Central

    Talpate, Karuna A.; Bhosale, Uma A.; Zambare, Mandar R.; Somani, Rahul S

    2014-01-01

    Purpose: Ethanol extract of Clitorea ternatea (EECT) was evaluated in diabetes-induced cognitive decline rat model for its nootropic and neuroprotective activity. Materials and Methods: Effect on spatial working memory, spatial reference memory and spatial working-reference memory was evaluated by Y maze, Morris water maze and Radial arm maze respectively. Neuroprotective effects of EECT was studied by assaying acetylcholinesterase, lipid peroxide, superoxide dismutase (SOD), total nitric oxide (NO), catalase (CAT) and glutathione (GSH) levels in the brain of diabetic rats. Results: The EECT (200 and 400 mg/kg) was found to cause significant increase in spatial working memory (P < 0.05), spatial reference memory (P < 0.001) and spatial working-reference (P < 0.001) in retention trials on Y maze, Morris water maze and Radial arm maze respectively. Whereas significant decrease in acetylcholinesterase activity (P < 0.05), lipid peroxide (P < 0.001), total NO (P < 0.001) and significant increase in SOD, CAT and GSH levels was observed in animals treated with EECT (200 and 400 mg/kg) compared to diabetic control group. Conclusions: The present data indicates that Clitorea ternatea tenders protection against diabetes induced cognitive decline and merits the need for further studies to elucidate its mode of action. PMID:24459404

  9. Increases of Catalase and Glutathione Peroxidase Expressions by Lacosamide Pretreatment Contributes to Neuroprotection Against Experimentally Induced Transient Cerebral Ischemia.

    PubMed

    Choi, Hyun Young; Park, Joon Ha; Chen, Bai Hui; Shin, Bich Na; Lee, Yun Lyul; Kim, In Hye; Cho, Jeong-Hwi; Lee, Tae-Kyeong; Lee, Jae-Chul; Won, Moo-Ho; Ahn, Ji Hyeon; Tae, Hyun-Jin; Yan, Bing Chun; Hwang, In Koo; Cho, Jun Hwi; Kim, Young-Myeong; Kim, Sung Koo

    2016-09-01

    Lacosamide is a new antiepileptic drug which is widely used to treat partial-onset seizures. In this study, we examined the neuroprotective effect of lacosamide against transient ischemic damage and expressions of antioxidant enzymes such as Zn-superoxide dismutase (SOD1), Mn-superoxide dismutase (SOD2), catalase (CAT) and glutathione peroxidase (GPX) in the hippocampal cornu ammonis 1 (CA1) region following 5 min of transient global cerebral ischemia in gerbils. We found that pre-treatment with 25 mg/kg lacosamide protected CA1 pyramidal neurons from transient global cerebral ischemic insult using hematoxylin-eosin staining and neuronal nuclear antigen immunohistochemistry. Transient ischemia dramatically changed expressions of SOD1, SOD2 and GPX, not CAT, in the CA1 pyramidal neurons. Lacosamide pre-treatment increased expressions of CAT and GPX, not SOD1 and 2, in the CA1 pyramidal neurons compared with controls, and their expressions induced by lacosamide pre-treatment were maintained after transient cerebral ischemia. In brief, pre-treatment with lacosamide protected hippocampal CA1 pyramidal neurons from ischemic damage induced by transient global cerebral ischemia, and the lacosamide-mediated neuroprotection may be closely related to increases of CAT and GPX expressions by lacosamide pre-treatment. PMID:27209305

  10. Neuroprotective Effect of Lycopene Against PTZ-induced Kindling Seizures in Mice: Possible Behavioural, Biochemical and Mitochondrial Dysfunction.

    PubMed

    Bhardwaj, Manveen; Kumar, Anil

    2016-02-01

    Oxidative stress and mitochondrial dysfunction are the major contributing factors in the pathophysiology of various neurological disorders. Recently, antioxidant therapies aimed at reducing oxidative stress gained a considerable attention in epilepsy treatment. Lycopene, a carotenoid antioxidant, has received scientific interest in recent years. So, the present study has been designed to evaluate the neuroprotective effect of lycopene against the pentylenetetrazol (PTZ)-induced kindling epilepsy. Laca mice received lycopene (2.5, 5 and 10 mg/kg) and sodium valproate for a period of 29 days and PTZ (40 mg/kg i.p (Intraperitoneal)) injection on alternative days. Various behavioural (kindling score), biochemical parameters (lipid peroxidation, superoxide dismutase, reduced glutathione, catalase and nitrite) and mitochondrial enzyme complex activities (I, II and IV) were assessed in the brain. Results depicted that repeated administration of a sub-convulsive dose of PTZ (40 mg/kg) significantly increased kindling score, oxidative damage and impaired mitochondrial enzyme complex activities (I, II and IV) as compared with naive animals. Lycopene (5 and 10 mg/kg) and sodium valproate (100 mg/kg) treatment for a duration of 29 days significantly attenuated kindling score, reversed oxidative damage and restored mitochondrial enzyme complex activities (I, II and IV) as compared with control. Thus, present study demonstrates the neuroprotective potential of lycopene in PTZ-induced kindling in mice. PMID:26633078

  11. White tea (Camellia sinensis Kuntze) exerts neuroprotection against hydrogen peroxide-induced toxicity in PC12 cells.

    PubMed

    López, Víctor; Calvo, Maria Isabel

    2011-03-01

    Tea is a popular beverage whose consumption is associated with prevention of certain disorders. The objective of the study was to investigate the potential neuroprotective effect of white tea extract (WTE) on hydrogen peroxide induced toxicity in PC12 cells. Cells were treated with various doses of WTE (10-250 μg/ml) before exposition to 250 μM hydrogen peroxide and cell survival was determined through the MTT and LDH assays. Oxidative stress was quantified in the cells after treatments as intracellular reactive oxygen species (ROS) production and the antioxidant activity of the extract was assessed in a cell free system in terms of free radical scavenging capacity. Results showed that WTE has a significant protective effect in the PC12 cell line against hydrogen peroxide as cell survival was significantly superior in WTE-treated cells compared to hydrogen peroxide-treated cells. A reduction on intracellular oxidative stress as well as radical scavenging properties were produced by WTE. Results suggest that WTE protects PC12 cells against H(2)O(2)-induced toxicity, and that an antioxidant mechanism through ROS scavenging may be in part responsible for cells neuroprotection. PMID:21271291

  12. Neuroprotective Effects of Inhibiting Fyn S-Nitrosylation on Cerebral Ischemia/Reperfusion-Induced Damage to CA1 Hippocampal Neurons

    PubMed Central

    Hao, Lingyun; Wei, Xuewen; Guo, Peng; Zhang, Guangyi; Qi, Suhua

    2016-01-01

    Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the effects of Fyn S-nitrosylation on brain damage. In vitro, Fyn could be S-nitrosylated by S-nitrosoglutathione (GSNO, an exogenous NO donor), and in vivo, endogenous NO synthesized by NO synthases (NOS) could enhance Fyn S-nitrosylation. Application of GSNO, 7-nitroindazole (7-NI, an inhibitor of neuronal NOS) and hydrogen maleate (MK-801, the N-methyl-d-aspartate receptor (NMDAR) antagonist) could decrease the S-nitrosylation and phosphorylation of Fyn induced by cerebral ischemia/reperfusion (I/R). Cresyl violet staining validated that these compounds exerted neuroprotective effects against the cerebral I/R-induced damage to hippocampal CA1 neurons. Taken together, in this study, we demonstrated that Fyn can be S-nitrosylated both in vitro and in vivo and that inhibiting S-nitrosylation can exert neuroprotective effects against cerebral I/R injury, potentially via NMDAR-mediated mechanisms. These findings may lead to a new field of inquiry to investigate the underlying pathogenesis of stroke and the development of novel treatment strategies. PMID:27420046

  13. Alkaloids from the hook-bearing branch of Uncariarhynchophylla and their neuroprotective effects against glutamate-induced HT22 cell death.

    PubMed

    Qi, Wen; Yue, Si-Jia; Sun, Jia-Hong; Simpkins, James W; Zhang, Lin; Yuan, Dan

    2014-01-01

    One new alkaloid, 4-geissoschizine N-oxide methyl ether (1), was isolated from the EtOH extract of the hook-bearing branch of Uncariarhynchophylla, together with 10 known alkaloids, 3-epi-geissoschizine methyl ether (2) isolated from U.rhynchophylla for the first time, geissoschizine methyl ether (3), 4-hirsuteine N-oxide (4), hirsuteine (5), hirsutine (6), 3α-dihydro-cadambine (7), 3β-isodihydro-cadambine (8), cadambine (9), strictosamide (10), and akuammigine (11). The structures were elucidated by spectroscopic methods including UV, ESI-QTOF MS, NMR, and circular dichroism experiments. Neuroprotective effects of 1-9 were investigated against 3 mM glutamate-induced HT22 cell death. The activity assay showed that 2, 3, 5, and 6 exhibited potent neuroprotective effects against glutamate-induced HT22 cell death. However, only weak neuroprotective activities were observed for 1, 4, 7, 8, and 9. PMID:24899363

  14. Neuroprotective effects of Asiaticoside

    PubMed Central

    Qi, Feng-yan; Yang, Le; Tian, Zhen; Zhao, Ming-gao; Liu, Shui-bing; An, Jia-ze

    2014-01-01

    In the central nervous system, Asiaticoside has been shown to attenuate in vitro neuronal damage caused by exposure to β-amyloid. In vivo studies demonstrated that Asiaticoside could attenuate neurobehavioral, neurochemical and histological changes in transient focal middle cerebral artery occlusion animals. In addition, Asiaticoside showed anxiolytic effects in acute and chronic stress animals. However, its potential neuroprotective properties in glutamate-induced excitotoxicity have not been fully studied. We investigated the neuroprotective effects of Asiaticoside in primary cultured mouse cortical neurons exposed to glutamate-induced excitotoxicity invoked by N-methyl-D-aspartate. Pretreatment with Asiaticoside decreased neuronal cell loss in a concentration-dependent manner and restored changes in expression of apoptotic-related proteins Bcl-2 and Bax. Asiaticoside pretreatment also attenuated the upregulation of NR2B expression, a subunit of N-methyl-D-aspartate receptors, but did not affect expression of NR2A subunits. Additionally, in cultured neurons, Asiaticoside significantly inhibited Ca2+ influx induced by N-methyl-D-aspartate. These experimental findings provide preliminary evidence that during excitotoxicity induced by N-methyl-D-aspartate exposure in cultured cortical neurons, the neuroprotective effects of Asiaticoside are mediated through inhibition of calcium influx. Aside from its anti-oxidant activity, down-regulation of NR2B-containing N-methyl-D-aspartate receptors may be one of the underlying mechanisms in Asiaticoside neuroprotection. PMID:25221579

  15. Early Combined Therapy with Pharmacologically Induced Hypothermia and Edaravone Exerts Neuroprotective Effects in a Rat Model of Intracerebral Hemorrhage.

    PubMed

    Zhu, Yonglin; Liu, Chunling; Sun, Zhikun

    2015-11-01

    In present study, we evaluated acute neuroprotective effects of combined therapy with pharmacologically induced hypothermia and edaravone in a rat model of intracerebral hemorrhage (ICH). ICH was caused by injection of 0.5 U of collagenase VII to the caudate nucleus of male Sprague-Dawley rats. Sham-treated animals receive injections of normal saline instead of collagenase VII. All animals were randomly divided into five groups: sham group, ICH group, hypothermia group, edavarone (10 mg/kg) group, and combined hypothermia + edavarone group. Hypothermia was induced by injection of the second-generation neurotensin receptor agonist HPI-201 (2 mg/kg at 1 h after ICH; 1 mg/kg at 4 and 7 h after ICH). Hypothermia was sustained for at least 6 h. The study outcomes were the extent of brain edema, permeability of the blood-brain barrier (Evan's blue dye), expression of matrix metalloproteinase-9 and inflammatory cytokines (IL-1β, IL-4, IL-6, and TNF-α), and expression of apoptosis-related proteins (caspase-3, cytochrome C, Bcl-2, and Bax). Brain edema, permeability of the blood-brain barrier, and expression of metalloproteinase-9 were increased, while expression of caspase-3 and Bcl-2 was decreased by ICH. We observed that the combined therapy was significantly more potent in reverting the above negative trends induced by ICH. In conclusion, our results indicate that a combination of pharmacologically induced hypothermia and edavarone leads to potentiation of their respective neuroprotective effects. PMID:27352357

  16. GPER1 mediates estrogen-induced neuroprotection against oxygen-glucose deprivation in the primary hippocampal neurons.

    PubMed

    Zhao, Tian-Zhi; Shi, Fei; Hu, Jun; He, Shi-Ming; Ding, Qian; Ma, Lian-Ting

    2016-07-22

    It is well-known that the neuroprotective effects of estrogen have potential in the prevention and amelioration of ischemic and degenerative neurological disorders, while the underlying mechanisms for estrogen actions are undefined. As an important mediator for the non-genomic functions of estrogen, GPER1 (G Protein-coupled Estrogen Receptor 1) has been suggested to involve in the beneficial roles of estrogen in neural cells. Here our studies on primary hippocampal neurons have focused on GPER1 in an in vitro model of ischemia using oxygen-glucose deprivation (OGD). GPER1 expression in the primary hippocampal neurons was stimulated by the OGD treatments. Both E2 (estradiol) and E2-BSA (membrane impermeable estradiol by covalent conjugation of bovine serum albumin) attenuated OGD-induced cell death in primary cultures of hippocampal neurons. Importantly, this membrane-mediated estrogen function requires GPER1 protein. Knocking down of GPER1 diminished, while overexpression of GPER1 potentiated, the protective roles of E2/E2-BSA following OGD. Additionally, the downstream mechanisms employed by membrane-associated estrogen signaling were found to include PI3K/Akt-dependent Ask1 inhibition in the primary hippocampal neurons. Overall, these research results could enhance our understanding of the neuroprotective actions for estrogen, and provide a new therapeutic target for improving stroke outcome and ameliorating degenerative neurological diseases. PMID:27113328

  17. Neurogenic neuroprotection: clinical perspectives

    PubMed Central

    Mandel, Mauricio; Fonoff, Erich Talamoni; Bor-Seng-Shu, Edson; Teixeira, Manoel Jacobsen; Chadi, Gerson

    2012-01-01

    Summary Neurogenic neuroprotection is a promising approach for treating patients with ischemic brain lesions. In rats, stimulation of the deep brain nuclei has been shown to reduce the volume of focal infarction. In this context, protection of neural tissue can be a rapid intervention that has a relatively long-lasting effect, making fastigial nucleus stimulation (FNS) a potentially valuable method for clinical application. Although the mechanisms of neuroprotection induced by FNS remain partially unclear, important data have been presented in the last two decades. A 1-h electrical FNS reduced, by 59%, infarctions triggered by permanent occlusion of the middle cerebral artery in Fisher rats. The acute effect of electrical FNS is likely mediated by a prolonged opening of potassium channels, and the sustained effect appears to be linked to inhibition of the apoptotic cascade. A better understanding of the neuronal circuitry underlying neurogenic neuroprotection may contribute to improving neurological outcomes in ischemic brain insults. PMID:23597434

  18. Neuroprotective effects of Buyang Huanwu decoction on cerebral ischemia-induced neuronal damage

    PubMed Central

    Mu, Qingchun; Liu, Pengfei; Hu, Xitong; Gao, Haijun; Zheng, Xu; Huang, Haiyan

    2014-01-01

    Among the various treatment methods for stroke, increasing attention has been paid to traditional Chinese medicines. Buyang Huanwu decoction is a commonly used traditional Chinese medicine for the treatment of stroke. This paper summarizes the active components of the Chinese herb, which is composed of Huangqi (Radix Astragali seu Hedysari), Danggui (Radix Angelica sinensis), Chishao (Radix Paeoniae Rubra), Chuanxiong (Rhizoma Ligustici Chuanxiong), Honghua (Flos Carthami), Taoren (Semen Persicae) and Dilong (Pheretima), and identifies the therapeutic targets and underlying mechanisms that contribute to the neuroprotective properties of Buyang Huanwu decoction. PMID:25368650

  19. CRITICAL ROLE OF LARGE CONDUCTANCE VOLTAGE- AND CALCIUM-ACTIVATED POTASSIUM CHANNELS IN LEPTIN-INDUCED NEUROPROTECTION OF N-METHYL-D-ASPARTATE-EXPOSED CORTICAL NEURONS

    PubMed Central

    Mancini, Maria; Soldovieri, Maria Virginia; Gessner, Guido; Wissuwa, Bianka; Barrese, Vincenzo; Boscia, Francesca; Secondo, Agnese; Miceli, Francesco; Franco, Cristina; Ambrosino, Paolo; Canzoniero, Lorella MariaTeresa; Bauer, Michael; Hoshi, Toshinori; Heinemann, Stefan H; Taglialatela, Maurizio

    2014-01-01

    In the present study, the neuroprotective effects of the adipokine leptin, and the molecular mechanism involved, have been studied in rat and mice cortical neurons exposed to N-methyl-D-Aspartate (NMDA) in vitro. In rat cortical neurons, leptin elicited neuroprotective effects against NMDA-induced cell death which were concentration-dependent (10–100 ng/ml) and largest when the adipokine was preincubated for 2 hours before the neurotoxic stimulus. In both rat and mouse cortical neurons, leptin-induced neuroprotection was fully antagonized by Paxilline (Pax, 0.01–1 μM) and Iberiotoxin (Ibtx, 1–100 nM), two blockers of Ca2+- and voltage-activated K+ channels (Slo1 BK channels), with EC50s (38±10 nM and 5±2 nM for Pax and Ibtx, respectively) close to those reported for Pax- and Ibtx-induced BK channel blockade; the BK channel opener NS1619 (1–30 μM) induced a concentration-dependent protection against NMDA-induced excitotoxicity. Moreover, cortical neurons from mice lacking one or both alleles coding for Slo1 BK channel pore-forming subunits were insensitive to leptin-induced neuroprotection. Finally, leptin exposure dose-dependently (10–100 ng/ml) increased intracellular Ca2+ levels in rat cortical neurons. In conclusion, our results suggest that Slo1 BK channel activation following increases in intracellular Ca2+ levels is a critical step for leptin-induced neuroprotection in NMDA-exposed cortical neurons in vitro, thus highlighting leptin-based intervention via BK channel activation as a potential strategy to counteract neurodegenerative diseases. PMID:24973659

  20. Neuroprotective effects of various doses of topiramate against methylphenidate induced oxidative stress and inflammation in rat isolated hippocampus.

    PubMed

    Motaghinejad, Majid; Motevalian, Manijeh; Shabab, Behnaz

    2016-03-01

    Methylphenidate (MPH) abuse causes neurodegeneration. The neuroprotective effects of topiramate (TPM) have been reported but its putative mechanism remains unclear. The current study evaluates the role of various doses of TPM on protection of rat hippocampal cells from MPH-induced oxidative stress and inflammation in vivo. Seventy adult male rats were divided into six groups. Group 1 received normal saline (0.7 mL/rat) and group 2 was injected with MPH (10 mg/kg) for 21 days. Groups 3, 4, 5, 6 and 7 concurrently were treated by MPH (10 mg/kg) and TPM (10, 30, 50, 70 and 100 mg/kg, intraperitoneally (i.p.)), respectively for 21 days. After drug administration, the open field test (OFT) was used to investigate motor activity. Oxidative, antioxidant and inflammatory factors were measured in isolated hippocampus. Also, the brain-derived neurotrophic factor (BDNF) level was measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. Cresyl violet staining of Dentate Gyrus (DG) and CA1 cell layers of the hippocampus were also performed. MPH significantly disturbs motor activity in OFT and TPM (70 and 100 mg/kg) decreased this disturbance. Also MPH significantly increased lipid peroxidation, mitochondrial reduced state of glutathione (GSH) level, interleukin (IL)-1β and tumour necrosis factor (TNF)-α and BDNF level in isolated hippocampal cells. Also superoxide dismutase, glutathione peroxidase and glutathione reductase activity significantly decreased. Various doses of TPM attenuated these effects and significantly decreased MPH-induced oxidative damage, inflammation and hippocampal cell loss and increased BDNF level. This study suggests that TPM has the potential to be used as a neuroprotective agent against oxidative stress and neuroinflammation induced by frequent use of MPH. PMID:26718459

  1. Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite.

    PubMed

    El-Remessy, Azza B; Khalil, Ibrahim E; Matragoon, Suraporn; Abou-Mohamed, Gamal; Tsai, Nai-Jer; Roon, Penny; Caldwell, Ruth B; Caldwell, Robert W; Green, Keith; Liou, Gregory I

    2003-11-01

    In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma. PMID:14578199

  2. Recurrent Sleep Fragmentation Induces Insulin and Neuroprotective Mechanisms in Middle-Aged Flies

    PubMed Central

    Williams, Michael J.; Perland, Emelie; Eriksson, Mikaela M.; Carlsson, Josef; Erlandsson, Daniel; Laan, Loora; Mahebali, Tabusi; Potter, Ella; Frediksson, Robert; Benedict, Christian; Schiöth, Helgi B.

    2016-01-01

    Lack of quality sleep increases central nervous system oxidative stress and impairs removal of neurotoxic soluble metabolites from brain parenchyma. During aging poor sleep quality, caused by sleep fragmentation, increases central nervous system cellular stress. Currently, it is not known how organisms offset age-related cytotoxic metabolite increases in order to safeguard neuronal survival. Furthermore, it is not understood how age and sleep fragmentation interact to affect oxidative stress protection pathways. We demonstrate sleep fragmentation increases systems that protect against oxidative damage and neuroprotective endoplasmic reticulum molecular chaperones, as well as neuronal insulin and dopaminergic expression in middle-aged Drosophila males. Interestingly, even after sleep recovery the expression of these genes was still upregulated in middle-aged flies. Finally, sleep fragmentation generates higher levels of reactive oxygen species (ROS) in middle-aged flies and after sleep recovery these levels remain significantly higher than in young flies. The fact that neuroprotective pathways remain upregulated in middle-aged flies beyond sleep fragmentation suggests it might represent a strong stressor for the brain during later life. PMID:27531979

  3. Hypoxia inducible factor prolyl hydroxylases as targets for neuroprotection by “antioxidant” metal chelators: from ferroptosis to stroke

    PubMed Central

    Speer, Rachel E.; Karuppagounder, Saravanan S.; Basso, Manuela; Sleiman, Sama; Kumar, Amit; Brand, David; Smirnova, Natalya; Gazaryan, Irina; Khim, Soah J.; Ratan, Rajiv R.

    2015-01-01

    Neurologic conditions including stroke, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are leading causes of death and long-term disability in the United States, and efforts to develop novel therapeutics for these conditions have historically had poor success in translating from bench to bedside. Hypoxia Inducible Factor-1alpha (HIF-1α) mediates a broad, evolutionarily conserved, endogenous adaptive program to hypoxia, and manipulation of components of the HIF pathway are neuroprotective in a number of human neurological diseases and experimental models. In this review, we discuss molecular components of one aspect of hypoxic adpatation in detail, and provide perspective on which targets within this pathway appear to be ripest for preventing and repairing neurodegeneration. Further, we highlight the role of HIF prolyl hydroxylases as emerging targets for the salutary effects of metal chelators on ferroptosis in vitro as well in animal models of neurological diseases. PMID:23376032

  4. Neuroprotective effects of cold-inducible RNA-binding protein during mild hypothermia on traumatic brain injury

    PubMed Central

    Wang, Guan; Zhang, Jian-ning; Guo, Jia-kui; Cai, Ying; Sun, Hong-sheng; Dong, Kun; Wu, Cheng-gang

    2016-01-01

    Cold-inducible RNA-binding protein (CIRP), a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5°C on traumatic brain injury in rats. Results demonstrated that mild hypothermia suppressed apoptosis in the cortex, hippocampus and hypothalamus, facilitated CIRP mRNA and protein expression in these regions, especially in the hypothalamus. The anti-apoptotic effect of mild hypothermia disappeared after CIRP silencing. There was no correlation between mitogen-activated extracellular signal-regulated kinase activation and CIRP silencing. CIRP silencing inhibited extracellular signal-regulated kinase-1/2 activation. These indicate that CIRP inhibits apoptosis by affecting extracellular signal-regulated kinase-1/2 activation, and exerts a neuroprotective effect during mild hypothermia for traumatic brain injury. PMID:27335561

  5. Neuroprotective Effects of a Standardized Flavonoid Extract from Safflower against a Rotenone-Induced Rat Model of Parkinson's Disease.

    PubMed

    Ablat, Nuramatjan; Lv, Deyong; Ren, Rutong; Xiaokaiti, Yilixiati; Ma, Xiang; Zhao, Xin; Sun, Yi; Lei, Hui; Xu, Jiamin; Ma, Yingcong; Qi, Xianrong; Ye, Min; Xu, Feng; Han, Hongbin; Pu, Xiaoping

    2016-01-01

    Parkinson's disease (PD) is a major age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra par compacta (SNpc). Rotenone is a neurotoxin that is routinely used to model PD to aid in understanding the mechanisms of neuronal death. Safflower (Carthamus tinctorius. L.) has long been used to treat cerebrovascular diseases in China. This plant contains flavonoids, which have been reported to be effective in models of neurodegenerative disease. We previously reported that kaempferol derivatives from safflower could bind DJ-1, a protein associated with PD, and that a flavonoid extract from safflower exhibited neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD. In this study, a standardized safflower flavonoid extract (SAFE) was isolated from safflower and found to primarily contain flavonoids. The aim of the current study was to confirm the neuroprotective effects of SAFE in rotenone-induced Parkinson rats. The results showed that SAFE treatment increased body weight and improved rearing behavior and grip strength. SAFE (35 or 70 mg/kg/day) treatment reversed the decreased protein expression of tyrosine hydroxylase, dopamine transporter and DJ-1 and increased the levels of dopamine and its metabolite. In contrast, acetylcholine levels were decreased. SAFE treatment also led to partial inhibition of PD-associated changes in extracellular space diffusion parameters. These changes were detected using a magnetic resonance imaging (MRI) tracer-based method, which provides novel information regarding neuronal loss and astrocyte activation. Thus, our results indicate that SAFE represents a potential therapeutic herbal treatment for PD. PMID:27563865

  6. Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats.

    PubMed

    Pourkhodadad, Soheila; Alirezaei, Masoud; Moghaddasi, Mehrnoush; Ahmadvand, Hassan; Karami, Manizheh; Delfan, Bahram; Khanipour, Zahra

    2016-09-01

    Alzheimer's disease is a progressive neurodegenerative disorder with decline in memory. The role of oxidative stress is well known in the pathogenesis of the disease. The purpose of this study was to evaluate pretreatment effects of oleuropein on oxidative status and cognitive dysfunction induced by colchicine in the hippocampal CA1 area. Male Wistar rats were pretreated orally once daily for 10 days with oleuropein at doses of 10, 15 and 20 mg/kg. Thereafter, colchicine (15 μg/rat) was administered into the CA1 area of the hippocampus to induce cognitive dysfunction. The Morris water maze was used to assess learning and memory. Biochemical parameters such as glutathione peroxidase and catalase activities, nitric oxide and malondialdehyde concentrations were measured to evaluate the antioxidant status in the rat hippocampus. Our results indicated that colchicine significantly impaired spatial memory and induced oxidative stress; in contrast, oleuropein pretreatment significantly improved learning and memory retention, and attenuated the oxidative damage. The results clearly indicate that oleuropein has neuroprotective effects against colchicine-induced cognitive dysfunction and oxidative damage in rats. PMID:26892487

  7. The Neuroprotective Role of Insulin Against MPP(+) -Induced Parkinson's Disease in Differentiated SH-SY5Y Cells.

    PubMed

    Ramalingam, Mahesh; Kim, Sung-Jin

    2016-04-01

    Parkinson's disease (PD) is a common chronic neurodegenerative disorder associated with aging that primarily caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SN). Retinoic acid (RA)-differentiated human neuroblastoma SH-SY5Y cells (SH-SY5Y+RA) have been broadly utilized in studies of mechanisms of the pathogenesis underlying 1-Methyl-4-phenyl pyridinium (MPP(+) )-induced PD models. Here, we investigated the neuroprotective mechanisms of insulin on MPP(+) -induced neurotoxicity on SH-SY5Y+RA cells. Recent studies suggest that insulin has a protective effect against oxidative stress but not been elucidated for PD. In this study, pretreatment of insulin prevented the cell death in a dose dependent manner and lowered nitric oxide (NO) release, reactive oxygen species (ROS), and calcium ion (Ca(2+) ) influx induced by MPP(+) . Insulin also elevated tyrosine hydroxylase (TH) and insulin signaling pathways in dopaminergic neuron through activating PI3K/Akt/GSK-3 survival pathways which in turn inhibits MPP(+) -induced iNOS and ERK activation, and Bax to Bcl-2 ratio. These results suggest that insulin has a protective effect on MPP(+) -neurotoxicity in SH-SY5Y+RA cells. J. Cell. Biochem. 117: 917-926, 2016. © 2015 Wiley Periodicals, Inc. PMID:26364587

  8. Neuroprotective Potential of Mesenchymal Stem Cell-Based Therapy in Acute Stages of TNBS-Induced Colitis in Guinea-Pigs

    PubMed Central

    Robinson, Ainsley M.; Miller, Sarah; Payne, Natalie; Boyd, Richard; Sakkal, Samy; Nurgali, Kulmira

    2015-01-01

    Background & Aims The therapeutic benefits of mesenchymal stem cells (MSCs), such as homing ability, multipotent differentiation capacity and secretion of soluble bioactive factors which exert neuroprotective, anti-inflammatory and immunomodulatory properties, have been attributed to attenuation of autoimmune, inflammatory and neurodegenerative disorders. In this study, we aimed to determine the earliest time point at which locally administered MSC-based therapies avert enteric neuronal loss and damage associated with intestinal inflammation in the guinea-pig model of colitis. Methods At 3 hours after induction of colitis by 2,4,6-trinitrobenzene-sulfonate (TNBS), guinea-pigs received either human bone marrow-derived MSCs, conditioned medium (CM), or unconditioned medium by enema into the colon. Colon tissues were collected 6, 24 and 72 hours after administration of TNBS. Effects on body weight, gross morphological damage, immune cell infiltration and myenteric neurons were evaluated. RT-PCR, flow cytometry and antibody array kit were used to identify neurotrophic and neuroprotective factors released by MSCs. Results MSC and CM treatments prevented body weight loss, reduced infiltration of leukocytes into the colon wall and the myenteric plexus, facilitated repair of damaged tissue and nerve fibers, averted myenteric neuronal loss, as well as changes in neuronal subpopulations. The neuroprotective effects of MSC and CM treatments were observed as early as 24 hours after induction of inflammation even though the inflammatory reaction at the level of the myenteric ganglia had not completely subsided. Substantial number of neurotrophic and neuroprotective factors released by MSCs was identified in their secretome. Conclusion MSC-based therapies applied at the acute stages of TNBS-induced colitis start exerting their neuroprotective effects towards enteric neurons by 24 hours post treatment. The neuroprotective efficacy of MSC-based therapies can be exerted

  9. Neuroprotective effect of bee venom is mediated by reduced astrocyte activation in a subchronic MPTP-induced model of Parkinson's disease.

    PubMed

    Kim, Mi Eun; Lee, Joo Yeon; Lee, Kyung Moon; Park, Hee Ra; Lee, Eunjin; Lee, Yujeong; Lee, Jun Sik; Lee, Jaewon

    2016-08-01

    Bee venom (BV), also known as apitoxin, is widely used in traditional oriental medicine to treat immune-related diseases. Recent studies suggest that BV could be beneficial for the treatment of neurodegenerative diseases. Parkinson's disease (PD) is the second most common neurodegenerative disease next to Alzheimer's disease, and PD pathologies are closely associated with neuroinflammation. Previous studies have suggested the neuroprotective effects of BV in animal models of PD are due to the modulation of inflammation. However, the molecular mechanisms responsible for the anti-neuroinflammatory effect of BV have not been elucidated in astrocytes. Here, the authors investigated the neuroprotective effects of BV and pramipexole (PPX; a positive control) in a subchronic MPTP-induced murine PD model. Both BV and PPX prevented MPTP-induced impairments in motor performance and reduced dopaminergic neuron loss, and furthermore, these neuroprotective effects of BV and PPX were found to be associated with reduced astroglial activation in vivo PD model. However, in MPP(+) treated primary cultured astrocytes, BV modulated astrocyte activation, whereas PPX did not, indicating that the neuroprotective effects of PPX were not mediated by neuroinflammation. These findings suggest that BV should be considered a potential therapeutic or preventive agent for PD and other neuroinflammatory associated disorders. PMID:27469335

  10. Isoflurane Preconditioning Induces Neuroprotection by Up-Regulation of TREK1 in a Rat Model of Spinal Cord Ischemic Injury

    PubMed Central

    Wang, Kun; Kong, Xiangang

    2016-01-01

    This study aimed to explore the neuroprotection and mechanism of isoflurane on rats with spinal cord ischemic injury. Total 40 adult male Sprague-Dawley rats were divided into the four groups (n=10). Group A was sham-operation group; group B was ischemia group; group C was isoflurane preconditioning group; group D was isoflurane preconditioning followed by ischemia treatment group. Then the expressions of TWIK-related K+ channel 1 (TREK1) in the four groups were detected by immunofluorescent assay, real time-polymerase chain reactions (RT-PCR) and western blot. The primary neurons of rats were isolated and cultured under normal and hypoxic conditions. Besides, the neurons under two conditions were transfected with green fluorescent protein (GFP)-TREK1 and lentivirual to overexpress and silence TREK1. Additionally, the neurons were treated with isoflurane or not. Then caspase-3 activity and cell cycle of neurons under normal and hypoxic conditions were detected. Furthermore, nicotinamide adenine dinucleotide hydrate (NADH) was detected using NAD+/NADH quantification colorimetric kit. Results showed that the mRNA and protein expressions of TREK1 increased significantly in group C and D. In neurons, when TREK1 silenced, isoflurane treatment improved the caspase-3 activity. In hypoxic condition, the caspase-3 activity and sub-G1 cell percentage significantly increased, however, when TREK1 overexpressed the caspase-3 activity and sub-G1 cell percentage decreased significantly. Furthermore, both isoflurane treatment and overexpression of TREK1 significantly decreased NADH. In conclusion, isoflurane-induced neuroprotection in spinal cord ischemic injury may be associated with the up-regulation of TREK1. PMID:27469140

  11. Anticonvulsive and neuroprotective effects of synergetic combination of phenytoin and gastrodin on the convulsion induced by penicillin in mice.

    PubMed

    Zhou, Ziqi; Lin, Yanzhu; Zheng, Hongyi; He, Yuzhong; Xu, Haohua; Zhang, Siheng; Weng, Wen; Li, Wei; Zhu, Linyan; Yang, Haifeng

    2015-08-01

    Phenytoin (PHT) is a commonly prescribed first-line antiepileptic drug. However, long-term administration of PHT can cause memory loss and balance disturbance. Gastrodin (GD) is the major bioactive component in Tianma and has sedative, anticonvulsive, memory strengthening, and neuroprotective effects. To combine the two drugs seems attractive; however, little was known about the efficacy of combination therapy. In this study, convulsive attack was successfully induced by penicillin. Isobolographic analysis, memory and balance behavior test, histopathological examination, and Western blot analysis were used to investigate whether the combination therapy of GD and PHT can enhance anticonvulsive effect and reduce the side effects associated with PHT. The GD alone (950.60 mg/kg) and the PHT alone (45.50 mg/kg) could produce an anticonvulsive effect, while comparable effect could be produced by PHT : GD = 1 : 50 (8.59 : 429.27 mg/kg), which reduce the dose of PHT by 81% and GD by 55%. After the chronic anticonvulsive experiments of 16 days, the balance disturbance and short-/long-term memory loss were observed in the PHT group, while the PHT + GD therapy can protect the normal balance and memory function. The neuron morphology of hippocampus was preserved, and the number of surviving neurons after combination therapy was more than the model group. The amount of NF-κB (p65) expression was increased in combination group. All above suggested the potential of the combination of PHT and GD enhances the anticonvulsive effect and the neuroprotective effect and reduces the PHT-associated memory and balance disturbance. The PHT + GD strategy would provide new possibilities as a novel promising methodology to treat epileptic patients. PMID:26018871

  12. Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

    PubMed Central

    Cao, Zhijuan; Balasubramanian, Adithya

    2013-01-01

    Traditional methods of therapeutic hypothermia show promise for neuroprotection against cerebral ischemia-reperfusion (I/R), however, with limitations. We examined effectiveness and specificity of pharmacological hypothermia (PH) by transient receptor potential vanilloid 1 (TRPV1) channel agonism in the treatment of focal cerebral I/R. Core temperature (Tcore) was measured after subcutaneous infusion of TRPV1 agonist dihydrocapsaicin (DHC) in conscious C57BL/6 WT and TRPV1 knockout (KO) mice. Acute measurements of heart rate (HR), mean arterial pressure (MAP), and cerebral perfusion were measured before and after DHC treatment. Focal cerebral I/R (1 h ischemia + 24 h reperfusion) was induced by distal middle cerebral artery occlusion. Hypothermia (>8 h) was initiated 90 min after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (behavioral testing) and infarct volume (TTC staining) were measured at 24 h. DHC (1.25 mg/kg) produced a stable drop in Tcore (33°C) in naive and I/R mouse models but not in TRPV1 KO mice. DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion but produced a slight transient drop in MAP (<6 mmHg). In stroke mice, DHC infusion produced hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects of DHC were absent in TRPV1 KO mice or mice maintained normothermic with heat support. PH via TRPV1 agonist appears to be a well-tolerated and effective method for promoting mild hypothermia in the conscious mouse. Furthermore, TRPV1 agonism produces effective hypothermia in I/R mice and significantly improves outcome when initiated 90 min after start of reperfusion. PMID:24305062

  13. Neuroprotective Effect of Coptis chinensis in MPP[Formula: see text] and MPTP-Induced Parkinson's Disease Models.

    PubMed

    Friedemann, Thomas; Ying, Yue; Wang, Weigang; Kramer, Edgar R; Schumacher, Udo; Fei, Jian; Schröder, Sven

    2016-01-01

    The rhizome of Coptis chinensis is commonly used in traditional Chinese medicine alone or in combination with other herbs to treat diseases characterized by causing oxidative stress including inflammatory diseases, diabetes mellitus and neurodegenerative diseases. In particular, there is emerging evidence that Coptis chinensis is effective in the treatment of neurodegenerative diseases associated with oxidative stress. Hence, the aim of this study was to investigate the neuroprotective effect of Coptis chinensis in vitro and in vivo using MPP[Formula: see text] and MPTP models of Parkinson's disease. MPP[Formula: see text] treated human SH-SY5Y neuroblastoma cells were used as a cell model of Parkinson's disease. A 24[Formula: see text]h pre-treatment of the cells with the watery extract of Coptis chinensis significantly increased cell viability, as well as the intracellular ATP concentration and attenuated apoptosis compared to the MPP[Formula: see text] control. Further experiments with the main alkaloids of Coptidis chinensis, berberine, coptisine, jaterorrhizine and palmatine revealed that berberine and coptisine were the main active compounds responsible for the observed neuroprotective effect. However, the full extract of Coptis chinensis was more effective than the tested single alkaloids. In the MPTP-induced animal model of Parkinson's disease, Coptis chinensis dose-dependently improved motor functions and increased tyrosine hydroxylase-positive neurons in the substantia nigra compared to the MPTP control. Based on the results of this work, Coptis chinensis and its main alkaloids could be considered potential candidates for the development of new treatment options for Parkinson's disease. PMID:27430912

  14. Neuroprotection induced by post-conditioning following ischemia/reperfusion in mice is associated with altered microRNA expression.

    PubMed

    Miao, Wei; Bao, Tian-Hao; Han, Jian-Hong; Yin, Mei; Zhang, Jie; Yan, Yong; Zhu, Yu-Hong

    2016-09-01

    Ischemic preconditioning and ischemic postconditioning (IPostC) represent promising strategies to reduce ischemia-reperfusion (I/R) injury and attenuate the lethal ischemic damage following stroke. However, the mechanism underlying this attenuation remains to be elucidated. It was hypothesized that alterations in microRNA (miRNA) expression in the cerebral cortex and hippocampus of mice following I/R is associated with the functional improvement induced by IPostC. Behavioral changes were assessed in a mouse model of I/R in the absence or presence of IPostC, followed by microarray analyses to investigate the expressional alterations of miRNAs in the cerebral cortex and hippocampus of mice. The results of the present study revealed that IPostC abrogated the neurological impairment and hippocampus‑associated cognitive deficits induced by I/R, and upregulated or downregulated the expression levels of numerous miRNAs. Furthermore, the upregulation of miR‑19a, and the downregulation of miR‑1, let‑7f and miR‑124 expression levels following IPostC was confirmed utilizing reverse transcription‑quantitative polymerase chain reaction. The results of the present study demonstrated that alterations in miRNA expression in the cerebral cortex and hippocampus of mice following I/R was associated with the neuroprotection induced by IPostC. PMID:27485299

  15. Neuroprotective Effect of Ginkgolide B on Bupivacaine-Induced Apoptosis in SH-SY5Y Cells

    PubMed Central

    Li, Le; Zhang, Qing-guo; Lai, Lu-ying; Wen, Xian-jie; Zheng, Ting; Cheung, Chi-wai; Zhou, Shu-qin; Xu, Shi-yuan

    2013-01-01

    Local anesthetics are used routinely and effectively. However, many are also known to activate neurotoxic pathways. We tested the neuroprotective efficacy of ginkgolide B (GB), an active component of Ginkgo biloba, against ROS-mediated neurotoxicity caused by the local anesthetic bupivacaine. SH-SY5Y cells were treated with different concentrations of bupivacaine alone or following preincubation with GB. Pretreatment with GB increased SH-SY5Y cell viability and attenuated intracellular ROS accumulation, apoptosis, mitochondrial dysfunction, and ER stress. GB suppressed bupivacaine-induced mitochondrial depolarization and mitochondria complex I and III inhibition and increased cleaved caspase-3 and Htra2 expression, which was strongly indicative of activation of mitochondria-dependent apoptosis with concomitantly enhanced expressions of Grp78, caspase-12 mRNA, protein, and ER stress. GB also improved ultrastructural changes indicative of mitochondrial and ER damage induced by bupivacaine. These results implicate bupivacaine-induced ROS-dependent mitochondria, ER dysfunction, and apoptosis, which can be attenuated by GB through its antioxidant property. PMID:24228138

  16. Neuroprotective effects of trans-caryophyllene against kainic acid induced seizure activity and oxidative stress in mice.

    PubMed

    Liu, Hao; Song, Zhi; Liao, Daguang; Zhang, Tianyi; Liu, Feng; Zhuang, Kai; Luo, Kui; Yang, Liang

    2015-01-01

    Trans-caryophyllene (TC), a component of essential oil found in many flowering plants, has shown its neuroprotective effects in various neurological disorders. However, the effects of TC on epilepsy haven't been reported before. In this study, we investigated the effect of TC on kainic acid-induced seizure activity caused by oxidative stress and pro-inflammation. We found that TC pretreatment significantly decreased seizure activity score compared to kainic acid treated group. Importantly, TC pretreatment leads to lowering the mortality in kainic acid treated mice. In addition, TC was found to significantly inhibit KA-induced generation of malondialdehyde. TC pretreatment also preserved the activity of GPx, SOD, and CAT. Notably, our data shows that an important property of TC is its capacity to exert cerebral anti-inflammatory effects by mitigating the expression of proinflammatory cytokines, such as TNF-α and IL-1β. These data suggest that TC has a potential protective effect on chemical induced seizure and brain damage. PMID:25417010

  17. Neuroprotective effect of endogenous cannabinoids on ischemic brain injury induced by the excess microglia-mediated inflammation

    PubMed Central

    Guo, Shuyun; Liu, Yanwu; Ma, Rui; Li, Jun; Su, Binxiao

    2016-01-01

    Increasing evidence has demonstrated the role of endogenous cannabinoids system (ECS) on protecting brain injury caused by ischemia (IMI). Papers reported that microglia-mediated inflammation has become one of the most pivotal mechanisms for IMI. This study was aimed to investigate the potential roles of ECS on neuron protection under microglia-mediated inflammation. Inflammatory cytokines level both in vitro (BV-2 cells) and in vivo (brain tissue from constructed IMI model and brain-isolated microglia) was detected. ECS levels were detected, and its effects on inflammations was also analyzed. Influence of microglia-mediated inflammation on neuron injury was analyzed. Moreover, the effects of ECS on protecting neuron injury were also analyzed. Our results showed that the levels of inflammatory cytokines including TNFα and IL-1β were higher while IKBα was lower in IMI model brain tissue, brain-isolated microglia and BV-2 cells compared to the control. Inflammation was activated in microglia, as well as the activation of ECS characterized by the increasing level of AEA and 2-AG. Furthermore, the activated microglia-mediated self-inflammation performed harmful influence on neurons via suppressing cell viability and inducing apoptosis. Moreover, ECS functioned as a protector on neuron injury though promoting cell proliferation and suppressing cell apoptosis which were caused by the activated BV-2 cells (LPS induced for 3 h). Our data suggested that ECS may play certain neuroprotective effects on microglia-mediated inflammations-induced IMI through anti-inflammatory function. PMID:27398146

  18. Magnetically softened iron oxide (MSIO) nanofluid and its application to thermally-induced heat shock proteins for ocular neuroprotection.

    PubMed

    Bae, Seongtae; Jeoung, Jin Wook; Jeun, Minhong; Jang, Jung-Tak; Park, Joo Hyun; Kim, Yu Jeong; Lee, Kwan; Kim, Minkyu; Lee, Jooyoung; Hwang, Hey Min; Paek, Sun Ha; Park, Ki Ho

    2016-09-01

    Magnetically softened iron oxide (MSIO) nanofluid, PEGylated (Mn0.5Zn0.5)Fe2O4, was successfully developed for local induction of heat shock proteins (HSPs) 72 in retinal ganglion cells (RGCs) for ocular neuroprotection. The MSIO nanofluid showed significantly enhanced alternating current (AC) magnetic heat induction characteristics including exceptionally high SLP (Specific Loss Power, > 2000 W/g). This phenomenon was resulted from the dramatically improved AC magnetic softness of MSIO caused by the magnetically tailored Mn(2+) and Zn(2+) distributions in Fe3O4. In addition, the MSIO nanofluid with ultra-thin surface coating layer thickness and high monodispersity allowed for a higher cellular uptake up to a 52.5% with RGCs and enhancing "relaxation power" for higher AC heating capability. The RGCs cultured with MSIO nanofluid successfully induced HSPs 72 by magnetic nanofluid hyperthermia (MNFH). Moreover, it was interestingly observed that systematic control of "AC magnetically-induced heating up rate" reaching to a constant heating temperature of HSPs 72 induction allowed to achieve maximized induction efficiency at the slowest AC heating up rate during MNFH. In addition to in-vitro experimental verification, the studies of MSIO infusion behavior using animal models and a newly designed magnetic coil system demonstrated that the MSIO has promising biotechnical feasibility for thermally-induced HSPs agents in future glaucoma clinics. PMID:27294536

  19. Neuroprotection induced by post-conditioning following ischemia/reperfusion in mice is associated with altered microRNA expression

    PubMed Central

    Miao, Wei; Bao, Tian-Hao; Han, Jian-Hong; Yin, Mei; Zhang, Jie; Yan, Yong; Zhu, Yu-Hong

    2016-01-01

    Ischemic preconditioning and ischemic postconditioning (IPostC) represent promising strategies to reduce ischemia-reperfusion (I/R) injury and attenuate the lethal ischemic damage following stroke. However, the mechanism underlying this attenuation remains to be elucidated. It was hypothesized that alterations in microRNA (miRNA) expression in the cerebral cortex and hippocampus of mice following I/R is associated with the functional improvement induced by IPostC. Behavioral changes were assessed in a mouse model of I/R in the absence or presence of IPostC, followed by microarray analyses to investigate the expressional alterations of miRNAs in the cerebral cortex and hippocampus of mice. The results of the present study revealed that IPostC abrogated the neurological impairment and hippocampus-associated cognitive deficits induced by I/R, and upregulated or downregulated the expression levels of numerous miRNAs. Furthermore, the upregulation of miR-19a, and the downregulation of miR-1, let-7f and miR-124 expression levels following IPostC was confirmed utilizing reverse transcription-quantitative polymerase chain reaction. The results of the present study demonstrated that alterations in miRNA expression in the cerebral cortex and hippocampus of mice following I/R was associated with the neuroprotection induced by IPostC. PMID:27485299

  20. Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin

    PubMed Central

    Ma, Ping; Liu, Xudong; Wu, Jiliang; Yan, Biao; Zhang, Yuchao; Lu, Yu; Wu, Yang; Liu, Chao; Guo, Junhui; Nanberg, Eewa; Bornehag, Carl-Gustaf; Yang, Xu

    2015-01-01

    Diisononyl phthalate (DINP) is a plasticizer that is frequently used as a substitute for other plasticizers whose use is prohibited in certain products. In vivo studies on the neurotoxicity of DINP are however, limited. This work aims to investigate whether DINP causes neurobehavioral changes in mice and to provide useful advice on preventing the occurrence of these adverse effects. Behavioral analysis showed that oral administration of 20 or 200 mg/kg/day DINP led to mouse cognitive deficits and anxiety. Brain histopathological observations, immunohistochemistry assays (cysteine-aspartic acid protease 3 [caspase-3], glial fibrillary acidic protein [GFAP]), oxidative stress assessments (reactive oxygen species [ROS], glutathione [GSH], superoxide dismutase [SOD] activities, 8-hydroxy-2-deoxyguanosine [8-OH-dG] and DNA-protein crosslinks [DPC]), and assessment of inflammation (tumor necrosis factor alpha [TNF-а] and interleukin-1 beta [IL-1β]) of mouse brains showed that there were histopathological alterations in the brain and increased levels of oxidative stress, and inflammation for these same groups. However, some of these effects were blocked by administration of melatonin (50 mg/kg/day). Down-regulation of oxidative stress was proposed to explain the neuroprotective effects of melatonin. The data suggests that DINP could cause cognitive deficits and anxiety in mice, and that melatonin could be used to avoid these adverse effects. PMID:26424168

  1. Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin.

    PubMed

    Ma, Ping; Liu, Xudong; Wu, Jiliang; Yan, Biao; Zhang, Yuchao; Lu, Yu; Wu, Yang; Liu, Chao; Guo, Junhui; Nanberg, Eewa; Bornehag, Carl-Gustaf; Yang, Xu

    2015-01-01

    Diisononyl phthalate (DINP) is a plasticizer that is frequently used as a substitute for other plasticizers whose use is prohibited in certain products. In vivo studies on the neurotoxicity of DINP are however, limited. This work aims to investigate whether DINP causes neurobehavioral changes in mice and to provide useful advice on preventing the occurrence of these adverse effects. Behavioral analysis showed that oral administration of 20 or 200 mg/kg/day DINP led to mouse cognitive deficits and anxiety. Brain histopathological observations, immunohistochemistry assays (cysteine-aspartic acid protease 3 [caspase-3], glial fibrillary acidic protein [GFAP]), oxidative stress assessments (reactive oxygen species [ROS], glutathione [GSH], superoxide dismutase [SOD] activities, 8-hydroxy-2-deoxyguanosine [8-OH-dG] and DNA-protein crosslinks [DPC]), and assessment of inflammation (tumor necrosis factor alpha [TNF-а] and interleukin-1 beta [IL-1β]) of mouse brains showed that there were histopathological alterations in the brain and increased levels of oxidative stress, and inflammation for these same groups. However, some of these effects were blocked by administration of melatonin (50 mg/kg/day). Down-regulation of oxidative stress was proposed to explain the neuroprotective effects of melatonin. The data suggests that DINP could cause cognitive deficits and anxiety in mice, and that melatonin could be used to avoid these adverse effects. PMID:26424168

  2. Neuroprotective efficacy of eugenol and isoeugenol in acrylamide-induced neuropathy in rats: behavioral and biochemical evidence.

    PubMed

    Prasad, Sathya N; Muralidhara

    2013-02-01

    The primary objective of this investigation was to assess the neuroprotective efficacy of spice active principles namely Eugenol (Eug) and isoeugenol (IE) in an acrylamide (ACR) neuropathy model in rats. In the present study, ACR administration (50 mg/kg bw, i.p. 3 times/week) for 5 weeks to growing rats caused typical symptoms of neuropathy. We found that treatment of ACR rats with spice active principles (10 mg/kg bw, for 5 weeks) caused marked improvement in gait score and responses in a battery of behavioral tests. Terminally, both spice active principles markedly attenuated ACR-induced markers of oxidative stress viz., reactive oxygen species (ROS), malondialdehyde (MDA) and nitric oxide (NO) in sciatic nerve (SN) as well as brain regions (cortex Ct, cerebellum Cb). Treatment with Eug restored the reduced glutathione levels in SN and brain regions. Interestingly, both spice active principles effectively diminished ACR-induced elevation in cytosolic calcium levels and acetylcholinesterase activity in SN and Ct. Further, the diminished activity of ATPase among ACR rats was enhanced in SN and restored in brain regions. Furthermore, Eug treatment significantly offset ACR-induced depletion in dopamine levels in brain regions. Collectively our findings suggest the propensity of these spice active principles to attenuate ACR-induced neuropathy. Further studies are necessary to understand the precise molecular mechanism/s by which these spice active principles attenuate neuropathy. Nevertheless, our data clearly demonstrate the beneficial effects of spice active principles in ACR-induced neuropathy in rats and suggest their possible therapeutic usage as an adjuvant in the management of other forms of neuropathy in humans. PMID:23161090

  3. [Neuroprotective effects of a novel antidiabetic drug (D-Ser2)Oxm on amyloid β protein-induced cytotoxicity].

    PubMed

    Han, Yu-Fei; Holscher, Christian; Wang, Zhao-Jun; Zhang, Jun; Yuan, Li; Tong, Jia-Qing; Wang, Dan-Dan; Wu, Mei-Na; Qi, Jin-Shun

    2016-06-25

    The accumulation and neurotoxicity of amyloid β protein (Aβ) in the brain is one of major pathological hallmarks of Alzheimer's disease (AD). The effective drugs against Aβ have been still deficient up to now. According to a most recent study, (D-Ser2) Oxm, a new antidiabetic drug, not only improves the disorders in plasma glucose and insulin in type 2 diabetes mellitus (T2DM) rats, but also exerts positive effects on hippocampal neurogenesis and synaptogenesis. However, it is still unclear whether (D-Ser2)Oxm can directly protect cultured neurons against Aβ1-42-induced cytotoxicity. In the present study, we investigated the neuroprotective effects of (D-Ser2)Oxm on the cultured primary hippocampal neurons by testing the cell viability, neuronal apoptosis, mitochondrial membrane potential and intracellular calcium concentration. The results showed that treatment with (D-Ser2)Oxm effectively reversed Aβ1-42-induced decline in cell viability (P < 0.001), and this protective effect could be inhibited by the pretreatment with exendin(9-39), a GLP-1 receptor blocker. (D-Ser2)Oxm treatment also decreased Aβ1-42-induced neuronal early apoptosis and down-regulated apoptotic protein caspase3. Meantime, (D-Ser2)Oxm treatment inhibited Aβ1-42-induced [Ca(2+)]i elevation, mitochondrial membrane potential depolarization, and glycogen synthase kinase-3β (GSK3β) activation. These results suggest that (D-Ser2)Oxm can protect hippocampal neurons against Aβ1-42-induced cytotoxicity and this effect may be related to activation of GLP-1 receptors, regulation of intracellular calcium homeostasis and stabilization of mitochondrial membrane potential. PMID:27350199

  4. A comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced memory impairments in rats.

    PubMed

    Jawaid, Talha; Jahan, Shah; Kamal, Mehnaz

    2015-01-01

    The comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced neuroinflammation in albino Wistar rats was studied. Male albino rats were administered with scopolamine to induce memory impairment. The standard nootropic agent, piracetam (200 mg/kg b.w., [i.p.]), perindopril (0.1 mg/kg b.w., [i.p.]), enalapril (0.1 mg/kg b.w., [i.p.]), and ramipril (0.1 mg/kg b.w., [i.p.]) were administered in different group of animals for 5 days. On 5(th) day, scopolamine (1 mg/kg b.w., i.p.) was administered after 60 min of the last dose of test drug. Memory function was evaluated in Morris water maze (MWM) test and pole climbing test (PCT). Biochemical estimations like glutathione (GSH), malondialdehyde (MDA), and acetylcholinesterase activity in the brain were estimated after completion of behavior study. All three test groups shows improvement in learning and memory in comparison to control group. Perindopril treated group showed a more effective significant decrease in escape latency time and transfer latency time compared to enalapril and ramipril treated group on day 4 in MWM test and PCT, respectively. Perindopril shows a significant reduction in MDA level and acetylcholinesterase activity and a significant rise in GSH level compared to enalapril and ramipril. The finding of this study indicates that Perindopril is more effective in memory retention compared to enalapril and ramipril. PMID:26317078

  5. Neuroprotective Effects of A Standardized Flavonoid Extract of Safflower Against Neurotoxin-Induced Cellular and Animal Models of Parkinson's Disease.

    PubMed

    Ren, Rutong; Shi, Chunyan; Cao, Jing; Sun, Yi; Zhao, Xin; Guo, Yongfei; Wang, Chen; Lei, Hui; Jiang, Hanjie; Ablat, Nuramatjan; Xu, Jiamin; Li, Wan; Ma, Yingcong; Qi, Xianrong; Ye, Min; Pu, Xiaoping; Han, Hongbin

    2016-01-01

    Safflower has long been used to treat cerebrovascular diseases in China. We previously reported that kaempferol derivatives of safflower can bind DJ-1, a protein associated with Parkinson's disease (PD), and flavonoid extract of safflower exhibited neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD. In this study, a standardized safflower flavonoid extract (SAFE) was isolated from safflower and mainly contained flavonoids. Two marker compounds of SAFE, kaempferol 3-O-rutinoside and anhydrosafflor yellow B, were proven to suppress microtubule destabilization and decreased cell area, respectively. We confirmed that SAFE in dripping pill form could improve behavioural performances in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD, partially via the suppression of α-synuclein overexpression or aggregation, as well as the suppression of reactive astrogliosis. Using an MRI tracer-based method, we found that 6-OHDA could change extracellular space (ECS) diffusion parameters, including a decrease in tortuosity and the rate constant of clearance and an increase in the elimination half-life of the tracer in the 6-OHDA-lesioned substantia nigra. SAFE treatment could partially inhibit the changes in ECS diffusion parameters, which might provide some information about neuronal loss and astrocyte activation. Consequently, our results indicate that SAFE is a potential therapeutic herbal product for treatment of PD. PMID:26906725

  6. Neuroprotective effects of aqueous extracts of Uncaria tomentosa: Insights from 6-OHDA induced cell damage and transgenic Caenorhabditis elegans model.

    PubMed

    Shi, Zhenhua; Lu, Zhongbing; Zhao, Yashuo; Wang, Yueqi; Zhao-Wilson, Xi; Guan, Peng; Duan, Xianglin; Chang, Yan-Zhong; Zhao, Baolu

    2013-06-01

    Previous pharmacological studies have indicated that AC11 (a standardized aqueous extract of Uncaria tomentosa) has beneficial effects on DNA repair and immune function. However, its benefits go beyond this. The present study utilized electron spin resonance (ESR) and spin trapping technique, as well as the 6-OHDA-induced cell damage and transgenic Caenorhabditis elegans models, towards exploring the antioxidant and neuroprotective ability of AC11. Our results showed that AC11 could scavenge several types of free radicals, especially hydroxyl radicals (60% of hydroxyl radicals were scavenged by 30 μg/ml of AC11). In SH-SY5Y cells, we found that AC11 could dose dependently protect 6-OHDA induced cell damage by increase cell viability and mitochondrial membrane potential. AC11 pretreatment also significantly decreased the level of lipid peroxidation, intracellular reactive oxygen species and nitric oxide in 6-OHDA treated cells. In NL5901 C. elegans, 10 μg/ml AC11 could reduce the aggregation of α-synuclein by 40%. These findings encourage further investigation on AC11 and its active constituent compounds, as possible therapeutic intervention against Parkinson's disease. PMID:23500604

  7. Cognitive deficits and decreased locomotor activity induced by single-walled carbon nanotubes and neuroprotective effects of ascorbic acid.

    PubMed

    Liu, Xudong; Zhang, Yuchao; Li, Jinquan; Wang, Dong; Wu, Yang; Li, Yan; Lu, Zhisong; Yu, Samuel C T; Li, Rui; Yang, Xu

    2014-01-01

    Single-walled carbon nanotubes (SWCNTs) have shown increasing promise in the field of biomedicine, especially in applications related to the nervous system. However, there are limited studies available on the neurotoxicity of SWCNTs used in vivo. In this study, neurobehavioral changes caused by SWCNTs in mice and oxidative stress were investigated. The results of ethological analysis (Morris water maze and open-field test), brain histopathological examination, and assessments of oxidative stress (reactive oxygen species [ROS], malondialdehyde [MDA], and glutathione [GSH]), inflammation (nuclear factor κB, tumor necrosis factor α, interleukin-1β), and apoptosis (cysteine-aspartic acid protease 3) in brains showed that 6.25 and 12.50 mg/kg/day SWCNTs in mice could induce cognitive deficits and decreased locomotor activity, brain histopathological alterations, and increased levels of oxidative stress, inflammation, and apoptosis in mouse brains; however, 3.125 mg/kg/day SWCNTs had zero or minor adverse effects in mice, and these effects were blocked by concurrent administration of ascorbic acid. Down-regulation of oxidative stress, inflammation, and apoptosis were proposed to explain the neuroprotective effects of ascorbic acid. This work suggests SWCNTs could induce cognitive deficits and decreased locomotor activity, and provides a strategy to avoid the adverse effects. PMID:24596461

  8. A comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced memory impairments in rats

    PubMed Central

    Jawaid, Talha; Jahan, Shah; Kamal, Mehnaz

    2015-01-01

    The comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced neuroinflammation in albino Wistar rats was studied. Male albino rats were administered with scopolamine to induce memory impairment. The standard nootropic agent, piracetam (200 mg/kg b.w., [i.p.]), perindopril (0.1 mg/kg b.w., [i.p.]), enalapril (0.1 mg/kg b.w., [i.p.]), and ramipril (0.1 mg/kg b.w., [i.p.]) were administered in different group of animals for 5 days. On 5th day, scopolamine (1 mg/kg b.w., i.p.) was administered after 60 min of the last dose of test drug. Memory function was evaluated in Morris water maze (MWM) test and pole climbing test (PCT). Biochemical estimations like glutathione (GSH), malondialdehyde (MDA), and acetylcholinesterase activity in the brain were estimated after completion of behavior study. All three test groups shows improvement in learning and memory in comparison to control group. Perindopril treated group showed a more effective significant decrease in escape latency time and transfer latency time compared to enalapril and ramipril treated group on day 4 in MWM test and PCT, respectively. Perindopril shows a significant reduction in MDA level and acetylcholinesterase activity and a significant rise in GSH level compared to enalapril and ramipril. The finding of this study indicates that Perindopril is more effective in memory retention compared to enalapril and ramipril. PMID:26317078

  9. Neuroprotective Effect of Puerarin on Glutamate-Induced Cytotoxicity in Differentiated Y-79 Cells via Inhibition of ROS Generation and Ca2+ Influx

    PubMed Central

    Wang, Ke; Zhu, Xue; Zhang, Kai; Wu, Zhifeng; Sun, Song; Zhou, Fanfan; Zhu, Ling

    2016-01-01

    Glutamate toxicity is estimated to be the key cause of photoreceptor degeneration in the pathogenesis of retinal degenerative diseases. Oxidative stress and Ca2+ influx induced by glutamate are responsible for the apoptosis process of photoreceptor degeneration. Puerarin, a primary component of Kudzu root, has been widely used in the clinical treatment of retinal degenerative diseases in China for decades; however, the detailed molecular mechanism underlying this effect remains unclear. In this study, the neuroprotective effect of puerarin against glutamate-induced cytotoxicity in the differentiated Y-79 cells was first investigated through cytotoxicity assay. Then the molecular mechanism of this effect regarding anti-oxidative stress and Ca2+ hemostasis was further explored with indirect immunofluorescence, flow cytometric analysis and western blot analysis. Our study showed that glutamate induced cell viability loss, excessive reactive oxygen species (ROS) generation, calcium overload and up-regulated cell apoptosis in differentiated Y-79 cells, which effect was significantly attenuated with the pre-treatment of puerarin in a dose-dependent manner. Furthermore, our data indicated that the neuroprotective effect of puerarin was potentially mediated through the inhibition of glutamate-induced activation of mitochondrial-dependent signaling pathway and calmodulin-dependent protein kinase II (CaMKII)-dependent apoptosis signal-regulating kinase 1(ASK-1)/c-Jun N-terminal kinase (JNK)/p38 signaling pathway. The present study supports the notion that puerarin may be a promising neuroprotective agent in the prevention of retinal degenerative diseases. PMID:27409614

  10. Neuroprotective Effect of Puerarin on Glutamate-Induced Cytotoxicity in Differentiated Y-79 Cells via Inhibition of ROS Generation and Ca(2+) Influx.

    PubMed

    Wang, Ke; Zhu, Xue; Zhang, Kai; Wu, Zhifeng; Sun, Song; Zhou, Fanfan; Zhu, Ling

    2016-01-01

    Glutamate toxicity is estimated to be the key cause of photoreceptor degeneration in the pathogenesis of retinal degenerative diseases. Oxidative stress and Ca(2+) influx induced by glutamate are responsible for the apoptosis process of photoreceptor degeneration. Puerarin, a primary component of Kudzu root, has been widely used in the clinical treatment of retinal degenerative diseases in China for decades; however, the detailed molecular mechanism underlying this effect remains unclear. In this study, the neuroprotective effect of puerarin against glutamate-induced cytotoxicity in the differentiated Y-79 cells was first investigated through cytotoxicity assay. Then the molecular mechanism of this effect regarding anti-oxidative stress and Ca(2+) hemostasis was further explored with indirect immunofluorescence, flow cytometric analysis and western blot analysis. Our study showed that glutamate induced cell viability loss, excessive reactive oxygen species (ROS) generation, calcium overload and up-regulated cell apoptosis in differentiated Y-79 cells, which effect was significantly attenuated with the pre-treatment of puerarin in a dose-dependent manner. Furthermore, our data indicated that the neuroprotective effect of puerarin was potentially mediated through the inhibition of glutamate-induced activation of mitochondrial-dependent signaling pathway and calmodulin-dependent protein kinase II (CaMKII)-dependent apoptosis signal-regulating kinase 1(ASK-1)/c-Jun N-terminal kinase (JNK)/p38 signaling pathway. The present study supports the notion that puerarin may be a promising neuroprotective agent in the prevention of retinal degenerative diseases. PMID:27409614

  11. G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

    PubMed Central

    Ivanov, Pavel; O’Day, Elizabeth; Emara, Mohamed M.; Wagner, Gerhard; Lieberman, Judy; Anderson, Paul

    2014-01-01

    Angiogenin (ANG) is a stress-activated ribonuclease that promotes the survival of motor neurons. Ribonuclease inactivating point mutations are found in a subset of patients with ALS, a fatal neurodegenerative disease with no cure. We recently showed that ANG cleaves tRNA within anticodon loops to produce 5′- and 3′-fragments known as tRNA-derived, stress-induced RNAs (tiRNAs). Selected 5′-tiRNAs (e.g., tiRNAAla, tiRNACys) cooperate with the translational repressor Y-box binding protein 1 (YB-1) to displace the cap-binding complex eIF4F from capped mRNA, inhibit translation initiation, and induce the assembly of stress granules (SGs). Here, we show that translationally active tiRNAs assemble unique G-quadruplex (G4) structures that are required for translation inhibition. We show that tiRNAAla binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5′-tiDNAAla (the DNA equivalent of 5′-tiRNAAla) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5′-tiDNAAla also assembles a G4 structure that allows it to enter motor neurons spontaneously and trigger a neuroprotective response in a YB-1–dependent manner. Remarkably, the ability of 5′-tiRNAAla to induce SG assembly is inhibited by G4 structures formed by pathological GGGGCC repeats found in C9ORF72, the most common genetic cause of ALS, suggesting that functional interactions between G4 RNAs may contribute to neurodegenerative disease. PMID:25404306

  12. Can medical herbs stimulate regeneration or neuroprotection and treat neuropathic pain in chemotherapy-induced peripheral neuropathy?

    PubMed

    Schröder, Sven; Beckmann, Kathrin; Franconi, Giovanna; Meyer-Hamme, Gesa; Friedemann, Thomas; Greten, Henry Johannes; Rostock, Matthias; Efferth, Thomas

    2013-01-01

    Chemotherapy-induced neuropathy (CIPN) has a relevant impact on the quality of life of cancer patients. There are no curative conventional treatments, so further options have to be investigated. We conducted a systematic review in English and Chinese language databases to illuminate the role of medical herbs. 26 relevant studies on 5 single herbs, one extract, one receptor-agonist, and 8 combinations of herbs were identified focusing on the single herbs Acorus calamus rhizoma, Cannabis sativa fructus, Chamomilla matricaria, Ginkgo biloba, Salvia officinalis, Sweet bee venom, Fritillaria cirrhosae bulbus, and the herbal combinations Bu Yang Huan Wu, modified Bu Yang Huan Wu plus Liuwei Di Huang, modified Chai Hu Long Gu Mu Li Wan, Geranii herba plus Aconiti lateralis praeparata radix , Niu Che Sen Qi Wan (Goshajinkigan), Gui Zhi Jia Shu Fu Tang (Keishikajutsubuto), Huang Qi Wu Wu Tang (Ogikeishigomotsuto), and Shao Yao Gan Cao Tang (Shakuyakukanzoto). The knowledge of mechanism of action is still limited, the quality of clinical trials needs further improvement, and studies have not yielded enough evidence to establish a standard practice, but a lot of promising substances have been identified. While CIPN has multiple mechanisms of neuronal degeneration, a combination of herbs or substances might deal with multiple targets for the aim of neuroprotection or neuroregeneration in CIPN. PMID:23983777

  13. Can Medical Herbs Stimulate Regeneration or Neuroprotection and Treat Neuropathic Pain in Chemotherapy-Induced Peripheral Neuropathy?

    PubMed Central

    Schröder, Sven; Beckmann, Kathrin; Franconi, Giovanna; Greten, Henry Johannes; Rostock, Matthias; Efferth, Thomas

    2013-01-01

    Chemotherapy-induced neuropathy (CIPN) has a relevant impact on the quality of life of cancer patients. There are no curative conventional treatments, so further options have to be investigated. We conducted a systematic review in English and Chinese language databases to illuminate the role of medical herbs. 26 relevant studies on 5 single herbs, one extract, one receptor-agonist, and 8 combinations of herbs were identified focusing on the single herbs Acorus calamus rhizoma, Cannabis sativa fructus, Chamomilla matricaria, Ginkgo biloba, Salvia officinalis, Sweet bee venom, Fritillaria cirrhosae bulbus, and the herbal combinations Bu Yang Huan Wu, modified Bu Yang Huan Wu plus Liuwei Di Huang, modified Chai Hu Long Gu Mu Li Wan, Geranii herba plus Aconiti lateralis praeparata radix , Niu Che Sen Qi Wan (Goshajinkigan), Gui Zhi Jia Shu Fu Tang (Keishikajutsubuto), Huang Qi Wu Wu Tang (Ogikeishigomotsuto), and Shao Yao Gan Cao Tang (Shakuyakukanzoto). The knowledge of mechanism of action is still limited, the quality of clinical trials needs further improvement, and studies have not yielded enough evidence to establish a standard practice, but a lot of promising substances have been identified. While CIPN has multiple mechanisms of neuronal degeneration, a combination of herbs or substances might deal with multiple targets for the aim of neuroprotection or neuroregeneration in CIPN. PMID:23983777

  14. Neuroprotection by Vitamin C Against Ethanol-Induced Neuroinflammation Associated Neurodegeneration in the Developing Rat Brain.

    PubMed

    Ahmad, Ashfaq; Shah, Shahid A; Badshah, Haroon; Kim, Min J; Ali, Tahir; Yoon, Gwang H; Kim, Tae H; Abid, Nouman B; Rehman, Shafiq Ur; Khan, Sohail; Kim, Myeong O

    2016-01-01

    Ethanol induces oxidative stress and its exposure during early developmental age causes neuronal cell death which leads to several neurological disorders. We previously reported that vitamin C can protect against ethanol-induced apoptotic cell death in the developing rat brain. Here, we extended our study to understand the therapeutic efficacy of vitamin C against ethanol-induced oxidative stress, neuroinflammation mediated neurodegeneration in postnatal day 7 (PND7) rat. A single episode of ethanol (5g/kg) subcutaneous administration to postnatal day 7 rat significantly induced the production of reactive oxygen species (ROS), and activated both microglia and astrocytes followed by the induction of different apoptotic markers. On the other hand, due to its free radical scavenging properties, vitamin C treatment significantly reduced the production of reactive oxygen species, suppressed both activated microglia and astrocytes and reversed other changes including elevated level of Bax/Bcl-2 ratio, cytochrome c and different caspases such as caspase-9 and caspase-3 induced by ethanol in developing rat brain. Moreover, vitamin C treatment also reduced ethanol-induced activation of Poly [ADP-Ribose] Polymerase 1(PARP-1) and neurodegeneration as evident from Flouro-Jade-B and Nissl stainined neuronal cell death in PND7 rat brain. These findings suggest that vitamin C mitigated ethanol-induced oxidative stress, neuroinflammation and apoptotic neuronal loss and may be beneficial against ethanol damaging effects in brain development. PMID:26831257

  15. ACTIVITY-DEPENDENT NEUROPROTECTIVE PROTEIN–DERIVED PEPTIDE, NAP, PREVENTING ALCOHOL-INDUCED APOPTOSIS IN FETAL BRAIN OF C57BL/6 MOUSE

    PubMed Central

    SARI, Y.

    2012-01-01

    Possible prevention of the effects of prenatal alcohol exposure has been investigated using peptides that were previously shown to be involved in neuroprotection both in vitro and in vivo. I focused in this study on investigating the neuro-protective effects of one of these peptides with regard to the determination of the downstream signaling pathways involved in neuroprotection. This peptide with the sequence NAPVSIPQ, known as NAP, a fragment of activity-dependent neuroprotective protein, demonstrated a potent protective effect against oxidative stress associated with alcohol exposure. On embryonic day 7 (E7), weight-matched C57BL/6 pregnant females were assigned the following groups: (1) Ethanol liquid diet group (ALC) 25% (4.49%, v/v) ethano-derived calories, (2) Pair-fed (PF) control group (3) Chow control group, (4) treatment groups with alcohol alongside i.p. injections of d-NAP (ALC/d-NAP, 20 or 30 μg/20 g body weight), (5) PF/d-NAP control group. On E13, fetal brains were collected and assayed for TdT-mediated dUTP nick end labeling (TUNEL) staining, caspase-3 colorimetric assay and ELISA for cytochrome c detection. My results show that NAP significantly prevented alcohol-induced weight reduction of the fetal brain. Apoptosis was determined by TUNEL staining; NAP administration significantly prevented alcohol-induced increases in TUNEL-positive cells in primordium cingulate cortex and basal ganglia eminence. The investigation of downstream signaling pathways involving NAP neuroprotection revealed that this peptide significantly prevented alcohol-induced increase in the concentrations of caspase-3 in E13 fetal brains. Moreover, ELISA for cytochrome c shows that NAP significantly prevented both alcohol-induced increases in the level of cytosolic cytochrome c and alcohol-induced decreases in the level of mitochondrial cytochrome c. These data provide an understanding of NAP intracellular target, and the downstream mechanisms of action that will pave a path

  16. Neuroprotective action of deer bone extract against glutamate or Aβ₁₋₄₂-induced oxidative stress in mouse hippocampal cells.

    PubMed

    Kim, Cho Rong; Jeon, Hye Lyun; Shin, Suk Kyung; Kim, Hyun Jeong; Ahn, Chang-Won; Jung, Sung Ug; Park, Soo-Hyun; Kim, Mee Ree

    2014-02-01

    Water extracts of deer bone, called nokgol in Korean, and deer antlers have been traditionally used as anti-aging medicines. Deer antler extract is known to possess various activities, including anti-aging or anti-amnesic activity. However, there are no reports about the neuroprotective effect of deer bone extract (DBE). The objective of this study was to examine the neuroprotective effect of DBE on glutamate-induced cell death of mouse hippocampal cells (HT-22 cells) and to elucidate the mode of neuroprotective action of DBE. In this study, HT-22 cells was pretreated with DBE before stimulation with glutamate, and then, the effects of DBE on cell viability, oxidative stress markers, and MAP kinases were determined. Separately, the effect of DBE on H₂O₂ or amyloid beta peptide (1-42) (Aβ₁₋₄₂)-induced cytotoxicity of HT-22 cells was evaluated. DBE protected HT-22 cells from glutamate-induced cell death and prevented the increase in lactate dehydrogenase leakage in HT-22 cells. DBE also prevented glutamate-induced oxidative stress, as indicated by increased reactive oxygen species and lipid peroxidation as well as by decreases in glutathione (GSH) levels and GSH peroxidase activity. In addition, DBE inhibited glutamate-induced activation of c-Jun N-terminal kinases (JNK), p38, and extracellular signal-regulated kinase, indicators of oxidative stress-induced cell death. Furthermore, DBE also protected against H₂O₂ and Aβ₁₋₄₂-induced cytotoxicity. These results suggest that DBE may be a useful functional agent for the prevention against neurodegenerative disorders involving oxidative stress. PMID:24460377

  17. Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells

    PubMed Central

    Zhong, Lijun; Zhou, Juntuo; Chen, Xi; Lou, Yaxin; Liu, Dan; Zou, Xiajuan; Yang, Bin; Yin, Yuxin; Pan, Yan

    2016-01-01

    B12 belongs to the coumarin class of compounds that have been shown to have various physiological and pharmacological activities including anti-inflammatory, antibacterial, and antioxidant. In the present study, we characterised the neuroprotective effects of B12 against H2O2-induced neuronal cell damage in SH-SY5Y cells. Protein expression profiling in combination with pathway analysis was deployed to investigate the molecular events associated with the neuroprotective effects in human neuronal cells using a label-free quantitative proteomics approach. A total of 22 proteins were significantly differentially expressed in H2O2-damaged cells with or without B12 treatment. Bioinformatics analysis using the Cytoscape platform indicated that poly pyrimidine tract binding protein 1 (PTBP1) was highly associated with the protective effect, and western blotting verified that PTBP1 was up-regulated in H2O2 + B12 treatment group, compared with the H2O2 treated group. PTBP RNAi experiments knocked down PTBP expression, which cancelled out the protective effect of B12 on cell viability. Thus, we infer that B12 neuroprotective activity involves up-regulation of PTBP1 and its associated signalling networks following H2O2-induced apoptosis in SH-SY5Y cells. B12 or related compounds may prove to be useful therapeutic agents for the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. PMID:26951766

  18. Involvement of ERK1/2 pathway in neuroprotective effects of pyrroloquinoline quinine against rotenone-induced SH-SY5Y cell injury.

    PubMed

    Zhang, Q; Zhang, J; Jiang, C; Qin, J; Ke, K; Ding, F

    2014-06-13

    Pyrroloquinoline quinone (PQQ), a redox cofactor in the mitochondrial respiratory chain, has been shown to protect neurons against glutamate-induced damage both in vitro and in vivo. In this study, specific inhibitors to each of the mitochondrial complexes were used to find out which reactive oxygen species (ROS)-generating sites could be affected by PQQ. Then we established an in vitro model of Parkinson's disease (PD) by exposing cultured SH-SY5Y dopaminergic cells to rotenone, a complex I inhibitor. The neuroprotective effects of PQQ were observed by pretreatment of SH-SY5Y cells with PQQ before rotenone injury, and the possible involvement of certain signaling pathways were investigated. PQQ pretreatment prevented SH-SY5Y cells from rotenone-induced apoptosis in a concentration-dependent manner. PQQ neuroprotection was associated with inhibition of intracellular ROS production, modulation of the expression of apoptosis-related Bcl-2 and Bax, and regulation of the level of superoxide dismutase, glutathione, and malondialdehyde. Meanwhile, PQQ up-regulated the gene expression of Ndufs 1, 2, and 4 (complex I subunits), and increased mitochondrial viability and mitochondrial DNA content. Furthermore, PQQ pretreatment activated ERK1/2 phosphorylation in rotenone-injured SH-SY5Y cells, while ERK1/2 inhibition suppressed PQQ neuroprotection. All the results suggested that PQQ could protect SH-SY5Y cells against rotenone injury by reducing ROS production and maintaining mitochondrial functions through activation of ERK1/2 pathway. PMID:24755484

  19. Cyclooxygenase-independent neuroprotective effects of aspirin against dopamine quinone-induced neurotoxicity.

    PubMed

    Asanuma, Masato; Miyazaki, Ikuko; Kikkawa, Yuri; Kimoto, Naotaka; Takeshima, Mika; Murakami, Shinki; Miyoshi, Ko

    2012-09-01

    Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property. PMID:22674083

  20. Parkinsonian toxin-induced oxidative stress inhibits basal autophagy in astrocytes via NQO2/quinone oxidoreductase 2: Implications for neuroprotection.

    PubMed

    Janda, Elzbieta; Lascala, Antonella; Carresi, Cristina; Parafati, Maddalena; Aprigliano, Serafina; Russo, Vanessa; Savoia, Claudia; Ziviani, Elena; Musolino, Vincenzo; Morani, Federica; Isidoro, Ciro; Mollace, Vincenzo

    2015-01-01

    Oxidative stress (OS) stimulates autophagy in different cellular systems, but it remains controversial if this rule can be generalized. We have analyzed the effect of chronic OS induced by the parkinsonian toxin paraquat (PQ) on autophagy in astrocytoma cells and primary astrocytes, which represent the first cellular target of neurotoxins in the brain. PQ decreased the basal levels of LC3-II and LC3-positive vesicles, and its colocalization with lysosomal markers, both in the absence and presence of chloroquine. This was paralleled by increased number and size of SQSTM1/p62 aggregates. Downregulation of autophagy was also observed in cells chronically exposed to hydrogen peroxide or nonlethal concentrations of PQ, and it was associated with a reduced astrocyte capability to protect dopaminergic cells from OS in co-cultures. Surprisingly, PQ treatment led to inhibition of MTOR, activation of MAPK8/JNK1 and MAPK1/ERK2-MAPK3/ERK1 and upregulation of BECN1/Beclin 1 expression, all signals typically correlating with induction of autophagy. Reduction of OS by NMDPEF, a specific NQO2 inhibitor, but not by N-acetylcysteine, abrogated the inhibitory effect of PQ and restored autophagic flux. Activation of NQO2 by PQ or menadione and genetic manipulation of its expression confirmed the role of this enzyme in the inhibitory action of PQ on autophagy. PQ did not induce NFE2L2/NRF2, but when it was co-administered with NMDPEF NFE2L2 activity was enhanced in a SQSTM1-independent fashion. Thus, a prolonged OS in astrocytes inhibits LC3 lipidation and impairs autophagosome formation and autophagic flux, in spite of concomitant activation of several pro-autophagic signals. These findings outline an unanticipated neuroprotective role of astrocyte autophagy and identify in NQO2 a novel pharmacological target for its positive modulation. PMID:26046590

  1. Egg white hydrolysate promotes neuroprotection for neuropathic disorders induced by chronic exposure to low concentrations of mercury.

    PubMed

    Rizzetti, Danize Aparecida; Fernandez, Francisca; Moreno, Silvia; Uranga Ocio, José Antonio; Peçanha, Franck Maciel; Vera, Gema; Vassallo, Dalton Valentim; Castro, Marta Miguel; Wiggers, Giulia Alessandra

    2016-09-01

    This study aims to investigate whether the egg white hydrolysate (EWH) acts on the neuropathic disorders associated with long-term Mercury (Hg) exposure in rats. 8- week-old male Wistar rats were treated for 60 days with: a) Control - saline solution (i.m.); b) Mercury - HgCl2 (1st dose 4.6μg/kg, subsequent doses 0.07μg/kg/day, i.m.); c) Hydrolysate - EWH (1g/kg/day, gavage); d) Mercury and Hydrolysate. Mechanical allodynia was assessed using Von Frey Hairs test; heat hyperalgesia by the plantar test; catalepsy by a modification of the "ring test" and spontaneous locomotor activity by a photocell activity chambers. Analyses were performed at 0, 30 and 60 days of treatment. Brain and plasma MDA, plasma NPSH and TNF-α determination and skin immunohistochemistry were performed at 60 days. Hg induced a reduction in mechanical sensitivity threshold at 30 and 60 days and in thermal sensitivity threshold at 60 days. At the end of treatment catalepsy was developed, but there was not significant alteration in spontaneous locomotor activity. Hg also increased brain and plasma MDA, plasma NPSH and TNF-α levels and the number of Merkel cell-neurite complex in the skin. EWH prevented the development of mechanical allodynia, thermal hyperalgesia and catalepsy induced by Hg and the increase in MDA concentration in brain and plasma and in the number of Merkel cell-neurite complex in the skin. In conclusion, EWH promotes neuroprotection against the toxic effects caused by Hg, demonstrating a beneficial therapeutic potential. PMID:27350078

  2. Minocycline modulates neuroprotective effect of hesperidin against quinolinic acid induced Huntington's disease like symptoms in rats: behavioral, biochemical, cellular and histological evidences.

    PubMed

    Kumar, Anil; Chaudhary, Tanya; Mishra, Jitendriya

    2013-11-15

    Emerging evidences indicate hesperidin, a citrus flavanone, attenuates neurodegenerative processes and related complications. Besides its anti-oxidant properties, the other probable mechanisms which underpin its neuroprotective potential are still not clear. In light of emerging role of flavonoids in modulating oxidative stress and neuro-inflammation, the study has been designed to explore the possible neuroprotective effect of hesperidin and its combination with minocycline (microglial inhibitor), against quinolinic acid (QA) induced Huntington's disease (HD) like symptoms in rats. Unilateral intrastriatal administration of QA (300 nmol/4 µl) significantly reduced body weight, impaired behavior (locomotor activity, beam balance and memory performance), caused oxidative damage (increased lipid peroxidation, nitrite concentration, depleted super oxide dismutase and reduced glutathione), demonstrated mitochondrial dysfunction (decreased Complex-I, II, III, and IV activities), increased striatal lesion volume and altered the levels of TNF-α, caspase-3 as well as BDNF expression, as compared to sham group. Meanwhile, chronic hesperidin (100mg/kg, p.o.) and minocycline (25mg/kg, p.o.) treatment for 21 days significantly attenuated the behavioral, biochemical and cellular alterations as compared to QA treated (control) animals, whereas hesperidin (50mg/kg, p.o.) treatment was found to be non-significant. However, treatment of hesperidin (50mg/kg) in combination with minocycline (25mg/kg) potentiated their neuroprotective effect, which was significant as compared to their effects per se in QA treated animals. Taken altogether, the results of the present study suggest a possible interplay of microglial modulation and anti-oxidant effect in neuroprotective potential of hesperidin against QA induced HD like symptoms in rats. PMID:24211676

  3. Pressure-Induced Alterations in PEDF and PEDF-R Expression: Implications for Neuroprotective Signaling in Glaucoma

    PubMed Central

    Lee, Sean J; Duncan, D’Anne S; Echevarria, Franklin D; McLaughlin, William M; Hatcher, Jeremy B; Sappington, Rebecca M

    2015-01-01

    Introduction Alterations in neuron-glia signaling are implicated in glaucoma, a neurodegenerative disease characterized by retinal ganglion cell (RGC) death. Pigment epithelium derived factor (PEDF) is a secreted protein with potential neuroprotective qualities in retinal disease, including chronic ocular hypertension. Here we sought to determine whether moderate, short-term elevations in IOP alter PEDF signaling and whether pressure-induced PEDF signaling directly impacts RGC apoptosis. Methods In retina from naïve mice and mice with unilateral, microbead-induced glaucoma, we examined expression and cell type-specific localization of PEDF and its receptor (PEDF-R), using quantitative PCR and immunohistochemistry. Using primary cultures of purified RGCs and Müller cells, we examined cell type-specific expression of PEDF in response to 48 hours of elevated hydrostatic pressure, using multiplex ELISA and immunocytochemistry. We also measured pressure-induced apoptosis of RGCs in the presence or absence of atglistatin, a potent and selective inhibitor of PEDF-R, and recombinant PEDF, using TUNEL assays. Results PEDF and PEDF-R are constitutively expressed in naïve retina, primarily in the ganglion cell and nerve fiber layers. Elevated IOP increases PEDF and PEDF-R expression, particularly associated with RGCs and Müller cells. Elevated pressure in vitro increased PEDF secretion by 6-fold in RGCs and trended towards an increase in expression by Müller cells, as compared to ambient pressure. This was accompanied by changes in the subcellular localization of PEDF-R in both cell types. Inhibition of PEDF signaling with atglistatin increased pressure-induced apoptosis in RGCs and treatment with recombinant PEDF inhibited pressure-induced apoptosis, both in a dose-dependent manner. Conclusion Our findings suggest that moderate, short-term elevations in IOP promote PEDF signaling via up-regulation of both PEDF and PEDF-R. Based on in vivo and in vitro studies, this PEDF

  4. The Neuroprotective Effect of Erythropoietin on Rotenone-Induced Neurotoxicity in SH-SY5Y Cells Through the Induction of Autophagy.

    PubMed

    Jang, Wooyoung; Kim, Hee Ju; Li, Huan; Jo, Kwang Deog; Lee, Moon Kyu; Yang, Hyun Ok

    2016-08-01

    Currently, the autophagy pathway is thought to be important for the pathogenesis of Parkinson's disease (PD), and the modulation of autophagy may be a novel strategy for the treatment of this disease. Erythropoietin (EPO) has been reported to have neuroprotective effects through anti-oxidative, anti-apoptotic, and anti-inflammatory mechanisms, and it has also been shown to modulate autophagy signaling in an oxygen toxicity model. Therefore, we investigated the effects of EPO on autophagy markers and evaluated its neuroprotective effect on rotenone-induced neurotoxicity. We adapted the rotenone-induced neurotoxicity model to SH-SY5Y cells as an in vitro model of PD. We measured cell viability using MTT and annexin V/propidium iodide assays and measured intracellular levels of reactive oxygen species. Immunofluorescence analysis was performed to measure the expression of LC3 and α-synuclein. Intracellular signaling proteins associated with autophagy were examined by immunoblot analysis. EPO mono-treatment increased the levels of mammalian target of rapamycin (mTOR)-independent/upstream autophagy markers, including Beclin-1, AMPK, and ULK-1. Rotenone treatment of SH-SY5Y cells reduced their viability, increased reactive oxygen species levels, and induced apoptosis and α-synuclein expression, and simultaneous exposure to EPO significantly reduced these effects. Rotenone enhanced mTOR expression and suppressed Beclin-1 expression, indicating suppression of the autophagy system. However, combined treatment with EPO restored Beclin-1 expression and decreased mTOR expression. EPO protects against rotenone-induced neurotoxicity in SH-SY5Y cells by enhancing autophagy-related signaling pathways. The experimental evidence for the EPO-induced neuroprotection against rotenone-induced dopaminergic neurotoxicity may significantly impact the development of future PD treatment strategies. PMID:26156288

  5. Vitamin C neuroprotection against dose-dependent glutamate-induced neurodegeneration in the postnatal brain.

    PubMed

    Shah, Shahid Ali; Yoon, Gwang Ho; Kim, Hyun-Ok; Kim, Myeong Ok

    2015-05-01

    Glutamate-induced excitotoxicity due to over-activation of glutamate receptors and associated energy depletion (phosphorylation and activation of AMPK) results in neuronal cell death in various neurological disorders. Restoration of energy balance during an excitotoxic insult is critical for neuronal survival. Ascorbic acid (vitamin C), an essential nutrient with well-known antioxidant potential, protects the brain from oxidative damage in various models of neurodegeneration. In this study, we reported the therapeutic efficacy of vitamin C in response to glutamate-induced excitation, resulting in energy depletion and apoptosis in the hippocampus of the developing rat brain. A single subcutaneous injection of glutamate at two different concentrations (5 and 10 mg/kg) in postnatal day 7 rat pups increased brain glutamate levels and increased the protein expression of neuronal apoptotic markers. Both doses of glutamate upregulated the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2, cytochrome-c release, caspase-3 activation and the expression of PARP-1. However, co-treatment of vitamin C (250 mg/kg) with glutamate decreased brain glutamate levels and reversed the changes induced by glutamate in the developing hippocampus. Interestingly, only a high dose of glutamate caused the phosphorylation and activation of AMPK and induced neuronal cell death, whereas a low dose of glutamate failed to mediate these effects. Vitamin C supplementation reduced the glutamate-induced phosphorylation of AMPK and attenuated neuronal cell death, as assessed morphologically by Fluoro Jade B in the hippocampal CA1 region of the developing brain. Taken together, our results indicated that glutamate in both concentrations is toxic to the immature rat brain, whereas vitamin C is pharmacologically effective against glutamate-induced neurodegeneration. PMID:25701025

  6. Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors.

    PubMed

    Campos, Carlos; Rocha, Nuno Barbosa F; Lattari, Eduardo; Paes, Flávia; Nardi, António E; Machado, Sérgio

    2016-06-01

    Age-related neurodegenerative disorders, like Alzheimer's or Parkinson's disease, are becoming a major issue to public health care. Currently, there is no effective pharmacological treatment to address cognitive impairment in these patients. Here, we aim to explore the role of exercise-induced trophic factor enhancement in the prevention or delay of cognitive decline in patients with neurodegenerative diseases. There is a significant amount of evidence from animal and human studies that links neurodegenerative related cognitive deficits with changes on brain and peripheral trophic factor levels. Several trials with elderly individuals and patients with neurodegenerative diseases report exercise induced cognitive improvements and changes on trophic factor levels including BDNF, IGF-I, among others. Further studies with healthy aging and clinical populations are needed to understand how diverse exercise interventions produce different variations in trophic factor signaling. Genetic profiles and potential confounders regarding trophic factors should also be addressed in future trials. PMID:27086703

  7. Neuroprotective Effects of Agomelatine and Vinpocetine Against Chronic Cerebral Hypoperfusion Induced Vascular Dementia.

    PubMed

    Gupta, Surbhi; Singh, Prabhat; Sharma, Brij Mohan; Sharma, Bhupesh

    2015-01-01

    Chronic cerebral hypoperfusion (CCH) has been considered as a critical cause for the development of cognitive decline and dementia of vascular origin. Melatonin receptors have been reported to be beneficial in improving memory deterioration. Phosphodiesterase-1 (PDE1) enzyme offers protection against cognitive impairments and cerebrovascular disorders. Aim of this study is to explore the role of agomelatine (a dual MT1 and MT2 melatonin receptor agonist) and vinpocetine (selective PDE1 inhibitor) in CCH induced vascular dementia (VaD). Two vessel occlusion (2VO) or bilateral common carotid arteries ligation method was performed to initiate a phase of chronic hypoperfusion in mice. 2VO animals have shown significant cognitive deficits (Morris water maze), cholinergic dysfunction (increased acetyl cholinesterase -AChE) activity alongwith increased brain oxidative stress (decreased brain catalase, glutathione, as well as superoxide dismutase with an increase in malondialdehyde levels), and significant increase in brain infarct size (2,3,5- triphenylterazolium chloride-TTC staining). Treatment of agomelatine and vinpocetine reduced CCH induced learning and memory deficits and limited cholinergic dysfunction, oxidative stress, and tissue damage, suggesting that agomelatine and vinpocetine may provide benefits in CCH induced VaD. PMID:26036976

  8. Red Lentil Extract: Neuroprotective Effects on Perphenazine Induced Catatonia in Rats

    PubMed Central

    Tarahomi, Shahram; Arzi, Ardeshir; Goudarzi, Mehdi; Bahadoram, Mohammad; Rashidi-Nooshabadi, Mohammadreza

    2016-01-01

    Introduction Parkinsonism is a neurodegenerative disease that is defined by certain symptoms such as muscle rigidity, impaired movement, catatonia, tremor and disorientation of body. Aim The aim was to investigate the effect of red lentil extract on perphenazine-induced Catatonia in model of rat. Materials and Methods This experimental study was done on 48 male albino rats (weight 180–200g) of the Sprague-Dawley strain. Animals were randomly divided into six groups and were pre-treated with a single dose of red lentil extract (200, 400, 800 and 1000 mg/kg), most effective dose of bromocriptine (30mg/kg) and normal saline (5ml/kg) via intraperitoneal (IP) route. perphenazine (5 mg/kg) was after 30 minutes, administered (IP) to induce catatonia. The scoring method of Morpurgo was used to determine the muscular rigidity of animals. Results The results showed that the 200mg/kg red lentil extract treated group had no significant reduction in catatonic responses after perphenazine administration in comparison with control group while the groups that received 800 and 1000mg/kg of red lentil extract showed significant difference (p<0.05) at all the time points. Conclusion The results revealed that hydroalcoholic extract of red lentil has protective effect on Catatonia induced by perphenazine in rats. So this extract may be probably beneficial for catatonia in Parkinsonism. PMID:27504309

  9. Antiapoptotic and neuroprotective role of Curcumin in Pentylenetetrazole (PTZ) induced kindling model in rat.

    PubMed

    Saha, Lekha; Chakrabarti, Amitava; Kumari, Sweta; Bhatia, Alka; Banerjee, Dibyojyoti

    2016-02-01

    Kindling, a sub threshold chemical or electrical stimulation, increases seizure duration and enhances accompanied behavior until it reaches a sort of equilibrium state. The present study aimed to explore the effect of curcumin on the development of kindling in PTZ kindled rats and its role in apoptosis and neuronal damage. In a PTZ kindled Wistar rat model, different doses of curcumin (100, 200 and 300 mg/kg) were administrated orally one hour before the PTZ injections on alternate day during the whole kindling days. The following parameters were compared between control and experimental groups: the course of kindling, stages of seizures, Histopathological scoring of hippocampus, antioxidant parameters in the hippocampus, DNA fragmentation and caspase-3 expression in hippocampus, and neuron-specific enolase in the blood. One way ANOVA followed by Bonferroni post hoc analysis and Fischer's Exact test were used for statistical analyses. PTZ, 30 mg/kg, induced kindling in rats after 32.0 ± 1.4 days. Curcumin showed dose-dependent anti-seizure effect. Curcumin (300 mg/kg) significantly increased the latency to myoclonic jerks, clonic seizures as well as generalized tonic-clonic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ kindling induced a significant neuronal injury, oxidative stress and apoptosis which were reversed by pretreatment with curcumin in a dose-dependent manner. Our study suggests that curcumin has a potential antiepileptogenic effect on kindling-induced epileptogenesis. PMID:26934781

  10. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease

    PubMed Central

    Balez, Rachelle; Steiner, Nicole; Engel, Martin; Muñoz, Sonia Sanz; Lum, Jeremy Stephen; Wu, Yizhen; Wang, Dadong; Vallotton, Pascal; Sachdev, Perminder; O’Connor, Michael; Sidhu, Kuldip; Münch, Gerald; Ooi, Lezanne

    2016-01-01

    Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, yet current therapeutic treatments are inadequate due to a complex disease pathogenesis. The plant polyphenol apigenin has been shown to have anti-inflammatory and neuroprotective properties in a number of cell and animal models; however a comprehensive assessment has not been performed in a human model of AD. Here we have used a human induced pluripotent stem cell (iPSC) model of familial and sporadic AD, in addition to healthy controls, to assess the neuroprotective activity of apigenin. The iPSC-derived AD neurons demonstrated a hyper-excitable calcium signalling phenotype, elevated levels of nitrite, increased cytotoxicity and apoptosis, reduced neurite length and increased susceptibility to inflammatory stress challenge from activated murine microglia, in comparison to control neurons. We identified that apigenin has potent anti-inflammatory properties with the ability to protect neurites and cell viability by promoting a global down-regulation of cytokine and nitric oxide (NO) release in inflammatory cells. In addition, we show that apigenin is able to protect iPSC-derived AD neurons via multiple means by reducing the frequency of spontaneous Ca2+ signals and significantly reducing caspase-3/7 mediated apoptosis. These data demonstrate the broad neuroprotective action of apigenin against AD pathogenesis in a human disease model. PMID:27514990

  11. Molecular programs induced by heat acclimation confer neuroprotection against TBI and hypoxic insults via cross-tolerance mechanisms

    PubMed Central

    Horowitz, Michal; Umschweif, Gali; Yacobi, Assaf; Shohami, Esther

    2015-01-01

    Neuroprotection following prolonged exposure to high ambient temperatures (heat acclimation HA) develops via altered molecular programs such as cross-tolerance Heat Acclimation-Neuroprotection Cross-Tolerance (HANCT). The mechanisms underlying cross-tolerance depend on enhanced “on-demand” protective pathways evolving during acclimation. The protection achieved is long lasting and limits the need for de novo recruitment of cytoprotective pathways upon exposure to novel stressors. Using mouse and rat acclimated phenotypes, we will focus on the impact of heat acclimation on Angiotensin II-AT2 receptors in neurogenesis and on HIF-1 as key mediators in spontaneous recovery and HANCT after traumatic brain injury (TBI). The neuroprotective consequences of heat acclimation on NMDA and AMPA receptors will be discussed using the global hypoxia model. A behavioral-molecular link will be crystallized. The differences between HANCT and consensus preconditioning will be reviewed. PMID:26283898

  12. Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1

    PubMed Central

    Baxter, Paul S; Martel, Marc-Andre; McMahon, Aoife; Kind, Peter C; Hardingham, Giles E

    2011-01-01

    Pituitary adenylate cyclase-activating peptide (PACAP) is a neuroprotective peptide which exerts its effects mainly through the cAMP-protein kinase A (PKA) pathway. Here, we show that in cortical neurons, PACAP-induced PKA signaling exerts a major part of its neuroprotective effects indirectly, by triggering action potential (AP) firing. Treatment of cortical neurons with PACAP induces a rapid and sustained PKA-dependent increase in AP firing and associated intracellular Ca2+ transients, which are essential for the anti-apoptotic actions of PACAP. Transient exposure to PACAP induces long-lasting neuroprotection in the face of apoptotic insults which is reliant on AP firing and the activation of cAMP response element (CRE) binding protein (CREB)-mediated gene expression. Although direct, activity-independent PKA signaling is sufficient to trigger phosphorylation on CREB’s activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression. Full activation is dependent on CREB-regulated transcription co-activator 1 (CRTC1), whose PACAP-induced nuclear import is dependent on firing activity-dependent calcineurin signaling. Over-expression of CRTC1 is sufficient to rescue PACAP-induced CRE-mediated gene expression in the face of activity-blockade, while dominant negative CRTC1 interferes with PACAP-induced, CREB-mediated neuroprotection. Thus, the enhancement of AP firing may play a significant role in the neuroprotective actions of PACAP and other adenylate cyclase-coupled ligands. PMID:21623792

  13. Potential neuroprotective effects of SIRT1 induced by glucose deprivation in PC12 cells.

    PubMed

    Fujino, Kotaro; Ogura, Yurina; Sato, Kazunori; Nedachi, Taku

    2013-12-17

    Nutrient availability is one of the most important signals regulating cellular fates including cell growth, differentiation, and death. Recent evidence suggests that the NAD(+)-dependent histone deacetylase sirtuin 1 (SIRT1) plays a prominent role in linking changes in nutritional availability with cellular fate regulation. SIRT1 expression is observed in neurons, yet the expressional and functional regulation of this protein is not fully understood. In the present study, we examined whether extracellular glucose concentration affects the expression and localization of SIRT1 in PC12 cells. Further, we examined levels of forkhead box O3a (FoxO3a), which is also controlled by changes in extracellular glucose concentration. We observed the total expression levels of SIRT1 and FoxO3a in PC12 cells were reduced when glucose availability increased via gene expressional control, at least in part. Nuclear localization of SIRT1 and FoxO3a was increased by glucose deprivation. Even though the changes in extracellular glucose concentration regulated SIRT1 and FoxO3a in a similar direction, the effects of nerve growth factor on these two proteins were completely different. Finally, we found the potent SIRT1 inhibitor enhanced glucose deprivation-induced cell death. Therefore, we propose that glucose deprivation-induced SIRT1 expression potentially plays a major role in protecting PC12 cells. PMID:24183892

  14. Neuroprotective Effect of Tauroursodeoxycholic Acid on N-Methyl-D-Aspartate-Induced Retinal Ganglion Cell Degeneration

    PubMed Central

    Fernández-Sánchez, Laura; Rondón, Netxibeth; Esquiva, Gema; Germain, Francisco; de la Villa, Pedro; Cuenca, Nicolás

    2015-01-01

    Retinal ganglion cell degeneration underlies the pathophysiology of diseases affecting the retina and optic nerve. Several studies have previously evidenced the anti-apoptotic properties of the bile constituent, tauroursodeoxycholic acid, in diverse models of photoreceptor degeneration. The aim of this study was to investigate the effects of systemic administration of tauroursodeoxycholic acid on N-methyl-D-aspartate (NMDA)-induced damage in the rat retina using a functional and morphological approach. Tauroursodeoxycholic acid was administered intraperitoneally before and after intravitreal injection of NMDA. Three days after insult, full-field electroretinograms showed reductions in the amplitudes of the positive and negative-scotopic threshold responses, scotopic a- and b-waves and oscillatory potentials. Quantitative morphological evaluation of whole-mount retinas demonstrated a reduction in the density of retinal ganglion cells. Systemic administration of tauroursodeoxycholic acid attenuated the functional impairment induced by NMDA, which correlated with a higher retinal ganglion cell density. Our findings sustain the efficacy of tauroursodeoxycholic acid administration in vivo, suggesting it would be a good candidate for the pharmacological treatment of degenerative diseases coursing with retinal ganglion cell loss. PMID:26379056

  15. Rosiglitazone activation of PPARγ-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced mitochondrial dysfunction and oxidative stress.

    PubMed

    Chiang, Ming-Chang; Nicol, Christopher J; Cheng, Yi-Chuan; Lin, Kuan-Hung; Yen, Chia-Hui; Lin, Chien-Hung

    2016-04-01

    Neuronal cell impairment, such as that induced by amyloid-beta (Aβ) protein, is a process with limited therapeutic interventions and often leads to long-term neurodegeneration common in disorders such as Alzheimer's disease. Interestingly, peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor whose ligands control many physiological and pathologic processes, and may be neuroprotective. We hypothesized that rosiglitazone, a PPARγ agonist, would prevent Aβ-mediated effects in human neural stem cells (hNSCs). Here, we show that rosiglitazone reverses, via PPARγ-dependent downregulation of caspase 3 and 9 activity, the Aβ-mediated decreases in hNSC cell viability. In addition, Aβ decreases hNSC messenger RNA (mRNA) levels of 2 neuroprotective factors (Bcl-2 and CREB), but co-treatment with rosiglitazone significantly rescues these effects. Rosiglitazone co-treated hNSCs also showed significantly increased mitochondrial function (reflected by levels of adenosine triphosphate and Mit mass), and PPARγ-dependent mRNA upregulation of PGC1α and mitochondrial genes (nuclear respiratory factor-1 and Tfam). Furthermore, hNSCs co-treated with rosiglitazone were significantly rescued from Aβ-induced oxidative stress and correlates with reversal of the Aβ-induced mRNA decrease in oxidative defense genes (superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 1). Taken together, these novel findings show that rosiglitazone-induced activation of PPARγ-dependent signaling rescues Aβ-mediated toxicity in hNSCs and provide evidence supporting a neuroprotective role for PPARγ activating drugs in Aβ-related diseases such as Alzheimer's disease. PMID:26973118

  16. Neuroprotective effect of astaxanthin against glutamate-induced cytotoxicity in HT22 cells: Involvement of the Akt/GSK-3β pathway.

    PubMed

    Wen, X; Huang, A; Hu, J; Zhong, Z; Liu, Y; Li, Z; Pan, X; Liu, Z

    2015-09-10

    Oxidative stress (OS) mediated the pathogenesis of Alzheimer's disease (AD). Astaxanthin (ATX) has been reported to exert antioxidant activities as well as neuroprotective effects in vivo and in vitro. But it is still unknown whether the Akt/glycogen synthase kinase-3β (GSK-3β) signaling mediated the neuroprotective effect of ATX in HT22 cells. Flow cytometric analysis was used to evaluate reactive oxygen species (ROS) generation. Caspase and PARP activity was measured. The expressions of heme oxygenase-1 (HO-1), nuclear factor-E2-related factor 2 (Nrf2), Bcl-2, Bax, apoptosis-inducing factor (AIF), cytochrome-c (Cyto-c), p-Akt and p-GSK-3β were evaluated to elucidate the underlying mechanism. Our results showed that ATX significantly attenuated glutamate-induced cell viability loss and lactate dehydrogenase (LDH) release, decreased the expression of caspase-3/8/9 activity and cleaved PARP, and suppressed the intracellular accumulation of ROS in HT22 cells after exposure to glutamate. ATX also increased the mitochondrial expression of AIF, Cyto-c as well as Bax while decreased Bcl-2. Moreover, ATX also induced the HO-1 expression in a dose and time-dependent manner, increased the antioxidant-responsive element (ARE) activity and nuclear Nrf2 expression. Furthermore, treatment with ATX restored the p-Akt and p-GSK-3β (Ser9) as well as HO-1 expression reduced by glutamate. This protective effect was partially blocked by the inhibitors lithium chloride treatment in HT22, indicating the involvement of Akt/GSK-3β inactivation during the neuroprotective effect of ATX. Our results provide the first evidence that ATX can protect glutamate-induced cytotoxicity in HT22 via attenuating caspase activation and mitochondrial dysfunction and modulating the Akt/GSK-3β signaling, indicating ATX may be useful for the treatment of neurodegenerative disorders such as AD. PMID:26197224

  17. A Hypothesis: Hydrogen Sulfide Might Be Neuroprotective against Subarachnoid Hemorrhage Induced Brain Injury

    PubMed Central

    Yu, Yong-Peng; Chi, Xiang-Lin; Liu, Li-Jun

    2014-01-01

    Gases such as nitric oxide (NO) and carbon monoxide (CO) play important roles both in normal physiology and in disease. Recent studies have shown that hydrogen sulfide (H2S) protects neurons against oxidative stress and ischemia-reperfusion injury and attenuates lipopolysaccharides (LPS) induced neuroinflammation in microglia, exhibiting anti-inflammatory and antiapoptotic activities. The gas H2S is emerging as a novel regulator of important physiologic functions such as arterial diameter, blood flow, and leukocyte adhesion. It has been known that multiple factors, including oxidative stress, free radicals, and neuronal nitric oxide synthesis as well as abnormal inflammatory responses, are involved in the mechanism underlying the brain injury after subarachnoid hemorrhage (SAH). Based on the multiple physiologic functions of H2S, we speculate that it might be a promising, effective, and specific therapy for brain injury after SAH. PMID:24707204

  18. Caffeine neuroprotects against dexamethasone-induced anxiety-like behaviour in the Zebrafish (Danio rerio).

    PubMed

    Khor, Yee Min; Soga, Tomoko; Parhar, Ishwar S

    2013-01-15

    The early-life stress has critical impact on brain development which can lead to long-term effects on brain functions during adulthood. It has been reported that caffeine possesses a protective effect in neurodegenerative diseases. Thus, this study investigates the potential of caffeine to protect brain functions from adverse effects due to stress exposure during early-life development in the male zebrafish. In the first part of this study, synthetic glucocorticoid, dexamethasone (DEX) (2-200 mg/L for 24 h) was used to induce stress effects in the zebrafish larvae from 4 to 5 days post-fertilisation (dpf) and the effect of DEX administration on zebrafish larvae on anxiety-like behaviour during adulthood in novel tank test was investigated. Next, the possible protective effect of caffeine pre-treatment (5-50 mg/L for 24 h from 3 to 4dpf) before DEX administration was studied. DEX-treated adult male zebrafish showed higher anxiety levels in behavioural tests, as seen in longer latency to enter the top part of the tank, lower transition numbers between the top and bottom parts with more time spent at the bottom and lesser time spent at the top and lower distance travelled at top part. The effect of DEX on anxiety-like behaviour was dose-dependent. Importantly, adult male zebrafish pre-treated with caffeine before DEX treatment did not show any anxiety-like behaviour. These results show that exposure to stress during early-life leads to anxiety-like behaviour in the adult male zebrafish but pre-treatment with caffeine protects from stress-induced anxiety. PMID:23044054

  19. The neuroprotective action of pyrroloquinoline quinone against glutamate-induced apoptosis in hippocampal neurons is mediated through the activation of PI3K/Akt pathway

    SciTech Connect

    Zhang Qi; Shen Mi; Ding Mei; Shen Dingding; Ding Fei

    2011-04-01

    Pyrroloquinoline quinone (PQQ), a cofactor in several enzyme-catalyzed redox reactions, possesses a potential capability of scavenging reactive oxygen species (ROS) and inhibiting cell apoptosis. In this study, we investigated the effects of PQQ on glutamate-induced cell death in primary cultured hippocampal neurons and the possible underlying mechanisms. We found that glutamate-induced apoptosis in cultured hippocampal neurons was significantly attenuated by the ensuing PQQ treatment, which also inhibited the glutamate-induced increase in Ca2+ influx, caspase-3 activity, and ROS production, and reversed the glutamate-induced decrease in Bcl-2/Bax ratio. The examination of signaling pathways revealed that PQQ treatment activated the phosphorylation of Akt and suppressed the glutamate-induced phosphorylation of c-Jun N-terminal protein kinase (JNK). And inhibition of phosphatidylinositol-3-kinase (PI3K)/Akt cascade by LY294002 and wortmannin significantly blocked the protective effects of PQQ, and alleviated the increase in Bcl-2/Bax ratio. Taken together, our results indicated that PQQ could protect primary cultured hippocampal neurons against glutamate-induced cell damage by scavenging ROS, reducing Ca2+ influx, and caspase-3 activity, and suggested that PQQ-activated PI3K/Akt signaling might be responsible for its neuroprotective action through modulation of glutamate-induced imbalance between Bcl-2 and Bax. - Research Highlights: >PQQ attenuated glutamate-induced cell apoptosis of cultured hippocampal neurons. >PQQ inhibited glutamate-induced Ca{sup 2+} influx and caspase-3 activity. >PQQ reduced glutamate-induced increase in ROS production. >PQQ affected phosphorylation of Akt and JNK signalings after glutamate injury. >PI3K/Akt was required for neuroprotection of PQQ by modulating Bcl-2/Bax ratio.

  20. The neuroprotective role of boric acid on aluminum chloride-induced neurotoxicity.

    PubMed

    Colak, Suat; Geyikoglu, Fatime; Keles, Osman Nuri; Türkez, Hasan; Topal, Ahmet; Unal, Bünyami

    2011-09-01

    This study was designed to investigate the qualitative and quantitative changes in brain tissue following aluminum chloride (AlCl(3)) administration and to determine whether boric acid (BA) has a protective effect against brain damage induced by AlCl( 3). For this aim, Sprague-Dawley rats were randomly separated into eight groups: (1) control, (2) AlCl(3) (5 mg/kg/day), (3, 4 and 5) BA (3.25, 36 and 58.5 mg/kg/day), (6, 7 and 8) AlCl(3) (5 mg/kg/day) plus BA (3.25, 36 and 58.5 mg/kg/day). After the animals were killed, the total numbers of neuron in the brain of all groups were determined using an unbiased stereological analysis. In addition to the stereological analysis, all brains were examined histopathologically by using light and electron microscopy. The stereological and histopathological results indicated a high damage of the rat brain tissues in the AlCl(3) and AlCl(3) + high dose BA (36 and 58.5) treatment groups. However, protective effects on neuron were observed in the AlCl(3) + low dose BA (3.25) group when compared other AlCl(3) groups. Our stereological and histopathological findings show that low-dose BA, as a proteasome inhibitor, can decrease the adverse effects of AlCl(3) on the cerebral cortex. PMID:21543463

  1. A cellular lipidomic study on the Aβ-induced neurotoxicity and neuroprotective effects of EGCG by using UPLC/MS-based glycerolipids profiling and multivariate analysis.

    PubMed

    Zhang, Hongyang; Wang, Jing-Rong; Yau, Lee Fong; Ho, Hing Man; Chan, Chi Leung; Hu, Ping; Liu, Liang; Jiang, Zhi-Hong

    2012-10-30

    The aim of this study was to investigate the cellular lipid metabolism associated with β-amyloid peptide (Aβ)-induced neurotoxicity as well as the neuroprotective effect of (-)-epigallocatechin gallate (EGCG), a major polyphenol in green tea. An ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS)-based lipidomic approach was developed to screen and identify changes of the glycerolipids (GL) upon Aβ treatment with or without the presence of EGCG in PC12 cells. Principle component analysis (PCA) showed that the Aβ-treated group was well separated from the control group, whereas the EGCG group was closer to the control group. The GL levels were significantly elevated in Aβ-treated cells compared with the control group, but were restored near to normal levels after EGCG treatment. The elevated phosphatidylcholines (PCs) levels observed in the Aβ-treated PC12 cells were quite probably the integrated results of the reduced phospholipase A(2) (PLA(2)) activity and the enhanced activity of lysophospholipid acyltransferases. Moreover, an increased liberation of arachidonic acid (AA) from PCs was observed as another important response of PC12 cells to the Aβ aggregates, implying an active inflammatory process occurring in Aβ induced neurotoxicity. EGCG treatment can reverse the deregulated metabolism of PCs, which might be one of the biochemical mechanisms contributing to its neuroprotective effect. Collectively, results obtained from the current lipidomic analyses of PC12 cells provided important insight into the biochemical mechanisms underlying Aβ-induced neurotoxicity and neuro protective effects of EGCG. This is the first report of the lipidomic study on the neuroprotective effect of EGCG. PMID:23032920

  2. Role of Dickkopf-1 (Dkk1), an Antagonist of the Wnt-β-Catenin Signaling Pathway, in Estrogen-Induced Neuroprotection and Attenuation of Tau Phosphorylation

    PubMed Central

    Zhang, Quan-Guang; Wang, Ruimin; Khan, Mohammad; Mahesh, Virendra; Brann, Darrell W.

    2009-01-01

    17β-Estradiol (E2) has been implicated to be neuroprotective in a variety of neurodegenerative disorders, although the mechanism remains poorly understood. The current study sheds light on this issue by demonstrating that low physiological levels of E2 protects the hippocampus CA1 against global cerebral ischemia by preventing elevation of dickkopf-1 (Dkk1), an antagonist of the Wnt-β-Catenin signaling pathway, which is a principal mediator of neurodegeneration in cerebral ischemia and Alzheimer’s disease. E2 inhibition of Dkk1 elevation correlated with a reduction of phospho-β-Catenin and elevation of nuclear β-Catenin levels, as well as enhancement of Wnt-3, suggesting E2 activation of the Wnt-β-Catenin signaling pathway. In agreement, the β-Catenin-downstream prosurvival factor, survivin was induced by E2 at 24 hr and 48 hr after cerebral ischemia, an effect observed only in surviving neurons, as degenerating neurons lacked survivin expression. E2 suppression of Dkk1 elevation was found to be due to attenuation of upstream JNK/c-Jun signaling, as E2 attenuated of JNK/c-Jun activation and a JNK inhibitor significantly blocked Dkk1 induction. Tau hyperphosphorylation has been implicated to have a prodeath role in Alzheimer’s disease and cerebral ischemia, and E2 attenuates tau hyperphosphorylation. Our study demonstrates that tau hyperphosphorylation is strongly induced after global cerebral ischemia, and that E2 inhibits tau hyperphosphorylation by suppressing activation of the JNK/c-Jun/Dkk1 signaling pathway. Finally, exogenous Dkk1 replacement via icv administration completely reversed E2 induced-neuroprotection, nuclear β-Catenin induction and phospho-tau attenuation, further suggesting that E2 inhibition of Dkk1 is a critical mechanism underlying its neuroprotective and phospho-tau regulatory effects following cerebral ischemia. PMID:18716201

  3. Running wheel exercise enhances recovery from nigrostriatal dopamine injury without inducing neuroprotection.

    PubMed

    O'Dell, S J; Gross, N B; Fricks, A N; Casiano, B D; Nguyen, T B; Marshall, J F

    2007-02-01

    Forced use of the forelimb contralateral to a unilateral injection of the dopaminergic neurotoxin 6-hydroxydopamine can promote recovery of motor function in that limb and can significantly decrease damage to dopamine terminals. The present study was conducted to determine (1) whether a form of voluntary exercise, wheel running, would improve motor performance in rats with such lesions, and (2) whether any beneficial effects of wheel running are attributable to ameliorating the dopaminergic damage. In experiment 1, rats were allowed to run in exercise wheels or kept in home cages for 2 1/2 weeks, then given stereotaxic infusions of 6-hydroxydopamine into the left striatum. The rats were replaced into their original environments (wheels or home cages) for four additional weeks, and asymmetries in forelimb use were quantified at 3, 10, 17, and 24 days postoperatively. After killing, dopaminergic damage was assessed by both quantifying 3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding to striatal dopamine transporters and counting tyrosine hydroxylase-positive cells in the substantia nigra. Exercised 6-hydroxydopamine-infused rats showed improved motor outcomes relative to sedentary lesioned controls, effects that were most apparent at postoperative days 17 and 24. Despite this behavioral improvement, 6-hydroxydopamine-induced loss of striatal dopamine transporters and tyrosine hydroxylase-positive nigral cells in exercised and sedentary groups did not differ. Since prior studies suggested that forced limb use improves motor performance by sparing nigrostriatal dopaminergic neurons from 6-hydroxydopamine damage, experiment 2 used a combined regimen of forced plus voluntary wheel running. Again, we found that the motor performance of exercised rats improved more rapidly than that of sedentary controls, but that there were no differences between these groups in the damage produced by 6-hydroxydopamine. It appears that voluntary

  4. Role of the pituitary–adrenal axis in granulocyte-colony stimulating factor-induced neuroprotection against hypoxia–ischemia in neonatal rats

    PubMed Central

    Charles, Mélissa S.; Ostrowski, Robert P.; Manaenko, Anatol; Duris, Kamil; Zhang, John H.; Tang, Jiping

    2013-01-01

    Several reports indicate that the activity of the hypothalamic–pituitary–adrenal axis (HPA) is increased after a brain insult and that its down-regulation can improve detrimental outcomes associated with ischemic brain injuries. Granulocyte-colony stimulating factor (G-CSF) is a neuroprotective drug shown in the naïve rat to regulate hormones of the HPA axis. In this study we investigate whether G-CSF confers its neuroprotective properties by influencing the HPA response after neonatal hypoxia–ischemia (HI). Following the Rice–Vannucci model, seven day old rats (P7) were subjected to unilateral carotid ligation followed by 2.5 h of hypoxia. To test our hypothesis, metyrapone was administered to inhibit the release of rodent specific glucocorticoid, corticosterone, at the adrenal level. Dexamethasone, a synthetic glucocorticoid, was administered to agonize the effects of corticosterone. Our results show that both G-CSF and metyrapone significantly reduced infarct volume while dexamethasone treatment did not reduce infarct size even when combined with G-CSF. The protective effects of G-CSF do not include blood brain barrier preservation as suggested by the brain edema results. G-CSF did not affect the pituitary released adrenocorticotropic hormone (ACTH) levels in the blood plasma at 4 h, but suppressed the increase of corticosterone in the blood. The administration of G-CSF and metyrapone increased weight gain, and significantly reduced the Bax/Bcl-2 ratio in the brain while dexamethasone reversed the effects of G-CSF. The combination of G-CSF and metyrapone significantly decreased caspase-3 protein levels in the brain, and the effect was antagonized by dexamethasone. We report that G-CSF is neuroprotective in neonatal HI by reducing infarct volume, by suppressing the HI-induced increase of the Bax/Bcl-2 ratio, and by decreasing corticosterone in the blood. Metyrapone was able to confer similar neuroprotection as G-CSF while dexamethasone reversed the

  5. Neuroprotection induced by N-acetylcysteine against cytosolic glutathione depletion-induced Ca2+ influx in dorsal root ganglion neurons of mice: role of TRPV1 channels.

    PubMed

    Nazıroğlu, M; Ciğ, B; Ozgül, C

    2013-07-01

    Glutathione (GSH) and N-acetylcysteine (NAC) are thiol-containing antioxidants, and also act through a direct reaction with free radicals. Transient receptor potential vanilloid 1 (TRPV1) is the principal transduction channel serving as a polymodal detector. Despite the importance of oxidative stress in pain sensitivity, its role in TRPV1 modulation is poorly understood. NAC may also have a regulator role on TRPV1 channel activity in the dorsal root ganglion (DRG) neuron. Therefore, we tested the effects of GSH and NAC on TRPV1 channel current, Ca(2+) influx, oxidative stress and caspase activity in the DRG of mice. DRG neurons were freshly isolated from mice and the neurons were incubated for 6 and 24h with buthionine sulfoximine (BSO). Pretreatment of cultured DRG neurons with NAC, results in a protection against oxidative damages. This neuroprotection is associated with the attenuation of a Ca(2+) influx triggered by oxidative agents such as H2O2, 5,5'-dithiobis-(2-nitrobenzoic acid) and GSH depletion via BSO. Here, we demonstrate the contribution of cytosolic factors (related to thiol group depletion) on the activation of TRPV1 channels in this mechanism. TRPV1 channels are activated by various agents including capsaicin (CAP), the pungent component of hot chili peppers, and are blocked by capsazepine. An oxidative environment also increased CAP-evoked TRPV1 currents in the neurons. When NAC and GSH were included in the patch pipette as well as extracellularly in the chamber, TRPV1 channels were not activated by CAP and H2O2. TRPV1 inhibitors, 2-aminoethyl diphenylborinate and N-(p-amylcinnamoyl)anthranilic acid strongly reduced BSO-induced oxidative toxicity and Ca(2+) influx, in a manner similar to pretreatment with NAC and GSH. Caspase-3 and -9 activities of all groups were not changed by the agonists or antagonists. In conclusion, in our experimental model, TRPV1 channels are involved in the oxidative stress-induced neuronal death, and negative modulation

  6. Neuroprotective effects of honokiol against beta-amyloid-induced neurotoxicity via GSK-3β and β-catenin signaling pathway in PC12 cells.

    PubMed

    Xian, Yan-Fang; Ip, Siu-Po; Mao, Qing-Qiu; Lin, Zhi-Xiu

    2016-07-01

    Beta-amyloid (Aβ) accumulation, one of the most important pathogenic traits of Alzheimer's disease (AD), has been reported to induce neurotoxicity in vitro as well as in vivo. Honokiol, isolated from the bark of Magnolia officinalis, has neuroprotective effects in different models of AD in vivo and in vitro. However, the exact mechanism for its neuroprotective effect is not well understood. The present study aimed to investigate the molecular mechanisms underlying the protective action of honokiol against Aβ1-42-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The results revealed that honokiol protected PC12 cells from Aβ1-42 induced cytotoxicity with increases in cell viability, GSH production and Bcl-2 expression, but decreases in the release of lactate dehydrogenase and cytochrome c, the amount of DNA fragmentation and MDA level, as well as Bax expression. Mechanistic study showed that honokiol could inhibit the activation of glycogen synthase kinase (GSK)-3β, attenuate the nuclear accumulation of β-catenin and suppress the phosphorylation of β-catenin (Ser33/Ser37/Thr41 site) in the Aβ1-42-treated PC12 cells. These results indicate that the anti-oxidative and anti-apoptotic effects of honokiol in Aβ1-42-treated PC12 cells may be mediated, at least in part, by regulation the GSK-3β and β-catenin signaling pathways. PMID:27131736

  7. Neuroprotective Effect of Gui Zhi (Ramulus Cinnamomi) on Ma Huang- (Herb Ephedra-) Induced Toxicity in Rats Treated with a Ma Huang-Gui Zhi Herb Pair

    PubMed Central

    Zheng, Fang-hao; Wei, Ping; Huo, Hui-ling; Xing, Xue-feng; Chen, Fei-long; Tan, Xiao-mei; Luo, Jia-bo

    2015-01-01

    Herb Ephedra (Ma Huang in Chinese) and Ramulus Cinnamomi (Gui Zhi in Chinese) are traditional Chinese herbs, often used together to treat asthma, nose and lung congestion, and fever with anhidrosis. Due to the adverse effects of ephedrine, clinical use of Ma Huang is restricted. However, Gui Zhi extract has been reported to decrease spontaneous activity in rats and exert anti-inflammatory and neuroprotective effects. The present study explored the possible inhibitory effect of Gui Zhi on Ma Huang-induced neurotoxicity in rats when the two herbs were used in combination. All Ma Huang and Ma Huang-Gui Zhi herb pair extracts were prepared using methods of traditional Chinese medicine and were normalized based on the ephedrine content. Two-month-old male Sprague-Dawley rats (n = 6 rats/group) were administered Ma Huang or the Ma Huang-Gui Zhi herb pair extracts for 7 days (ephedrine = 48 mg/kg), and locomotor activity was measured. After 7 days, oxidative damage in the prefrontal cortex was measured. Gui Zhi decreased hyperactivity and sensitization produced by repeated Ma Huang administration and attenuated oxidative stress induced by Ma Huang. The results of this study demonstrate the neuroprotective potential of Gui Zhi in Ma Huang-induced hyperactivity and oxidative damage in the prefrontal cortex of rats when used in combination. PMID:25691910

  8. ERKs and mitochondria-related pathways are essential for glycyrrhizic acid-mediated neuroprotection against glutamate-induced toxicity in differentiated PC12 cells

    PubMed Central

    Wang, D.; Guo, T.Q.; Wang, Z.Y.; Lu, J.H.; Liu, D.P.; Meng, Q.F.; Xie, J.; Zhang, X.L.; Liu, Y.; Teng, L.S.

    2014-01-01

    The present study focuses on the neuroprotective effect of glycyrrhizic acid (GA, a major compound separated from Glycyrrhiza Radix, which is a crude Chinese traditional drug) against glutamate-induced cytotoxicity in differentiated PC12 (DPC12) cells. The results showed that GA treatment improved cell viability and ameliorated abnormal glutamate-induced alterations in mitochondria in DPC12 cells. GA reversed glutamate-suppressed B-cell lymphoma 2 levels, inhibited glutamate-enhanced expressions of Bax and cleaved caspase 3, and reduced cytochrome C (Cyto C) release. Exposure to glutamate strongly inhibited phosphorylation of AKT (protein kinase B) and extracellular signal-regulated kinases (ERKs); however, GA pretreatment enhanced activation of ERKs but not AKT. The presence of PD98059 (a mitogen-activated protein/extracellular signal-regulated kinase kinase [MEK] inhibitor) but not LY294002 (a phosphoinositide 3-kinase [PI3K] inhibitor) diminished the potency of GA for improving viability of glutamate-exposed DPC12 cells. These results indicated that ERKs and mitochondria-related pathways are essential for the neuroprotective effect of GA against glutamate-induced toxicity in DPC12 cells. The present study provides experimental evidence supporting GA as a potential therapeutic agent for use in the treatment of neurodegenerative diseases. PMID:25075574

  9. Physiological and Molecular Characteristics of Elicitin-Induced Systemic Acquired Resistance in Tobacco.

    PubMed Central

    Keller, H.; Blein, J. P.; Bonnet, P.; Ricci, P.

    1996-01-01

    Elicitins are low molecular weight proteins secreted by all Phytophthora species analyzed so far. Application of the purified proteins to tobacco Nicotiana tabacum leads to the induction of resistance to subsequent inoculations with the black shank-causing agent, Phytophthora parasitica var nicotianae. In this paper, we describe the systemic characteristics of elicitin-induced acquired resistance in tobacco. Elicitin application is followed by the rapid translocation of the protein in the plant. The basic elicitin, cryptogein, induces necrosis formation in the leaves, which results from accumulation of the protein in these organs. Necrosis does not seem to be essential for the establishment of systemic acquired resistance (SAR), since resistance induced by the acidic elicitin, capsicein, is not accompanied by the development of visible symptoms on the leaves. Both elicitins trigger the coordinate accumulation of transcripts from nine genes, previously described to be expressed during establishment of SAR. Additionally, elicitin treatment leads to the activation of the multiple response gene str 246. In leaves, transcript accumulation was found to be higher in all cases in response to cryptogein compared to capsicein treatment. These results, along with northern hybridization analysis following infiltration of leaves with cryptogein, indicate that SAR genes appear to be expressed locally, corresponding to necrosis formation as well as systemically during induction of resistance. To our knowledge, elicitins are the only well-characterized, pathogen-derived molecules that trigger SAR in a plant. PMID:12226188

  10. Neuroprotective properties of a protein kinase inhibitor against ischaemia-induced neuronal damage in rats and gerbils.

    PubMed Central

    Satoh, S.; Ikegaki, I.; Suzuki, Y.; Asano, T.; Shibuya, M.; Hidaka, H.

    1996-01-01

    1. The neuroprotective properties of fasudil (HA1077), a novel protein kinase inhibitor, were evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in Mongolian gerbils and cerebral microembolization in rats. 2. The cytoprotective effect of fasudil on delayed neuronal death in gerbils was compared with the effects of nimodipine, a calcium channel antagonist and ozagrel, a thromboxane A2 synthetase inhibitor. The average of the neuronal cell density in the ischaemic control group was 17.8 +/- 2.1 cells mm-1, whereas fasudil (30 mg kg-1) significantly diminished the loss of CA1 neurones with the average of the neuronal cell density of 101.0 +/- 22.0 cells mm-1; nimodipine (10 mg kg-1) and ozagrel (30 mg kg-1) did not significantly protect against the ischaemia-induced neuronal loss. 3. In the rat model, the effects of fasudil on the histological and neurological consequences of cerebral microembolization produced via the injection of microspheres were examined. Twenty-four hours after the injection of microspheres into the internal carotid artery, all animals in the control group showed typical symptoms of stroke. Neurological function was significantly improved in the fasudil-treated animals. In the controls, the infarcted area in a cortical slice selected to include the hippocampal area was 0.25 +/- 0.01 cm2 (mean +/- s.e.mean) (43.9 +/- 2.4% of cortical section of the half hemisphere); the difference was significant compared to the mean area of 32.7 +/- 2.8 and 21.5 +/- 4.8% observed in rats treated with fasudil (3, 10 mg kg-1), respectively. Fasudil (10 mg kg-1) significantly suppressed the increased water content in ischaemic brain tissues (saline-treated rats, 82.4 +/- 0.2% vs fasudil-treated rats, 81.0 +/- 0.4%). 4. These results suggest that: (i) various protein kinases are involved in the pathogenesis of ischaemic injury; and (ii) the inhibition of protein kinases may be efficacious in preventing neuronal death

  11. Neuroprotective effects of vinpocetine and its major metabolite cis-apovincaminic acid on NMDA-induced neurotoxicity in a rat entorhinal cortex lesion model.

    PubMed

    Nyakas, Csaba; Felszeghy, Klára; Szabó, Róbert; Keijser, Jan N; Luiten, Paul G M; Szombathelyi, Zsolt; Tihanyi, Károly

    2009-01-01

    Vinpocetine (ethyl-apovincaminate, Cavinton), a synthetic derivative of the Vinca minor alkaloid vincamine, has been used now for decades for prevention and treatment of cerebrovascular diseases predisposing to development of dementia. Both vinpocetine and its main metabolite cis-apovincaminic acid (cAVA) exert a neuroprotective type of action. Bilateral N-methyl-D-aspartate (NMDA)-induced neurodegeneration in the entorhinal cortex of rat was used as a dementia model to confirm the neuroprotective action of these compounds in vivo. NMDA-lesioned rats were treated 60 min before lesion and throughout 3 postoperative days with a 10 mg/kg intraperitoneal dose of vinpocetine or cAVA. Behavioral tests started after termination of drug treatment and consisted of novel object recognition, social discrimination, and spontaneous alternation in a Y-maze, and spatial learning in the Morris water maze. At the end of behavioral testing brains were perfused with fixative and the size of the excitotoxic neuronal lesion and that of microglial activation around the lesion were assayed quantitatively on brain sections immunostained for neuron-specific nuclear protein (NeuN) and integrin CD11b, respectively. Entorhinal NMDA lesions impaired recognition of novel objects and the new social partner, and suppressed spontaneous alternation and spatial learning performance in the Morris maze. Both vinpocetine and cAVA effectively attenuated the behavioral deficits, and significantly decreased lesion size and the region of microglia activation. Both lesion-induced attention deficit and learning disabilities were markedly alleviated by vinpocetine and cAVA. The morphological findings corroborated the behavioral observations and indicated reduced lesion size and microglia activation especially after vinpocetine treatment which supports an in vivo neuroprotective mode of action of vinpocitine and a less potent action of cAVA. PMID:19492990

  12. Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection.

    PubMed

    Wu, Yuqiu; Kazumura, Kimiko; Maruyama, Wakako; Osawa, Toshihiko; Naoi, Makoto

    2015-10-01

    Rasagiline and selegiline, inhibitors of type B monoamine oxidase (MAO-B), protect neurons from cell death in cellular and animal models. Suppression of mitochondrial membrane permeabilization and subsequent activation of apoptosis cascade, and induction of anti-apoptotic, pro-survival genes are proposed to contribute the anti-apoptotic function. Rasagiline suppresses neurotoxin- and oxidative stress-induced membrane permeabilization in isolated mitochondria, but the mechanism has been not fully clarified. In this paper, regulation of the mitochondrial permeability transition pore by rasagiline and selegiline was examined in apoptosis induced by PK11195, a ligand of the outer membrane translocator protein 18 kDa (TSPO) in SH-SY5Y cells. The pore opening was quantitatively measured using a simultaneous monitoring system for calcium (Ca(2+)) and superoxide (O2(-)) (Ishibashi et al. in Biochem Biophys Res Commun 344:571-580, 2006). The association of the pore opening with Ca(2+) efflux and ROS increase was proved by the inhibition of Bcl-2 overexpression and cyclosporine A treatment. Potency to release Ca(2+) was correlated with the cytotoxicity of TSPO antagonists, PK11195, FGIN-1-27 and protoporphyrin IX, whereas a TSPO agonist, 4-chloro-diazepamine, did not significantly increase Ca(2+) or cause cell death. Rasagiline and selegiline inhibited mitochondrial Ca(2+) efflux through the mitochondrial permeability transition pore dose dependently. Ca(2+) efflux was confirmed as the initial signal in mitochondrial apoptotic cascade, and the suppression of Ca(2+) efflux may account for the neuroprotective function of rasagiline and selegiline. The quantitative measurement of Ca(2+) efflux can be applied to determine anti-apoptotic activity of neuroprotective compounds. The role of mitochondrial Ca(2+) release in neuronal death and also in neuroprotection by MAO-B inhibitors is discussed. PMID:25863936

  13. Serotonergic Hyperactivity as a Potential Factor in Developmental, Acquired and Drug-Induced Synesthesia

    PubMed Central

    Brogaard, Berit

    2013-01-01

    Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any) among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions. PMID:24155703

  14. Serotonergic hyperactivity as a potential factor in developmental, acquired and drug-induced synesthesia.

    PubMed

    Brogaard, Berit

    2013-01-01

    Though synesthesia research has seen a huge growth in recent decades, and tremendous progress has been made in terms of understanding the mechanism and cause of synesthesia, we are still left mostly in the dark when it comes to the mechanistic commonalities (if any) among developmental, acquired and drug-induced synesthesia. We know that many forms of synesthesia involve aberrant structural or functional brain connectivity. Proposed mechanisms include direct projection and disinhibited feedback mechanisms, in which information from two otherwise structurally or functionally separate brain regions mix. We also know that synesthesia sometimes runs in families. However, it is unclear what causes its onset. Studies of psychedelic drugs, such as psilocybin, LSD and mescaline, reveal that exposure to these drugs can induce synesthesia. One neurotransmitter suspected to be central to the perceptual changes is serotonin. Excessive serotonin in the brain may cause many of the characteristics of psychedelic intoxication. Excessive serotonin levels may also play a role in synesthesia acquired after brain injury. In brain injury sudden cell death floods local brain regions with serotonin and glutamate. This neurotransmitter flooding could perhaps result in unusual feature binding. Finally, developmental synesthesia that occurs in individuals with autism may be a result of alterations in the serotonergic system, leading to a blockage of regular gating mechanisms. I conclude on these grounds that one commonality among at least some cases of acquired, developmental and drug-induced synesthesia may be the presence of excessive levels of serotonin, which increases the excitability and connectedness of sensory brain regions. PMID:24155703

  15. Acquired localized hypertrichosis induced by internal fixation and plaster cast application.

    PubMed

    Ma, Hui-Jun; Yang, Yang; Ma, Hui-Yong; Jia, Chi-Yu; Li, Ting-Hui

    2013-08-01

    Hypertrichosis refers to increased vellus hair growth and is independent to androgen excess. The acquired localized hypertrichosis (ALH) is one of the typical hypertrichosis, which mainly results from chronic irritation, inflammation, friction, and occlusion by plaster of Paris. Here, we report a young boy who had ALH on his right hand following a closed fracture with internal fixation and plaster cast application. The case is unusual because the hairy area is limited to the operative region of internal fixation. We suggest that the local vascular changes and skin inflammation induced by internal fixation and plaster cast application may be associated with ALH. PMID:24003283

  16. Increased Mitochondrial DNA Induces Acquired Docetaxel Resistance in Head and Neck Cancer Cells

    PubMed Central

    Mizumachi, T; Suzuki, S; Naito, A; Carcel-Trullols, J; Evans, TT; Spring, PM; Oridate, N; Furuta, Y; Fukuda, S; Higuchi, M

    2008-01-01

    Docetaxel is one of the most effective chemotherapeutic agents against cancer; nevertheless, some patients develop resistance. Unfortunately, their causes and mechanisms remain unknown. We created docetaxel-resistant DRHEp2 from human laryngeal cancer HEp2 and investigated the roles of mitochondrial DNA (mtDNA) and ROS on docetaxel resistance. DRHEp2 had greatly increased mtDNA content. Reduction of mtDNA content in DRHEp2 by ethidium bromide treatment reduced the resistance. These results indicate the possible roles of mtDNA-coded enzymes in mitochondrial respiratory chain (MRC) in resistant mechanisms. Oligomycin A, an Fo-ATPase inhibitor, eliminated docetaxel resistance in DRHEp2. In contrast, inhibitors of other MRC did not. RNA interference targeted to Fo-ATPase d-subunit restored docetaxel-induced cytotoxicity to DRHEp2. These results indicate the roles of Fo-ATPase for resistant mechanisms. Docetaxel induced ROS generation in HEp2 but not in DRHEp2 and antioxidant pyrrolidine dithiocarbamate eliminated docetaxel-induced cytotoxicity, suggesting roles of ROS in docetaxel-induced cell death. Furthermore, inhibition of Fo-ATPase by Oligomycin A induced docetaxel–mediated ROS generation in DRHEp2. Taken together, DRHEp2 acquired docetaxel resistance through increasing Fo-ATPase, which led to diminish docetaxel-induced ROS generation and subsequently inhibited cell death. In conclusion, mtDNA plays an important role in developing docetaxel resistance through the reduction of ROS generation by regulating Fo-ATPase. PMID:17637738

  17. Presenilin 1 promotes trypsin-induced neuroprotection via the PAR2/ERK signaling pathway. Effects of presenilin 1 FAD mutations.

    PubMed

    Nikolakopoulou, Angeliki M; Georgakopoulos, Anastasios; Robakis, Nikolaos K

    2016-06-01

    Mutants of presenilin 1 (PS1) increase neuronal cell death causing autosomal-dominant familial Alzheimer's disease (FAD). Recent literature shows that treatment of neuronal cultures with low concentrations of trypsin, a member of the serine family of proteases, protects neurons from toxic insults by binding to the proteinase-activated receptor 2 and stimulating survival kinase extracellular signal-regulated kinase (ERK 1/2). Other studies show that PS1 is necessary for the neuroprotective activity of specific neurotrophic factors, such as brain-derived neurotrophic factor, against excitotoxicity and oxidative stress. Here, we show that treatment of mouse cortical neuronal cultures with trypsin activates ERK1/2 and protects neurons against glutamate excitoxicity. The trypsin-dependent ERK activation and neuroprotection requires both alleles of PS1 because neither PS1 knockout nor PS1 hemizygous neuronal cultures can use exogenous trypsin to activate ERK1/2 or increase neuronal survival. The protective effect of PS1 does not depend on its γ-secretase activity because inhibitors of γ-secretase have no effect on trypsin-mediated neuroprotection. Importantly, cortical neuronal cultures either heterozygous or homozygous for PS1 FAD mutants are unable to use trypsin to activate ERK1/2 and rescue neurons from excitotoxicity, indicating that FAD mutants inhibit trypsin-dependent neuroprotection in an autosomal-dominant manner. Furthermore, our data support the theory that PS FAD mutants increase neurodegeneration by inhibiting the ability of neurons to use cellular factors as protective agents against toxic insults. PMID:27143420

  18. Estrogen replacement therapy-induced neuroprotection against brain ischemia-reperfusion injury involves the activation of astrocytes via estrogen receptor β

    PubMed Central

    Ma, Yulong; Guo, Hang; Zhang, Lixia; Tao, Liang; Yin, Anqi; Liu, Zhaoyu; Li, Yan; Dong, Hailong; Xiong, Lize; Hou, Wugang

    2016-01-01

    The incidence of ischemic stroke is significantly increased in postmenopausal women. However, the neuroprotective effects of estrogen replacement therapy (ERT) against stroke remain controversial, and the role of astrocytes in ERT has rarely been explored. In this study, we investigated the effects of estrogen and selective estrogen receptor (ER) agonists on astrocytes activation and neuronal apoptosis in mice under conditions of cell culture oxygen and glucose deprivation and reperfusion (OGD-R), and global cerebral ischemia (GCI). We demonstrated that hippocampal astrocytes primarily express ERβ. In astrocytes, 2.5–20 nM 17β-estradiol (E2) or 10 nM DPN (ERβ agonist) not 10 nM PPT (ERα agonist), significantly increased GFAP expression. And 10 nM E2, DPN or E2+MPP (ERα antagonist), but not PPT or E2+PHTPP (ERβ antagonist), significantly reduced neuronal apoptosis following the subjection of astrocyte and neuronal cocultures to OGD-R. We also found that either 50 μg/kg E2 or 8 mg/kg DPN replacement (3 weeks) significantly increased GFAP expression and reduced GCI-induced neuronal apoptosis in hippocampal CA1 region of ovariectomized mice. These results indicate that estrogen-induced neuroprotection against ischemia-reperfusion injury involves activation of astrocytes via ERβ. Thus, the discovery and design of astrocyte-selective ERβ modulators may offer a new strategy for ERT of ischemic stroke. PMID:26891996

  19. Possible Involvement of Nitric Oxide Modulatory Mechanisms in the Neuroprotective Effect of Centella asiatica Against Sleep Deprivation Induced Anxiety Like Behaviour, Oxidative Damage and Neuroinflammation.

    PubMed

    Chanana, Priyanka; Kumar, Anil

    2016-04-01

    Sleep deprivation (SD) is an experience of inadequate or poor quality of sleep that may produce significant alterations in multiple neural systems. Centella asiatica (CA) is a psychoactive medicinal herb with immense therapeutic potential. The present study was designed to explore the possible nitric oxide (NO) modulatory mechanism in the neuroprotective effect of CA against SD induced anxiety like behaviour, oxidative damage and neuroinflammation. Male laca mice were sleep deprived for 72 h, and CA (150 and 300 mg/kg) was administered alone and in combination with NO modulators for 8 days, starting five days before 72-h SD exposure. Various behavioural (locomotor activity, elevated plus maze) and biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite levels and superoxide dismutase activity), neuroinflammation marker (TNF-alpha) were assessed subsequently. CA (150 and 300 mg/kg) treatment for 8 days significantly improved locomotor activity, anti-anxiety like effect and attenuated oxidative damage and TNF α level as compared to sleep-deprived 72-h group. Also while the neuroprotective effect of CA was increased by NO antagonists, it was diminished by NO agonists. The present study suggests that NO modulatory mechanism could be involved in the protective effect of CA against SD-induced anxiety-like behaviour, oxidative damage and neuroinflammation in mice. PMID:26848139

  20. Comparison of Neuroprotective Effects of Melissa officinalis Total Extract and Its Acidic and Non-Acidic Fractions against A β-Induced Toxicity

    PubMed Central

    Sepand, Mohammad Reza; Soodi, Maliheh; Hajimehdipoor, Homa; Soleimani, Masoud; Sahraei, Ehsan

    2013-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disease that was characterized with deposit of beta amyloid (Aβ) aggregate in senile plaque. Oxidative damage to neurons and loss of cholinergic neurons in forebrain region are observed in this disease. Melissa officinalis is a medicinal plant from Lamiaceae family, used traditionally in the treatment of cognitive disorders. It has cholinomimetic and potent antioxidant activity. In the present study, we investigated the possible neuroprotective effects of total ethanolic extract, acidic and nonacidic fraction of Melissa officinalis on Aβ-induced cytotoxicity and oxidative stress in PC12 cells and also measured their in-vitro anticholinesterase activity. PC12 cells were incubated with the extract and fractions prior to the incubation with Aβ and cell toxicity was assessed by MTT assay. In addition, productions of reactive oxygen species (ROS), Malondialdehyde (MDA) as a biomarker of lipid peroxidation and glutathione peroxidase activity were measured. Pretreatment of cells with total extract and acidic fraction (not non-acidic fraction) had protective effect against Aβ-induced oxidative changes and cell death. In concentrations in which both total extracts of an acidic fraction showed neuroprotective effects, inhibition of cholinesterase activity was not significant. Then, the protective effects of Melissa officinalis total extract and acidic fraction were not attributed to their anticholinesterase activity. Acidic fraction showed more potent protective effect compared to the total extract, leading to the fact that polyphenolic compounds and terpenoic acids are the most effective components in the total extract concentrated in this fraction. PMID:24250617

  1. Dose-dependent neuroprotective effect of caffeine on a rotenone-induced rat model of parkinsonism: A histological study.

    PubMed

    Soliman, Amira M; Fathalla, Ahmed M; Moustafa, Ahmed A

    2016-06-01

    Several lines of evidence have demonstrated an inverse relationship between caffeine utilization and Parkinson's disease (PD) progression. Caffeine is a methylxanthine known as a non-specific inhibitor of adenosine (A2A and A1) receptors in the cerebrum and demonstrated to be a neuroprotective medication. In this study, the neuroprotective efficacy of two different doses of caffeine ranging above the usual consumption dose and below the toxic dose was investigated using histopathological and immunohistochemical methods. Thirty-two male rats were randomly divided into 4 groups, with 8 in each group: vehicle control (1ml/kg/48h for 12 days), rotenone (1.5mg/kg/48h, s.c. for 12 days), low-dose Caffeine-treated: (10mg/kg IP. daily for 12 days), high-dose Caffeine-treated (20mg IP daily for 12 days). Twenty-four hours after the last rotenone injection, animals were sacrificed and brains were sectioned and prepared for histopathological staining with hematoxylinand eosin, cresyl violet and Mallory's phosphotungestic acid haematoxylinand for immunohistochemical staining of tyrosine hydroxylase. Our study showed that the treatment with caffeine improved histopathological degeneration in the substantia nigra parts compacta (SNpc) neurons and hindered the reduction in dopamine concentration caused by rotenone. We also found that a higher dose of caffeine was more effective against histopathological degeneration. These results suggest that caffeine has a dose-dependent neuroprotective effect. PMID:27132082

  2. Neuroprotection induced by N-acetylcysteine and selenium against traumatic brain injury-induced apoptosis and calcium entry in hippocampus of rat.

    PubMed

    Nazıroğlu, Mustafa; Senol, Nilgün; Ghazizadeh, Vahid; Yürüker, Vehbi

    2014-08-01

    Neurodegeneration associated with acute central nervous system injuries and diseases such as spinal cord injury and traumatic brain injury (TBI) are reported to be mediated by the regulation of apoptosis and oxidative stress through Ca(2+) influx. The thiol redox system antioxidants, such as N-acetylcysteine (NAC) and selenium (Se), display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties. However, there are no reports on hippocampal apoptosis, cytosolic reactive oxygen species (ROS), or Ca(2+) values in rats with an induced TBI. Therefore, we tested the effects of Se and NAC administration on apoptosis, oxidative stress, and Ca(2+) influx through TRPV1 channel activations in the hippocampus of TBI-induced rats. The 32 rats were divided into four groups: control, TBI, TBI + NAC, and TBI + Se groups. Intraperitoneal administrations of NAC and Se were performed at 1, 24, 48, and 72 h after TBI induction. After 3 days, the hippocampal neurons were freshly isolated from the rats. In cytosolic-free Ca(2+) analyses, the neurons were stimulated with the TRPV1 channel agonist capsaicin, a pungent compound found in hot chili peppers. Cytosolic-free Ca(2+), apoptosis, cytosolic ROS levels, and caspase-3 and -9 activities were higher in the TBI group than control. The values in the hippocampus were decreased by Se and NAC administrations. In conclusion, we observed that NAC and Se have protective effects on oxidative stress, apoptosis, and Ca(2+) entry via TRPV1 channel activation in the hippocampus of this TBI model, but the effect of NAC appears to be much greater than that of Se. They are both interesting candidates for studying the amelioration of TBIs. PMID:24842665

  3. Neuroprotection of (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Against Hydrogen Peroxide and Lipopolysaccharide Induced Injury via Modulating Arachidonic Acid Network and p38-MAPK Signaling.

    PubMed

    Shen, Jiao-Ning; Xu, Liu-Xin; Shan, Lei; Zhang, Wei-Dong; Li, Hong-Lin; Wang, Rui

    2015-01-01

    Oxidative stress and neuroinflammation are highly relevant to the pathological processes of various neurodegenerative diseases including Alzheimer's disease (AD). (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), a novel 5-lipoxygenase inhibitor, was isolated from the whole plant of Incarvillea mairei var granditlora (Wehrhahn) Grierson. In this study, we investigated the protective effect of HOEC on hydrogen peroxide (H2O2) and lipopolysaccharide (LPS) -induced cytotoxicity and neuroinflammation in vitro and in vivo. MTT assay, LDH release assay, morphological observation and Hoechst 33342/PI dual staining followed by EIA, immunofluorescence staining and Western Blotting analysis were performed to elucidate the neuroprotective effect of HOEC. Treatment with HOEC at various concentrations prior to H2O2 exposure significantly enhanced cell viability, decreased LDH release, prevented cell morphologic changes and apoptosis. Instead of PGE2 reduction, HOEC markedly inhibited the production of LTB4 and suppressed the macrophage-mediated neurotoxicity. Western blotting and immunofluorescence staining showed that HOEC inhibited H2O2-induced p38 phosphorylation and NF-κB activation. Neuroprotective effect of HOEC was abolished by a p38 inhibitor. Further in vivo studies of LPS-induced neuroinflammation confirmed the anti-inflammatory effects of HOEC. These findings that HOEC protects SH-SY5Y cells from H2O2 and LPS-induced injury via arachidonic acid network modulation followed by p38 MAPK and NF-κB signaling, might make HOEC be considered as a therapeutic candidate for prevention and treatment of neurodegenerative diseases involving oxidative stress or/and inflammation. PMID:26510982

  4. The Neuroprotection of Liraglutide Against Ischaemia-induced Apoptosis through the Activation of the PI3K/AKT and MAPK Pathways

    PubMed Central

    Zhu, Huili; Zhang, Yusheng; Shi, Zhongshan; Lu, Dan; Li, Tingting; Ding, Yan; Ruan, Yiwen; Xu, Anding

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases glucose-dependent insulin secretion to reduce the glucose level. Liraglutide, a long-acting GLP-1 analogue, has been found to have neuroprotective action in various experimental models. However, the protective mechanisms of liraglutide in ischaemic stroke remain unclear. Here, we demonstrated that liraglutide significantly decreased the infarct volume, improved neurologic deficits, and lowered stress-related hyperglycaemia without causing hypoglycaemia in a rat model of middle cerebral artery occlusion (MCAO). Liraglutide inhibited cell apoptosis by reducing excessive reactive oxygen species (ROS) and improving the function of mitochondria in neurons under oxygen glucose deprivation (OGD) in vitro and MCAO in vivo. Liraglutide up-regulated the phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinases (ERK) and inhibited the phosphorylation of c-jun-NH2-terminal kinase (JNK) and p38. Moreover, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and/or the ERK inhibitor U0126 counteracted the protective effect of liraglutide. Taken together, these results suggest that liraglutide exerts neuroprotective action against ischaemia-induced apoptosis through the reduction of ROS and the activation of the PI3K/AKT and mitogen-activated protein kinase (MAPK) pathways. Therefore, liraglutide has therapeutic potential for patients with ischaemic stroke, especially those with Type 2 diabetes mellitus or stress hyperglycaemia. PMID:27240461

  5. The Neuroprotection of Liraglutide Against Ischaemia-induced Apoptosis through the Activation of the PI3K/AKT and MAPK Pathways.

    PubMed

    Zhu, Huili; Zhang, Yusheng; Shi, Zhongshan; Lu, Dan; Li, Tingting; Ding, Yan; Ruan, Yiwen; Xu, Anding

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases glucose-dependent insulin secretion to reduce the glucose level. Liraglutide, a long-acting GLP-1 analogue, has been found to have neuroprotective action in various experimental models. However, the protective mechanisms of liraglutide in ischaemic stroke remain unclear. Here, we demonstrated that liraglutide significantly decreased the infarct volume, improved neurologic deficits, and lowered stress-related hyperglycaemia without causing hypoglycaemia in a rat model of middle cerebral artery occlusion (MCAO). Liraglutide inhibited cell apoptosis by reducing excessive reactive oxygen species (ROS) and improving the function of mitochondria in neurons under oxygen glucose deprivation (OGD) in vitro and MCAO in vivo. Liraglutide up-regulated the phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinases (ERK) and inhibited the phosphorylation of c-jun-NH2-terminal kinase (JNK) and p38. Moreover, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and/or the ERK inhibitor U0126 counteracted the protective effect of liraglutide. Taken together, these results suggest that liraglutide exerts neuroprotective action against ischaemia-induced apoptosis through the reduction of ROS and the activation of the PI3K/AKT and mitogen-activated protein kinase (MAPK) pathways. Therefore, liraglutide has therapeutic potential for patients with ischaemic stroke, especially those with Type 2 diabetes mellitus or stress hyperglycaemia. PMID:27240461

  6. Neuroprotective Effects of Methyl 3,4-Dihydroxybenzoate against TBHP-Induced Oxidative Damage in SH-SY5Y Cells.

    PubMed

    Cai, Liang; Wang, Li-Fang; Pan, Jun-Ping; Mi, Xiang-Nan; Zhang, Zheng; Geng, Hai-Ju; Wang, Jia-Hui; Hu, Song-Hui; Zhang, Wei; Gao, Qin; Wu, Wu-Tian; Luo, Huan-Min

    2016-01-01

    This study investigated the neuroprotective effects of methyl 3,4-dihydroxybenzoate (MDHB) against t-butyl hydroperoxide (TBHP) induced oxidative damage in SH-SY5Y (human neuroblastoma cells) and the underlying mechanisms. SH-SY5Y were cultured in DMEM + 10% FBS for 24 h and pretreated with different concentrations of MDHB or N-acetyl-l-cysteine (NAC) for 4 h prior to the addition of 40 μM TBHP for 24 h. Cell viability was analyzed using the methylthiazolyltetrazolium (MTT) and lactate dehydrogenase (LDH) assays. An annexin V-FITC assay was used to detect cell apoptosis rates. The 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay was used to determine intracellular ROS levels. The activities of antioxidative enzymes (GSH-Px and SOD) were measured using commercially available kits. The oxidative DNA damage marker 8-OHdG was detected using ELISA. Western blotting was used to determine the expression of Bcl-2, Bax, caspase 3, p-Akt and Akt proteins in treated SH-SY5Y cells. Our results showed that MDHB is an effective neuroprotective compound that can mitigate oxidative stress and inhibit apoptosis in SH-SY5Y cells. PMID:27556437

  7. Acquired hemophilia possibly induced by etanercept in a patient with rheumatoid arthritis.

    PubMed

    Banse, Christopher; Benhamou, Ygal; Lequerré, Thierry; Le Cam-Duchez, Véronique; Lévesque, Hervé; Vittecoq, Olivier

    2015-05-01

    A 47-year-old woman with rheumatoid arthritis (RA) treated successively with infliximab, abatacept, and etanercept spontaneously developed subcutaneous bruises and a noncompressive hematoma 11 months after starting etanercept therapy (50mg/week). Her prothrombin time was normal but her activated partial thromboplastin time was increased to 2.48 (normal range, 0.85-1.17). She had a circulating anticoagulant (Rosner index, 45; normal,<13) due to an anti-factor VIII antibody in a titer of 45 Bethesda units. Her factor VIII level was less than 1% (normal range, 55-150). The etanercept and leflunomide were stopped and prednisone was given in a daily dosage of 1mg/kg, in combination with rituximab, two 1-g doses at an interval of 2 weeks. After 5 months, persistence of the anti-factor VIII antibody prompted the initiation of azathioprine therapy, 2mg/kg/d. A remission was achieved 9 months after the diagnosis of acquired hemophilia and was sustained at last follow-up after 3 years. This new case of acquired hemophilia in a patient with RA may reflect a simple association or an inducing role of etanercept. PMID:25617259

  8. Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis.

    PubMed

    Benedek, Gil; Zhang, Jun; Bodhankar, Sheetal; Nguyen, Ha; Kent, Gail; Jordan, Kelley; Manning, Dustin; Vandenbark, Arthur A; Offner, Halina

    2016-04-15

    Sex hormones promote immunoregulatory effects on multiple sclerosis. The current study evaluated estrogen effects on regulatory B cells and resident CNS microglia during experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate an estrogen-dependent induction of multiple regulatory B cell markers indicative of IL-10 dependent as well as IFN-γ dependent pathways. Moreover, although estrogen pretreatment of EAE mice inhibited the infiltration of pro-inflammatory cells into the CNS, it enhanced the frequency of regulatory B cells and M2 microglia. Our study suggests that estrogen has a broad effect on the development of regulatory B cells during EAE, which in turn could promote neuroprotection. PMID:27049561

  9. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment.

    PubMed

    Zippelius, Alfred; Schreiner, Jens; Herzig, Petra; Müller, Philipp

    2015-03-01

    CD40 stimulation on antigen-presenting cells (APC) allows direct activation of CD8(+) cytotoxic T cells, independent of CD4⁺ T-cell help. Agonistic anti-CD40 antibodies have been demonstrated to induce beneficial antitumor T-cell responses in mouse models of cancer and early clinical trials. We report here that anti-CD40 treatment induces programmed death ligand-1 (PD-L1) upregulation on tumor-infiltrating monocytes and macrophages, which was strictly dependent on T cells and IFNγ. PD-L1 expression could be counteracted by coadministration of antibodies blocking the PD-1 (programmed death-1)/PD-L1 axis as shown for T cells from tumor models and human donors. The combined treatment was highly synergistic and induced complete tumor rejection in about 50% of mice bearing MC-38 colon and EMT-6 breast tumors. Mechanistically, this was reflected by a strong increase of IFNγ and granzyme-B production in intratumoral CD8⁺ T cells. Concomitant CTLA-4 blockade further improved rejection of established tumors in mice. This study uncovers a novel mechanism of acquired resistance upon agonistic CD40 stimulation and proposes that the concomitant blockade of the PD-1/PD-L1 axis is a viable therapeutic strategy to optimize clinical outcomes. PMID:25623164

  10. Neuroprotective effects of the Phellinus linteus ethyl acetate extract against H2O2-induced apoptotic cell death of SK-N-MC cells.

    PubMed

    Choi, Doo Jin; Cho, Sarang; Seo, Jeong Yeon; Lee, Hyang Burm; Park, Yong Il

    2016-01-01

    Numerous studies have suggested that neuronal cells are protected against oxidative stress-induced cell damage by antioxidants, such as polyphenolic compounds. Phellinus linteus (PL) has traditionally been used to treat various symptoms in East Asian countries. In the present study, we prepared an ethyl acetate extract from the fruiting bodies of PL (PLEA) using hot water extraction, ethanol precipitation, and ethyl acetate extraction. The PLEA contained polyphenols as its major chemical component, and thus, we predicted that it may exhibit antioxidant and neuroprotective effects against oxidative stress. The results showed that the pretreatment of human brain neuroblastoma SK-N-MC cells with the PLEA (0.1-5 μg/mL) significantly and dose-dependently reduced the cytotoxicity of H2O2 and the intracellular ROS levels and enhanced the expression of HO-1 (heme oxygenase-1) and antioxidant enzymes, such as CAT (catalase), GPx-1 (glutathione peroxidase-1), and SOD-1 and -2 (superoxide dismutase-1 and -2). The PLEA also directly scavenged free radicals. PLEA pretreatment also significantly attenuated DNA fragmentation and suppressed the mRNA expression and activation of mitogen-activated protein kinases extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 kinase, which are induced by oxidative stress and lead to cell death. PLEA pretreatment inhibited the activation of the apoptosis-related proteins caspase-3 and poly (ADP-ribose) polymerase. These results demonstrate that the PLEA has neuroprotective effects against oxidative stress (H2O2)-induced neuronal cell death via its antioxidant and anti-apoptotic properties. PLEA should be investigated in an in vivo model on its potential to prevent or ameliorate neurodegenerative disease. PMID:26773779

  11. HIF1α is Necessary for Exercise-Induced Neuroprotection while HIF2α is Needed for Dopaminergic Neuron Survival in the Substantia Nigra pars compacta

    PubMed Central

    Smeyne, Michelle; Sladen, Paul; Jiao, Yun; Dragatsis, Ioannis; Smeyne, Richard Jay

    2015-01-01

    Exercise reduces the risk of developing a number of neurological disorders and increases the efficiency of cellular energy production. However, overly strenuous exercise produces oxidative stress. Proper oxygenation is crucial for the health of all tissues, and tight regulation of cellular oxygen is critical to balance O2 levels and redox homeostasis in the brain. Hypoxia Inducible Factor (HIF)1α and HIF2α are transcription factors regulated by cellular oxygen concentration that initiate gene regulation of vascular development, redox homeostasis, and cell cycle control. HIF1α and HIF2α contribute to important adaptive mechanisms that occur when oxygen and ROS homeostasis become unbalanced. It has been shown that preconditioning by exposure to a stressor prior to a hypoxic event reduces damage that would otherwise occur. Previously we reported that three months of exercise protects SNpc DA neurons from toxicity caused by Complex I inhibition. Here, we identify the cells in the SNpc that express HIF1α and HIF2α and show that running exercise produces hypoxia in SNpc DA neurons, and alters the expression of HIF1α and HIF2α. In mice carrying a conditional knockout of Hif1α in postnatal neurons we observe that exercise alone produces SNpc TH+ DA neuron loss. Loss of HIF1α also abolishes exercise-induced neuroprotection. In mice lacking Hif2α in postnatal neurons, the number of TH+ DA neurons in the adult SNpc is diminished, but three months of exercise rescues this loss. We conclude that HIF1α is necessary for exercise-induced neuroprotection and both HIF1α and HIF2α are necessary for the survival and function of adult SNpc DA neurons. PMID:25796140

  12. Dimethyl fumarate, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and macrophage-mediated neurotoxicity; a novel candidate for HIV-neuroprotection1

    PubMed Central

    Cross, Stephanie A.; Cook, Denise R.; Chi, Anthony W.S.; Vance, Patricia J.; Kolson, Lorraine L.; Wong, Bethany J.; Jordan-Sciutto, Kelly L.; Kolson, Dennis L.

    2011-01-01

    Despite antiretroviral therapy (ART), HIV infection promotes cognitive dysfunction and neurodegeneration through persistent inflammation and neurotoxin release from infected and/or activated macrophages/microglia. Furthermore, inflammation and immune activation within both the central nervous system (CNS) and periphery correlate with disease progression and morbidity in ART-treated individuals. Accordingly, drugs targeting these pathological processes in the CNS and systemic compartments are needed for effective, adjunctive therapy. Using our in vitro model of HIV-mediated neurotoxicity, in which HIV infected monocyte-derived macrophages (MDM) release excitatory neurotoxins, we show that HIV infection dysregulates the macrophage antioxidant response and reduces levels of heme oxygenase-1 (HO-1). Furthermore, restoration of HO-1 expression in HIV-infected MDM reduces neurotoxin release without altering HIV replication. Given these novel observations, we have identified dimethyl fumarate (DMF), used to treat psoriasis and showing promising results in clinical trials for multiple sclerosis, as a potential neuroprotectant and HIV disease-modifying agent. DMF, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and neurotoxin release. Two distinct mechanisms are proposed; inhibition of NF-κB nuclear translocation and signaling, which could contribute to the suppression of HIV replication, and induction of HO-1, which is associated with decreased neurotoxin release. Finally, we found that DMF attenuates CCL2-induced monocyte chemotaxis, suggesting that DMF could decrease recruitment of activated monocytes to the CNS in response to inflammatory mediators. We propose that dysregulation of the antioxidant response during HIV infection drives macrophage-mediated neurotoxicity and that DMF could serve as an adjunctive neuroprotectant and HIV disease modifier in ART-treated individuals. PMID:21976775

  13. Neuroprotective properties of marrow-isolated adult multilineage-inducible cells in rat hippocampus following global cerebral ischemia are enhanced when complexed to biomimetic microcarriers.

    PubMed

    Garbayo, Elisa; Raval, Ami P; Curtis, Kevin M; Della-Morte, David; Gomez, Lourdes A; D'Ippolito, Gianluca; Reiner, Teresita; Perez-Stable, Carlos; Howard, Guy A; Perez-Pinzon, Miguel A; Montero-Menei, Claudia N; Schiller, Paul C

    2011-12-01

    Cell-based therapies for global cerebral ischemia represent promising approaches for neuronal damage prevention and tissue repair promotion. We examined the potential of marrow-isolated adult multilineage-inducible (MIAMI) cells, a homogeneous subpopulation of immature human mesenchymal stromal cell, injected into the hippocampus to prevent neuronal damage induced by global ischemia using rat organotypic hippocampal slices exposed to oxygen-glucose deprivation and rats subjected to asphyxial cardiac arrest. We next examined the value of combining fibronectin-coated biomimetic microcarriers (FN-BMMs) with epidermal growth factor (EGF)/basic fibroblast growth factor (bFGF) pre-treated MIAMI compared to EGF/bFGF pre-treated MIAMI cells alone, for their in vitro and in vivo neuroprotective capacity. Naïve and EGF/bFGF pre-treated MIAMI cells significantly protected the Cornu Ammonis layer 1 (CA1) against ischemic death in hippocampal slices and increased CA1 survival in rats. MIAMI cells therapeutic value was significantly increased when delivering the cells complexed with FN-BMMs, probably by increasing stem cell survival and paracrine secretion of pro-survival and/or anti-inflammatory molecules as concluded from survival, differentiation and gene expression analysis. Four days after oxygen and glucose deprivation and asphyxial cardiac arrest, few transplanted cells administered alone survived in the brain whereas stem cell survival improved when injected complexed with FN-BMMs. Interestingly, a large fraction of the transplanted cells administered alone or in complexes expressed βIII-tubulin suggesting that partial neuronal transdifferentiation may be a contributing factor to the neuroprotective mechanism of MIAMI cells. PMID:21496021

  14. NEUROPROTECTIVE PROPERTIES OF MARROW-ISOLATED ADULT MULTILINEAGE INDUCIBLE CELLS IN RAT HIPPOCAMPUS FOLLOWING GLOBAL CEREBRAL ISCHEMIA ARE ENHANCED WHEN COMPLEXED TO BIOMIMETIC MICROCARRIERS

    PubMed Central

    Garbayo, E.; Raval, A.P.; Curtis, K.M.; Della-Morte, D.; Gomez, L.A.; D'Ippolito, G.; Reiner, T.; Perez-Stable, C.; Howard, G.A.; Perez-Pinzon, M.A.; Montero-Menei, C.N.; Schiller, P.C.

    2015-01-01

    Cell-based therapies for global cerebral ischemia represent promising approaches for neuronal damage prevention and tissue repair promotion. We examined the potential of Marrow-Isolated Adult Multilineage Inducible (MIAMI) cells, a homogeneous subpopulation of immature human mesenchymal stromal cell, injected into the hippocampus to prevent neuronal damage induced by global ischemia using rat organotypic hippocampal slices exposed to oxygen-glucose deprivation (OGD) and rats subjected to asphyxial cardiac arrest (ACA). We next examined the value of combining fibronectin-coated biomimetic microcarriers (FN-BMMs) with EGF/bFGF pre-treated MIAMI compared to EGF/bFGF pre-treated MIAMI cells alone, for their in vitro and in vivo neuroprotective capacity. Naïve and EGF/bFGF pre-treated MIAMI cells significantly protected the Cornu Ammonis layer 1 (CA1) against ischemic death in hippocampal slices and increased CA1 survival in rats. MIAMI cells therapeutic value was significantly increased when delivering the cells complexed with FN-BMMs, probably by increasing stem cell survival and paracrine secretion of pro-survival and/or anti-inflammatory molecules as concluded from survival, differentiation and gene expression analysis. Four days after OGD and ACA, few transplanted cells administered alone survived in the brain whereas stem cell survival improved when injected complexed with FN-BMMs. Interestingly, a large fraction of the transplanted cells administered alone or in complexes expressed βIII-Tubulin suggesting that partial neuronal transdifferentiation may be a contributing factor to the neuroprotective mechanism of MIAMI cells. PMID:21496021

  15. Development of a neuroprotective peptide that preserves survival pathways by preventing Kidins220/ARMS calpain processing induced by excitotoxicity.

    PubMed

    Gamir-Morralla, A; López-Menéndez, C; Ayuso-Dolado, S; Tejeda, G S; Montaner, J; Rosell, A; Iglesias, T; Díaz-Guerra, M

    2015-01-01

    Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), has a central role in the coordination of receptor crosstalk and the integration of signaling pathways essential for neuronal differentiation, survival and function. This protein is a shared downstream effector for neurotrophin- and ephrin-receptors signaling that also interacts with the N-methyl-d-aspartate type of glutamate receptors (NMDARs). Failures in neurotrophic support and glutamate signaling are involved in pathologies related to excitotoxicity and/or neurodegeneration, where different components of these dynamic protein complexes result altered by a combination of mechanisms. In the case of Kidins220/ARMS, overactivation of NMDARs in excitotoxicity and cerebral ischemia triggers its downregulation, which contributes to neuronal death. This key role in neuronal life/death decisions encouraged us to investigate Kidins220/ARMS as a novel therapeutic target for neuroprotection. As the main mechanism of Kidins220/ARMS downregulation in excitotoxicity is proteolysis by calpain, we decided to develop cell-penetrating peptides (CPPs) that could result in neuroprotection by interference of this processing. To this aim, we first analyzed in detail Kidins220/ARMS cleavage produced in vitro and in vivo, identifying a major calpain processing site in its C-terminal region (between amino acids 1669 and 1670) within a sequence motif highly conserved in vertebrates. Then, we designed a 25-amino acids CPP (Tat-K) containing a short Kidins220/ARMS sequence enclosing the identified calpain site (amino acids 1668-1681) fused to the HIV-1 Tat protein basic domain, able to confer membrane permeability to attached cargoes. Transduction of cortical neurons with Tat-K reduced Kidins220/ARMS calpain processing in a dose- and time-dependent manner upon excitotoxic damage and allowed preservation of the activity of pERK1/2 and pCREB, signaling molecules central to

  16. Development of a neuroprotective peptide that preserves survival pathways by preventing Kidins220/ARMS calpain processing induced by excitotoxicity

    PubMed Central

    Gamir-Morralla, A; López-Menéndez, C; Ayuso-Dolado, S; Tejeda, G S; Montaner, J; Rosell, A; Iglesias, T; Díaz-Guerra, M

    2015-01-01

    Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), has a central role in the coordination of receptor crosstalk and the integration of signaling pathways essential for neuronal differentiation, survival and function. This protein is a shared downstream effector for neurotrophin- and ephrin-receptors signaling that also interacts with the N-methyl-d-aspartate type of glutamate receptors (NMDARs). Failures in neurotrophic support and glutamate signaling are involved in pathologies related to excitotoxicity and/or neurodegeneration, where different components of these dynamic protein complexes result altered by a combination of mechanisms. In the case of Kidins220/ARMS, overactivation of NMDARs in excitotoxicity and cerebral ischemia triggers its downregulation, which contributes to neuronal death. This key role in neuronal life/death decisions encouraged us to investigate Kidins220/ARMS as a novel therapeutic target for neuroprotection. As the main mechanism of Kidins220/ARMS downregulation in excitotoxicity is proteolysis by calpain, we decided to develop cell-penetrating peptides (CPPs) that could result in neuroprotection by interference of this processing. To this aim, we first analyzed in detail Kidins220/ARMS cleavage produced in vitro and in vivo, identifying a major calpain processing site in its C-terminal region (between amino acids 1669 and 1670) within a sequence motif highly conserved in vertebrates. Then, we designed a 25-amino acids CPP (Tat-K) containing a short Kidins220/ARMS sequence enclosing the identified calpain site (amino acids 1668–1681) fused to the HIV-1 Tat protein basic domain, able to confer membrane permeability to attached cargoes. Transduction of cortical neurons with Tat-K reduced Kidins220/ARMS calpain processing in a dose- and time-dependent manner upon excitotoxic damage and allowed preservation of the activity of pERK1/2 and pCREB, signaling molecules central to

  17. Neuroprotective effects of adenosine isolated from Cordyceps cicadae against oxidative and ER stress damages induced by glutamate in PC12 cells.

    PubMed

    Olatunji, Opeyemi J; Feng, Yan; Olatunji, Oyenike O; Tang, Jian; Ouyang, Zhen; Su, Zhaoliang; Wang, Dujun; Yu, Xiaofeng

    2016-06-01

    Glutamate has been proven to induce oxidative stress through the formation of reactive oxygen species (ROS) and increased calcium overload which results in neuronal injury, development of neurodegenerative diseases and death. Adenosine is one of the bioactive nucleosides found in Cordyceps cicadae and it has displayed several pharmacological activities including neuroprotection. In this study, the protective effects of adenosine from C. cicadae against glutamate-induce oxidative stress in PC12 cells were evaluated. The exposure of PC12 cells to glutamate (5mM) induced the formation of ROS, increased Ca(2+) influx, endoplasmic reticulum (ER) stress and up regulated the expression of pro-apoptotic factor Bax. However, pretreatment with adenosine markedly increased cell viability, decreased the elevated levels of ROS and Ca(2+) induced by glutamate. Furthermore adenosine increased the activities of GSH-Px and SOD, as well as retained mitochondria membrane potential (MMP), increased Bcl-2/Bax ratio, and reduced the expression of ERK, p38, and JNK. Overall, our results suggest that adenosine may be a promising potential therapeutic agent for the prevention and treatment of neurodegenerative disorders. PMID:27114365

  18. Effects of the root bark of Paeonia suffruticosa on mitochondria-mediated neuroprotection in an MPTP-induced model of Parkinson's disease.

    PubMed

    Kim, Hyo Geun; Park, Gunhyuk; Piao, Ying; Kang, Min Seo; Pak, Youngmi Kim; Hong, Seon-Pyo; Oh, Myung Sook

    2014-03-01

    Parkinson's disease (PD) is generally characterized by the progressive loss of dopaminergic neurons projecting from the substantia nigra pars compacta (SNpc) to the striatum that results in movement dysfunction, but also entails mitochondrial dysfunction. The purpose of this study is to evaluate the protective effects of Moutan Cortex Radicis (MCE, Moutan peony) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like symptoms and to elucidate the underlying mechanisms of action, with a focus on mitochondrial function. In a rat primary mesencephalic culture system, MCE significantly protected dopaminergic neurons from the neurotoxic effects of 1-methyl-4-phenylpyridinium (MPP(+)), an active form of MPTP. Additionally, in a subacute mouse model of MPTP-induced PD, MCE resulted in enhanced recovery from PD-like motor symptoms, including increased locomotor activity and reduced bradykinesia. MCE increased dopamine availability and protected against MPTP-induced dopaminergic neuronal damage. Moreover, MCE inhibited MPTP-induced mitochondrial dysfunction and resulted in increased expression of phosphorylated Akt, ND9, mitochondrial transcription factor A, and H2AX in the SNpc. Mitochondria-mediated apoptosis was also inhibited, via the regulation of B-cell lymphoma family proteins and the inhibition of cytochrome C release and caspase-3 activation. These results indicate that MCE has neuroprotective effects in PD models and may be useful for preventing or treating PD. PMID:24389454

  19. Immunomodulatory and neuroprotective effects of ginsenoside Rg1 in the MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) -induced mouse model of Parkinson's disease.

    PubMed

    Zhou, Ting-ting; Zu, Guo; Wang, Xi; Zhang, Xiao-gang; Li, Shao; Liang, Zhan-hua; Zhao, Jie

    2015-12-01

    Ginsenoside Rg1, one of the biologically active ingredients of ginseng, has been considered to be a candidate neuroprotective drug. The objective of the study was to study the protective effects of Rg1 through the peripheral and central inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Rg1 treatment protected TH-positive cells in the SNpc region from MPTP toxicity measured with immunofluoresence. The protein expression levels of TH in the SNpc region of MPTP-induced mice following treatment with Rg1 were higher than MPTP-induced mice which were tested with Western blot. The ratio of CD3(+)CD4(+) to CD3(+)CD8(+) T cells and CD4(+)CD25(+)Foxp3(+) regulatory T cells in the blood increased in MPTP-induced mice following treatment with Rg1 which were detected by flow cytometry analysis. Moreover, Rg1 reduced the serum concentrations of proinflammatory cytokines TNF-α, IFN-γ, IL-1β and IL-6 which were tested with enzyme-linked immunosorbent assay (ELISA). In addition, Rg1 inhibited the activation of microglia and reduced the infiltration of CD3(+) T cells into the SNpc region which were measured by immunofluorescence. Our results indicated that Rg1 may represent a promising drug for the treatment of PD via the regulation of the peripheral and central inflammation. PMID:26548343

  20. The neuroprotection of cannabidiol against MPP⁺-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson's disease.

    PubMed

    Santos, Neife Aparecida Guinaim; Martins, Nádia Maria; Sisti, Flávia Malvestio; Fernandes, Laís Silva; Ferreira, Rafaela Scalco; Queiroz, Regina Helena Costa; Santos, Antônio Cardozo

    2015-12-25

    Cannabidiol (CBD) is a non-psychoactive constituent of Cannabis sativa with potential to treat neurodegenerative diseases. Its neuroprotection has been mainly associated with anti-inflammatory and antioxidant events; however, other mechanisms might be involved. We investigated the involvement of neuritogenesis, NGF receptors (trkA), NGF, and neuronal proteins in the mechanism of neuroprotection of CBD against MPP(+) toxicity in PC12 cells. CBD increased cell viability, differentiation, and the expression of axonal (GAP-43) and synaptic (synaptophysin and synapsin I) proteins. Its neuritogenic effect was not dependent or additive to NGF, but it was inhibited by K252a (trkA inhibitor). CBD did not increase the expression of NGF, but protected against its decrease induced by MPP(+), probably by an indirect mechanism. We also evaluated the neuritogenesis in SH-SY5Y cells, which do not express trkA receptors. CBD did not induce neuritogenesis in this cellular model, which supports the involvement of trkA receptors. This is the first study to report the involvement of neuronal proteins and trkA in the neuroprotection of CBD. Our findings suggest that CBD has a neurorestorative potential independent of NGF that might contribute to its neuroprotection against MPP(+), a neurotoxin relevant to Parkinson's disease. PMID:26556726

  1. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance

    NASA Astrophysics Data System (ADS)

    Boehm, Thomas; Folkman, Judah; Browder, Timothy; O'Reilly, Michael S.

    1997-11-01

    Acquired drug resistance is a major problem in the treatment of cancer. Of the more than 500,000 annual deaths from cancer in the United States, many follow the development of resistance to chemotherapy. The emergence of resistance depends in part on the genetic instability, heterogeneity and high mutational rate of tumour cells. In contrast, endothelial cells are genetically stable, homogenous and have a low mutational rate. Therefore, antiangiogenic therapy directed against a tumour's endothelial cells should, in principle, induce little or no drug resistance. Endostatin, a potent angiogenesis inhibitor, was administered to mice bearing Lewis lung carcinoma, T241 fibrosarcoma or B16F10 melanoma. Treatment was stopped when tumours had regressed. Tumours were then allowed to re-grow and endostatin therapy was resumed. After 6, 4 or 2 treatment cycles, respectively, no tumours recurred after discontinuation of therapy. These experiments show that drug resistance does not develop in three tumour types treated with a potent angiogenesis inhibitor. An unexpected finding is that repeated cycles of antiangiogenic therapy are followed by prolonged tumour dormancy without further therapy.

  2. Neuroprotective Effects of Biochanin A against β-Amyloid-Induced Neurotoxicity in PC12 Cells via a Mitochondrial-Dependent Apoptosis Pathway.

    PubMed

    Tan, Ji Wei; Kim, Min Kyu

    2016-01-01

    Alzheimer's disease is considered one of the major neurodegenerative diseases and is characterized by the production of β-amyloid (Aβ) proteins and progressive loss of neurons. Biochanin A, a phytoestrogen compound found mainly in Trifolium pratense, was used in the present study as a potential alternative to estrogen replacement therapy via the investigation of its neuroprotective effects against Aβ25-35-induced toxicity, as well as of its potential mechanisms of action in PC12 cells. Exposure of these cells to the Aβ25-35 protein significantly increased cell viability loss and apoptosis. However, the effects induced by Aβ25-35 were markedly reversed in the present of biochanin A. Pretreatment with biochanin A attenuated the cytotoxic effect of the Aβ25-35 protein by decreasing viability loss, LDH release, and caspase activity in cells. Moreover, we found that expression of cytochrome c and Puma were reduced, alongside with the restoration of Bcl-2/Bax and Bcl-xL/Bax ratio in the presence of biochanin A, which led to a decrease in the apoptotic rate. These data demonstrate that mitochondria are involved in the protective effect of biochanin A against Aβ25-35 and that this drug attenuated Aβ25-35-induced PC12 cell injury and apoptosis by preventing mitochondrial dysfunction. Thus, biochanin A might raise a possibility as a potential therapeutic agent for Alzheimer's disease and other related neurodegenerative diseases. PMID:27120593

  3. The Neuro-Protective Effect of the Methanolic Extract of Perilla frutescens var. japonicaand Rosmarinic Acid against H₂O₂-Induced Oxidative Stress in C6 Glial Cells.

    PubMed

    Lee, Ah Young; Wu, Ting Ting; Hwang, Bo Ra; Lee, Jaemin; Lee, Myoung-Hee; Lee, Sanghyun; Cho, Eun Ju

    2016-05-01

    Neurodegenerative diseases are often associated with oxidative damage in neuronal cells. This study was conducted to investigate the neuro-protective effect of methanolic (MeOH) extract of Perilla frutescens var. japonica and its one of the major compounds, rosmarinic acid, under oxidative stress induced by hydrogen peroxide (H₂O₂) in C6 glial cells. Exposure of C6 glial cells to H₂O₂ enhanced oxidative damage as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and thiobarbituric acid-reactive substance assays. The MeOH extract and rosmarinic acid prevented oxidative stress by increasing cell viability and inhibiting cellular lipid peroxidation. In addition, the MeOH extract and rosmarinic acid reduced H₂O₂-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the transcriptional level. Moreover, iNOS and COX-2 protein expression was down-regulated in H₂O₂-indcued C6 glial cells treated with the MeOH extract and rosmarinic acid. These findings suggest that P. frutescens var. japonica and rosmarinic acid could prevent the progression of neurodegenerative diseases through attenuation of neuronal oxidative stress. PMID:27133263

  4. Jujuboside A, a neuroprotective agent from semen Ziziphi Spinosae ameliorates behavioral disorders of the dementia mouse model induced by Aβ 1-42.

    PubMed

    Liu, Zhi; Zhao, Xu; Liu, Bing; Liu, Ai-jing; Li, Huan; Mao, Xin; Wu, Bo; Bi, Kai-shun; Jia, Ying

    2014-09-01

    Semen Ziziphi Spinosae (SZS) has been used as a hypnotic-sedative medicine for thousands of years. Recently, SZS has also shown notable neuroprotective activities via anti-oxidative and anti-inflammatory effects in dementia animals. Jujuboside A (JuA), isolated from SZS, has been proved to be a major hypnotic-sedative component of SZS. In the present study, we firstly evaluated the effects of intracerebroventricular (ICV) injection of JuA (0.02 and 0.2mg/kg) for five consecutive days on cognitive impairment induced by ICV injection of Aβ 1-42. The results showed that ICV treatment with JuA significantly mitigated learning and memory impairment in mice induced by Aβ 1-42 as measured by the Y-maze, active avoidance and Morris water maze. Furthermore, ICV treatment with JuA reduced the level of Aβ 1-42 in hippocampus, significantly inhibited the activities of acetylcholinesterase (AChE) and NO, and decreased the amount of the increased malondialdehyde (MDA) in the hippocampus and cerebral cortex of mice treated with ICV injection of Aβ 1-42. Shrinkage of nuclei, swollen and eccentrically dispersed neuronal bodies were observed in hippocampus of AD mice induced by Aβ 1-42, however, JuA noticeably improved the histopathological damage. Cumulatively, the present study indicates that JuA may serve as a potential therapeutic agent for the treatment of Alzheimer' disease. PMID:24886882

  5. Mitochondria Related Pathway Is Essential for Polysaccharides Purified from Sparassis crispa Mediated Neuro-Protection against Glutamate-Induced Toxicity in Differentiated PC12 Cells

    PubMed Central

    Hu, Shuang; Wang, Di; Zhang, Junrong; Du, Mengyan; Cheng, Yingkun; Liu, Yan; Zhang, Ning; Wang, Di; Wu, Yi

    2016-01-01

    The present study aims to explore the neuro-protective effects of purified Sparassis crispa polysaccharides against l-glutamic acid (l-Glu)-induced differentiated PC12 (DPC12) cell damages and its underlying mechanisms. The Sparassis crispa water extract was purified by a DEAE-52 cellulose anion exchange column and a Sepharose G-100 column. A fraction with a molecular weight of 75 kDa and a diameter of 88.9 nm, entitled SCWEA, was obtained. SCWEA was identified with a triple helix with (1→3)-linked Rha in the backbone, and (1→2) linkages and (1→6) linkages in the side bone. Our results indicated that the pre-treatment of DPC12 cells with SCWEA prior to l-Glu exposure effectively reversed the reduction on cell viability (by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay) and reduced l-Glu-induced apoptosis (by Hoechst staining). SCWEA decreased the accumulation of intracellular reactive oxygen species, blocked Ca2+ influx and prevented depolarization of the mitochondrial membrane potential in DPC12 cells. Furthermore, SCWEA normalized expression of anti-apoptotic proteins in l-Glu-explored DPC12 cells. These results suggested that SCWEA protects against l-Glu-induced neuronal apoptosis in DPC12 cells and may be a promising candidate for treatment against neurodegenerative disease. PMID:26821016

  6. Neuroprotective effects of orientin on hydrogen peroxide‑induced apoptosis in SH‑SY5Y cells.

    PubMed

    Law, Benjamin Ngee Tiing; Ling, Anna Pick Kiong; Koh, Rhun Yian; Chye, Soi Moi; Wong, Ying Pei

    2014-03-01

    Neurodegenerative diseases remain a global issue which affects the ageing population. Efforts towards determining their aetiologies to understand their pathogenic mechanisms are underway in order to identify a pathway through which therapeutic measures can be applied. One such pathogenic mechanism, oxidative stress (OS), is widely considered to be involved in neurodegenerative disease. Antioxidants, most notably flavonoids, have promising potential for therapeutic use as shown in in vitro and in vivo studies. In view of the importance of flavonoids for combating OS, this study investigated the neuroprotective effects of orientin, which has been reported to be capable of crossing the blood‑brain barrier. The maximum non‑toxic dose (MNTD) of orientin against SH‑SY5Y neuroblastoma cells was determined using a 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT) assay. The effects of the MNTD and the half MNTD (½MNTD) of orientin on cell cycle progression and intracellular reactive oxygen species (ROS) levels, as well as the activity of caspases 3/7, 8 and 9 after exposure to 150 µM of hydrogen peroxide (H2O2) were also determined using flow cytometry, a 2',7'‑dichlorodihydrofluorescein‑diacetate (DCFH‑DA) assay and caspase assay kits, respectively. The results revealed that orientin at ≤20 µM was not cytotoxic to SH‑SY5Y cells. After treatment with orientin at the MNTD, the percentage of apoptotic cells was significantly reduced compared with that in cells treated with 150 µM H2O2 alone. The results also showed that, although orientin at the MNTD and ½MNTD did not reduce intracellular ROS levels, it significantly inhibited the activity of caspases 3/7. Caspase 9 was significantly inactivated with orientin at the MNTD. Findings from this study suggest that the neuroprotection conferred by orientin was the result of the intracellular mediation of caspase activity. PMID:24366367

  7. Acute Blockage of Notch Signaling by DAPT Induces Neuroprotection and Neurogenesis in the Neonatal Rat Brain After Stroke.

    PubMed

    Li, Zhongxia; Wang, Jiangping; Zhao, Congying; Ren, Keming; Xia, Zhezhi; Yu, Huimin; Jiang, Kewen

    2016-04-01

    Notch signaling is critically involved in various biological events. Notch undergoes cleavage by the γ-secretase enzyme to release Notch intracellular domain that will translocate into nucleus to result in expression of target gene. γ-Secretase inhibitors have been developed as potential treatments for neurological degenerative diseases, but its effects against ischemic injury remain relatively uncertain. In the present study, we demonstrated that N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor not only rescued the cerebral hypoperfusion or ischemia neonatal rats from death, reduced apoptosis in penumbra, but also reduced brain infarct size. Furthermore, DAPT elicited some morphologic hallmarks such as neurogenesis and angiogenesis that related to the brain repair and functional recovery after stroke: increased accumulations of newborn cells in the peri-infarct region with a higher fraction of them adopting immature neuronal and glial markers instead of microglial markers on 5 days, enhanced vascular densities in penumbra at 14 days, and evident regulations of the gene profiles associated with neurogenesis in penumbral tissues. The current results suggest that DAPT is a potential neuroprotectants against ischemic injury in immature brain, and future treatment strategies such as clinical trials using γ-secretase inhibitors would be an attractive therapy for perinatal ischemia. PMID:26691164

  8. Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus.

    PubMed

    Rojas, Asheebo; Ganesh, Thota; Lelutiu, Nadia; Gueorguieva, Paoula; Dingledine, Raymond

    2015-06-01

    Exposure to high levels of organophosphorus compounds (OP) can induce status epilepticus (SE) in humans and rodents via acute cholinergic toxicity, leading to neurodegeneration and brain inflammation. Currently there is no treatment to combat the neuropathologies associated with OP exposure. We recently demonstrated that inhibition of the EP2 receptor for PGE2 reduces neuronal injury in mice following pilocarpine-induced SE. Here, we investigated the therapeutic effects of an EP2 inhibitor (TG6-10-1) in a rat model of SE using diisopropyl fluorophosphate (DFP). We tested the hypothesis that EP2 receptor inhibition initiated well after the onset of DFP-induced SE reduces the associated neuropathologies. Adult male Sprague-Dawley rats were injected with pyridostigmine bromide (0.1 mg/kg, sc) and atropine methylbromide (20 mg/kg, sc) followed by DFP (9.5 mg/kg, ip) to induce SE. DFP administration resulted in prolonged upregulation of COX-2. The rats were administered TG6-10-1 or vehicle (ip) at various time points relative to DFP exposure. Treatment with TG6-10-1 or vehicle did not alter the observed behavioral seizures, however six doses of TG6-10-1 starting 80-150 min after the onset of DFP-induced SE significantly reduced neurodegeneration in the hippocampus, blunted the inflammatory cytokine burst, reduced microglial activation and decreased weight loss in the days after status epilepticus. By contrast, astrogliosis was unaffected by EP2 inhibition 4 d after DFP. Transient treatments with the EP2 antagonist 1 h before DFP, or beginning 4 h after DFP, were ineffective. Delayed mortality, which was low (10%) after DFP, was unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor within a time window that coincides with the induction of cyclooxygenase-2 by DFP is neuroprotective and accelerates functional recovery of rats. PMID:25656476

  9. Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus

    PubMed Central

    Rojas, Asheebo; Ganesh, Thota; Lelutiu, Nadia; Gueorguieva, Paoula; Dingledine, Raymond

    2015-01-01

    Exposure to high levels of organophosphorus compounds (OP) can induce status epilepticus (SE) in humans and rodents via acute cholinergic toxicity, leading to neurodegeneration and brain inflammation. Currently there is no treatment to combat the neuropathologies associated with OP exposure. We recently demonstrated that inhibition of the EP2 receptor for PGE2 reduces neuronal injury in mice following pilocarpine-induced SE. Here, we investigated the therapeutic effects of an EP2 inhibitor (TG6-10-1) in a rat model of SE using diisopropyl fluorophosphate (DFP). We tested the hypothesis that EP2 receptor inhibition initiated well after the onset of DFP-induced SE reduces the associated neuropathologies. Adult male Sprague-Dawley rats were injected with pyridostigmine bromide (0.1 mg/kg, sc) and atropine methylbromide (20 mg/kg, sc) followed by DFP (9.5 mg/kg, ip) to induce SE. DFP administration resulted in prolonged upregulation of COX-2. The rats were administered TG6-10-1 or vehicle (ip) at various time points relative to DFP exposure. Treatment with TG6-10-1 or vehicle did not alter the observed behavioral seizures, however six doses of TG6-10-1 starting 80-150 min after the onset of DFP-induced SE significantly reduced neurodegeneration in the hippocampus, blunted the inflammatory cytokine burst, reduced microglial activation and decreased weight loss in the days after status epilepticus. By contrast, astrogliosis was unaffected by EP2 inhibition 4 d after DFP. Transient treatments with the EP2 antagonist 1 h before DFP, or beginning 4 h after DFP, were ineffective. Delayed mortality, which was low (10%) after DFP, was unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor within a time window that coincides with the induction of cyclooxygenase-2 by DFP is neuroprotective and accelerates functional recovery of rats. PMID:25656476

  10. Neuroprotective Effects of A Standardized Flavonoid Extract of Safflower Against Neurotoxin-Induced Cellular and Animal Models of Parkinson’s Disease

    PubMed Central

    Ren, Rutong; Shi, Chunyan; Cao, Jing; Sun, Yi; Zhao, Xin; Guo, Yongfei; Wang, Chen; Lei, Hui; Jiang, Hanjie; Ablat, Nuramatjan; Xu, Jiamin; Li, Wan; Ma, Yingcong; Qi, Xianrong; Ye, Min; Pu, Xiaoping; Han, Hongbin

    2016-01-01

    Safflower has long been used to treat cerebrovascular diseases in China. We previously reported that kaempferol derivatives of safflower can bind DJ-1, a protein associated with Parkinson’s disease (PD), and flavonoid extract of safflower exhibited neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD. In this study, a standardized safflower flavonoid extract (SAFE) was isolated from safflower and mainly contained flavonoids. Two marker compounds of SAFE, kaempferol 3-O-rutinoside and anhydrosafflor yellow B, were proven to suppress microtubule destabilization and decreased cell area, respectively. We confirmed that SAFE in dripping pill form could improve behavioural performances in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD, partially via the suppression of α-synuclein overexpression or aggregation, as well as the suppression of reactive astrogliosis. Using an MRI tracer-based method, we found that 6-OHDA could change extracellular space (ECS) diffusion parameters, including a decrease in tortuosity and the rate constant of clearance and an increase in the elimination half-life of the tracer in the 6-OHDA-lesioned substantia nigra. SAFE treatment could partially inhibit the changes in ECS diffusion parameters, which might provide some information about neuronal loss and astrocyte activation. Consequently, our results indicate that SAFE is a potential therapeutic herbal product for treatment of PD. PMID:26906725

  11. Alkaline peroxide treatment induces acquired unruly hair by apparently affecting distinct macrofibrils.

    PubMed

    Nawa, Teppei; Kawaguchi, Aiko; Kitano, Hiroki; Yamamoto, Toshihiko; Fujinami, So; Asao, Naoki; Nakajima, Ken

    2013-01-01

    Individual hairs can be inherently curly; however, bleach treatment can cause damaged hairs to acquire a curl, a phenomenon we term acquired unintentional unruly hair. Because there have been no reports concerning acquired unintentional unruly hair, the influence of bleach treatment with alkaline peroxide that produce this phenomenon was investigated. First, it was validated that the radius of curvature in many curly hairs is reduced upon bleach treatment. Next, the influence of bleach treatment on the mechanical properties of inner components was studied by the force curve method using atomic force microscopy. This measurement revealed four types of macrofibrils-on the orthocortex- or the paracortex-like structure, and on the concave or the convex side-have different mechanical properties. Macrofibrils on the orthocortex-like structure on the convex side were especially influenced by alkaline peroxide treatment, and may be particularly important to acquired unintentional unruly hair. PMID:23931089

  12. Neuroprotective effect of nitric oxide donor isosorbide-dinitrate against oxidative stress induced by ethidium bromide in rat brain

    PubMed Central

    Abdel-Salam, Omar M.E.; Khadrawy, Yasser Ashry; Mohammed, Nadia A.

    2012-01-01

    This study investigated the effect of systemic administration of isosorbide-dinitrate (ISDN) on oxidative stress and brain monoamines in a toxic model of brain demyelination evoked by intracerebral injection (i.c.i) of ethidium bromide (10 µl of 0.1 %). Rats received saline (control) or ISDN at 5 or 10 mg/kg for 10 days prior to injection of ethidium bromide. Rats were euthanized one day later, and then the levels of reduced glutathione (GSH), lipid peroxidation (malondialdehyde; MDA), nitric oxide (nitrite/nitrate), acetylcholinesterase (AChE) activity, paraoxonase activity as well as monoamine levels (serotonin, dopamine and noradrenaline) were assessed in the brain cortex in different treatment groups. The i.c.i of ethidium bromide resulted in increased oxidative stress in the cortex one day after its injection; (i) MDA increased by 36.9 %; (ii) GSH decreased by 20.8 %, while (iii) nitric oxide increased by 60.3 %; (iv) AChE and paraoxonase activities in cortex decreased by 35.9 % and 29.4 %, respectively; (v) serotonin was significantly increased. In ethidium bromide-treated rats, pretreatment with ISDN at 10 mg/kg decreased cortical MDA by 23.9 %. Reduced glutathione was increased by 25.1 % ISDN at 10 mg/kg, while nitric oxide showed a 32.8 and 41.7 % decrease after 5 and 10 mg/kg of ISDN, respectively. Acetylcholinesterase activity increased by 24.3 % by 10 mg/kg of ISDN. Paraoxonase activity showed further decrease by 72.2 and 83.8 % after treatment with 5 and 10 mg/kg of ISDN, respectively. The administration of ISDN decreased the level of serotonin and noradrenaline compared with the ethidium bromide only treated group. Overall, the present findings suggest neuroprotective effect of ISDN against oxidative stress in this model of chemical demyelination.

  13. Acquired hyperpigmentations*

    PubMed Central

    Cestari, Tania Ferreira; Dantas, Lia Pinheiro; Boza, Juliana Catucci

    2014-01-01

    Cutaneous hyperpigmentations are frequent complaints, motivating around 8.5% of all dermatological consultations in our country. They can be congenital, with different patterns of inheritance, or acquired in consequence of skin problems, systemic diseases or secondary to environmental factors. The vast majority of them are linked to alterations on the pigment melanin, induced by different mechanisms. This review will focus on the major acquired hyperpigmentations associated with increased melanin, reviewing their mechanisms of action and possible preventive measures. Particularly prominent aspects of diagnosis and therapy will be emphasized, with focus on melasma, post-inflammatory hyperpigmentation, periorbital pigmentation, dermatosis papulosa nigra, phytophotodermatoses, flagellate dermatosis, erythema dyschromicum perstans, cervical poikiloderma (Poikiloderma of Civatte), acanthosis nigricans, cutaneous amyloidosis and reticulated confluent dermatitis PMID:24626644

  14. A Novel In Vivo Model of Focal Light Emitting Diode-Induced Cone-Photoreceptor Phototoxicity: Neuroprotection Afforded by Brimonidine, BDNF, PEDF or bFGF

    PubMed Central

    García-Ayuso, Diego; Alarcón-Martínez, Luis; Jiménez-López, Manuel; Bernal-Garro, José Manuel; Nieto-López, Leticia; Nadal-Nicolás, Francisco Manuel; Villegas-Pérez, María Paz; Wheeler, Larry A.; Vidal-Sanz, Manuel

    2014-01-01

    We have investigated the effects of light-emitting diode (LED)-induced phototoxicity (LIP) on cone-photoreceptors and their protection with brimonidine (BMD), brain-derived neurotrophic factor (BDNF), pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF) or basic fibroblast growth factor (bFGF). In anesthetized, dark adapted, adult albino rats a blue (400 nm) LED was placed perpendicular to the cornea (10 sec, 200 lux) and the effects were investigated using Spectral Domain Optical Coherence Tomography (SD-OCT) and/or analysing the retina in oriented cross-sections or wholemounts immune-labelled for L- and S-opsin and counterstained with the nuclear stain DAPI. The effects of topical BMD (1%) or, intravitreally injected BDNF (5 µg), PEDF (2 µg), CNTF (0.4 µg) or bFGF (1 µg) after LIP were examined on wholemounts at 7 days. SD-OCT showed damage in a circular region of the superotemporal retina, whose diameter varied from 1,842.4±84.5 µm (at 24 hours) to 1,407.7±52.8 µm (at 7 days). This region had a progressive thickness diminution from 183.4±5 µm (at 12 h) to 114.6±6 µm (at 7 d). Oriented cross-sections showed within the light-damaged region of the retina massive loss of rods and cone-photoreceptors. Wholemounts documented a circular region containing lower numbers of L- and S-cones. Within a circular area (1 mm or 1.3 mm radius, respectively) in the left and in its corresponding region of the contralateral-fellow-retina, total L- or S-cones were 7,118±842 or 661±125 for the LED exposed retinas (n = 7) and 14,040±1,860 or 2,255±193 for the fellow retinas (n = 7), respectively. BMD, BDNF, PEDF and bFGF but not CNTF showed significant neuroprotective effects on L- or S-cones. We conclude that LIP results in rod and cone-photoreceptor loss, and is a reliable, quantifiable model to study cone-photoreceptor degeneration. Intravitreal BDNF, PEDF or bFGF, or topical BMD afford significant cone neuroprotection in this model

  15. [Neuroprotective activity of the proline-containing dipeptide noopept on the model of brain ischemia induced by the middle cerebral artery occlusion].

    PubMed

    Gavrilova, S A; Us, K S; Ostrovskaia, R U; Koshelev, V B

    2006-01-01

    The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111) on the extent of ischemic cortical stroke was investigated in experiments on white mongrel male rats with ischemia induced by a combination of the middle cerebral artery occlusion with ipsilateral common carotid artery ligation. Animals were treated with noopept (0.5 mg/kg, i.p.) according to the following schedule: 15 min and 2, 24, and 48 h after the occlusion. Test rats were decapitated 72 h after occlusion, brains were extracted and frozen, and thin brain slices were stained with 2,3,5-triphenyltetrazolium chloride. The slices were scanned and processed using Auc 1 computer program, which estimates the percentage of damaged area relative to that of the whole ipsilateral hemisphere. The conditions of coagulation the distal segment of middle cerebral artery were selected, which caused necrosis localized in the fronto-parietal and dorso-lateral regions of the brain cortex without any damage of subcortical structures. The extent of the brain damage in control group (treated by saline) was 18.6%, while that in the group treated with noopept was 12.2%, thus demonstrating a decrease in the infarction area by 34.5% (p < 05). The data on noopept efficacy on the model of the extensive ischemic injury of brain cortex show that this drug has good prospects for use in the neuroprotective treatment of stroke. PMID:16995431

  16. The mechanisms involved in the long-lasting neuroprotective effect of fluoxetine against MDMA (‘ecstasy')-induced degeneration of 5-HT nerve endings in rat brain

    PubMed Central

    Sanchez, V; Camarero, J; Esteban, B; Peter, M J; Green, A R; Colado, M I

    2001-01-01

    It has been reported that co-administration of fluoxetine with 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') prevents MDMA-induced degeneration of 5-HT nerve endings in rat brain. The mechanisms involved have now been investigated. MDMA (15 mg kg−1, i.p.) administration produced a neurotoxic loss of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in cortex, hippocampus and striatum and a reduction in cortical [3H]-paroxetine binding 7 days later. Fluoxetine (10 mg kg−1, i.p., ×2, 60 min apart) administered concurrently with MDMA or given 2 and 4 days earlier provided complete protection, and significant protection when given 7 days earlier. Fluvoxamine (15 mg kg−1, i.p., ×2, 60 min apart) only produced neuroprotection when administered concurrently. Fluoxetine (10 mg kg−1, ×2) markedly increased the KD and reduced the Bmax of cortical [3H]-paroxetine binding 2 and 4 days later. The Bmax was still decreased 7 days later, but the KD was unchanged. [3H]-Paroxetine binding characteristics were unchanged 24 h after fluvoxamine (15 mg kg−1, ×2). A significant cerebral concentration of fluoxetine plus norfluoxetine was detected over the 7 days following fluoxetine administration. The fluvoxamine concentration had decreased markedly by 24 h. Pretreatment with fluoxetine (10 mg kg−1, ×2) failed to alter cerebral MDMA accumulation compared to saline pretreated controls. Neither fluoxetine or fluvoxamine altered MDMA-induced acute hyperthermia. These data demonstrate that fluoxetine produces long-lasting protection against MDMA-induced neurodegeneration, an effect apparently related to the presence of the drug and its active metabolite inhibiting the 5-HT transporter. Fluoxetine does not alter the metabolism of MDMA or its rate of cerebral accumulation. PMID:11522596

  17. Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system.

    PubMed

    Kim, Heung Deok; Jeong, Kyoung Hoon; Jung, Un Ju; Kim, Sang Ryong

    2016-02-01

    We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD. PMID:26878791

  18. Multiple transport systems mediate virus-induced acquired resistance to oxidative stress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this paper, we report the phenomenon of acquired cross-tolerance to oxidative (UV-C and H2O2) stress in Nicotiana benthamiana plants infected with Potato virus X (PVX) and investigate the functional expression of transport systems in mediating this phenomenon. By combining multiple approaches, we...

  19. Inhibition of Nuclear Translocation of Apoptosis-Inducing Factor Is an Essential Mechanism of the Neuroprotective Activity of Pigment Epithelium-Derived Factor in a Rat Model of Retinal Degeneration

    PubMed Central

    Murakami, Yusuke; Ikeda, Yasuhiro; Yonemitsu, Yoshikazu; Onimaru, Mitsuho; Nakagawa, Kazunori; Kohno, Ri-ichiro; Miyazaki, Masanori; Hisatomi, Toshio; Nakamura, Makoto; Yabe, Takeshi; Hasegawa, Mamoru; Ishibashi, Tatsuro; Sueishi, Katsuo

    2008-01-01

    Photoreceptor apoptosis is a critical process of retinal degeneration in retinitis pigmentosa (RP), a group of retinal degenerative diseases that result from rod and cone photoreceptor cell death and represent a major cause of adult blindness. We previously demonstrated the efficient prevention of photoreceptor apoptosis by intraocular gene transfer of pigment epithelium-derived factor (PEDF) in animal models of RP; however, the underlying mechanism of the neuroprotective activity of PEDF remains elusive. In this study, we show that an apoptosis-inducing factor (AIF)-related pathway is an essential target of PEDF-mediated neuroprotection. PEDF rescued serum starvation-induced apoptosis, which is mediated by AIF but not by caspases, of R28 cells derived from the rat retina by preventing translocation of AIF into the nucleus. Nuclear translocation of AIF was also observed in the apoptotic photoreceptors of Royal College of Surgeons rats, a well-known animal model of RP that carries a mutation of the Mertk gene. Lentivirus-mediated retinal gene transfer of PEDF prevented the nuclear translocation of AIF in vivo, resulting in the inhibition of the apoptotic loss of their photoreceptors in association with up-regulated Bcl-2 expression, which mediates the mitochondrial release of AIF. These findings clearly demonstrate that AIF is an essential executioner of photoreceptor apoptosis in inherited retinal degeneration and provide a therapeutic rationale for PEDF-mediated neuroprotective gene therapy for individuals with RP. PMID:18845835

  20. Neuroprotection in Glaucoma.

    PubMed

    Doozandeh, Azadeh; Yazdani, Shahin

    2016-01-01

    Glaucoma is a degenerative optic neuropathy characterized by retinal ganglion cell (RGC) loss and visual field defects. It is known that in some glaucoma patients, death of RGCs continues despite intraocular pressure (IOP) reduction. Neuroprotection in the field of glaucoma is defined as any treatment, independent of IOP reduction, which prevents RGC death. Glutamate antagonists, ginkgo biloba extract, neurotrophic factors, antioxidants, calcium channel blockers, brimonidine, glaucoma medications with blood regulatory effect and nitric oxide synthase inhibitors are among compounds with possible neuroprotective activity in preclinical studies. A few agents (such as brimonidine or memantine) with neuroprotective effects in experimental studies have advanced to clinical trials; however the results of clinical trials for these agents have not been conclusive. Nevertheless, lack of compelling clinical evidence has not prevented the off-label use of some of these compounds in glaucoma practice. Stem cell transplantation has been reported to halt experimental neurodegenerative disease processes in the absence of cell replacement. It has been hypothesized that transplantation of some types of stem cells activates multiple neuroprotective pathways via secretion of various factors. The advantage of this approach is a prolonged and targeted effect. Important concerns in this field include the secretion of unwanted harmful mediators, graft survival issues and tumorigenesis. Neuroprotection in glaucoma, pharmacologically or by stem cell transplantation, is an interesting subject waiting for broad and multidisciplinary collaborative studies to better clarify its role in clinical practice. PMID:27413504

  1. Neuroprotection in Glaucoma

    PubMed Central

    Doozandeh, Azadeh; Yazdani, Shahin

    2016-01-01

    Glaucoma is a degenerative optic neuropathy characterized by retinal ganglion cell (RGC) loss and visual field defects. It is known that in some glaucoma patients, death of RGCs continues despite intraocular pressure (IOP) reduction. Neuroprotection in the field of glaucoma is defined as any treatment, independent of IOP reduction, which prevents RGC death. Glutamate antagonists, ginkgo biloba extract, neurotrophic factors, antioxidants, calcium channel blockers, brimonidine, glaucoma medications with blood regulatory effect and nitric oxide synthase inhibitors are among compounds with possible neuroprotective activity in preclinical studies. A few agents (such as brimonidine or memantine) with neuroprotective effects in experimental studies have advanced to clinical trials; however the results of clinical trials for these agents have not been conclusive. Nevertheless, lack of compelling clinical evidence has not prevented the off-label use of some of these compounds in glaucoma practice. Stem cell transplantation has been reported to halt experimental neurodegenerative disease processes in the absence of cell replacement. It has been hypothesized that transplantation of some types of stem cells activates multiple neuroprotective pathways via secretion of various factors. The advantage of this approach is a prolonged and targeted effect. Important concerns in this field include the secretion of unwanted harmful mediators, graft survival issues and tumorigenesis. Neuroprotection in glaucoma, pharmacologically or by stem cell transplantation, is an interesting subject waiting for broad and multidisciplinary collaborative studies to better clarify its role in clinical practice. PMID:27413504

  2. Modulation of the Nitrergic Pathway via Activation of PPAR-γ Contributes to the Neuroprotective Effect of Pioglitazone Against Streptozotocin-Induced Memory Dysfunction.

    PubMed

    Prakash, Atish; Kumar, Anil; Ming, Long Chiau; Mani, Vasudevan; Majeed, Abu Bakar Abdul

    2015-07-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by impaired memory function and oxidative damage. NO is a major signaling molecule produced in the central nervous system to modulate neurological activity through modulating nitric oxide synthase. Recently, PPAR-γ agonists have shown neuroprotective effects in neurodegenerative disorders. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. The present study was designed to investigate the possible nitric oxide mechanism in the protective effect of pioglitazone against streptozotocin (STZ)-induced memory dysfunction. Wistar rats were intracerebroventricularly (ICV) injected with STZ. Then rats were treated with pioglitazone, NO modulators [L-arginine and nitro-L-arginine methyl ester (L-NAME)] for 21 days. Behavioral alterations were assessed in between the study period. Animals were sacrificed immediately after behavioral session, and mito-oxidative parameters, TNF-α, IL-6, and caspase-3 activity were measured. STZ-treated rats showed a memory deficit and significantly increased in mito-oxidative damage and inflammatory mediators and apoptosis in the hippocampus. Chronic treatment of pioglitazone significantly improved memory retention and attenuated mito-oxidative damage parameters, inflammatory markers, and apoptosis in STZ-treated rats. However, L-arginine pretreatment with lower dose of pioglitazone has not produced any protective effect as compared to per se. Furthermore, pretreatment of L-NAME significantly potentiated its protective effect, which indicates the involvement of nitric oxide for activation of PPAR-γ action. These results demonstrate that pioglitazone offers protection against STZ-induced memory dysfunction possibly due to its antioxidant, anti-inflammatory, and anti-apoptotic action mediating nitric oxide pathways and, therefore, could have a therapeutic potential in AD. PMID:25854775

  3. The inhibition of transforming growth factor beta-activated kinase 1 contributed to neuroprotection via inflammatory reaction in pilocarpine-induced rats with epilepsy.

    PubMed

    Tian, Q; Xiao, Q; Yu, W; Gu, M; Zhao, N; Lü, Y

    2016-06-14

    Recently, more and more studies support that inflammation is involved in the pathogenesis of epilepsy. Although TGFβ signaling is involved in epileptogenesis, whether TGFβ-associated neuroinflammation is sufficient to regulate epilepsy remains unknown to date. Furthermore, tumor necrosis factor-α receptor-associated factor-6 (TRAF6), transforming growth factor beta-activated kinase 1 (TAK1), which are the key elements of TGFβ-associated inflammation, is still unclear in epilepsy. Therefore, the present study aimed to explore the role of TRAF6 and TAK1 in pilocarpine-induced epileptic rat model. Firstly, the gene levels and protein expression of TRAF6 and TAK1 were detected in different time points after pilocarpine-induced status epilepticus (SE). 5z-7-oxozeaenol treatment (TAK1 antagonist) was then performed; the changes in TRAF6, TAK1, phosphorylated-TAK1 (P-TAK1), interleukin-1β (IL-1β) levels, neuronal survival and apoptosis, and seizure activity were detected. Our results showed that expressions of TRAF6 were increased after SE, reached the peak in 7day, maintained at the high level to 30days, and the TAK1, P-TAK1 levels were increased after SE following time. After 5z-7-oxozeaenol treatment in epileptic rats, TRAF6-TAK1-P-TAK1 signaling protein expressions were reduced, inflammatory cytokine IL-1β expression was decreased, neuron survival index was improved, the neuron apoptosis index was decreased and seizure durations were alleviated. In conclusion, the expression of TRAF6 and TAK1 are related to the progression of epilepsy. TAK1 might be a potential intervention target for the treatment of epilepsy via neuroprotection. PMID:27012613

  4. Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways.

    PubMed

    Siddiq, Ambreena; Aminova, Leila R; Troy, Carol M; Suh, Kyungsun; Messer, Zachary; Semenza, Gregg L; Ratan, Rajiv R

    2009-07-01

    Oxidative stress contributes to tissue injury in conditions ranging from cardiovascular disease to stroke, spinal cord injury, neurodegeneration, and perhaps even aging. Yet the efficacy of antioxidants in human disease has been mixed at best. We need a better understanding of the mechanisms by which established antioxidants combat oxidative stress. Iron chelators are well established inhibitors of oxidative death in both neural and non-neural tissues, but their precise mechanism of action remains elusive. The prevailing but not completely substantiated view is that iron chelators prevent oxidative injury by suppressing Fenton chemistry and the formation of highly reactive hydroxyl radicals. Here, we show that iron chelation protects, rather unexpectedly, by inhibiting the hypoxia-inducible factor prolyl 4-hydroxylase isoform 1 (PHD1), an iron and 2-oxoglutarate-dependent dioxygenase. PHD1 and its isoforms 2 and 3 are best known for stabilizing transcriptional regulators involved in hypoxic adaptation, such as HIF-1alpha and cAMP response element-binding protein (CREB). Yet we find that global hypoxia-inducible factor (HIF)-PHD inhibition protects neurons even when HIF-1alpha and CREB are directly suppressed. Moreover, two global HIF-PHD inhibitors continued to be neuroprotective even in the presence of diminished HIF-2alpha levels, which itself increases neuronal susceptibility to oxidative stress. Finally, RNA interference to PHD1 but not isoforms PHD2 or PHD3 prevents oxidative death, independent of HIF activation. Together, these studies suggest that iron chelators can prevent normoxic oxidative neuronal death through selective inhibition of PHD1 but independent of HIF-1alpha and CREB; and that HIF-2alpha, not HIF-1alpha, regulates susceptibility to normoxic oxidative neuronal death. PMID:19587290

  5. Neuroprotective compounds of Tilia amurensis

    PubMed Central

    Lee, Bohyung; Weon, Jin Bae; Eom, Min Rye; Jung, Youn Sik; Ma, Choong Je

    2015-01-01

    Background: Tilia amurensis (Tiliacese) has been used for anti-tumor and anti-inflammatory in Korea, China, and Japan. Objective: In this study, we isolated five compounds from T. amurensis and determined whether protected neuronal cells against glutamate-induced oxidative stress in HT22 cells. Materials and Methods: Compounds were isolated using chromatographic techniques including silica gel, Sephadex LH-20 open column and high performance liquid chromatography analysis, and evaluated neuroprotective effect in HT22 cells by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Results: β-D-fructofuranosyl α-D-glucopyranoside (1), (-)-epicatechin (2), nudiposide (3), lyoniside (4), and scopoletin (5) were isolated by bioactivity-guided fractionation from the ethyl acetate fraction of T. amurensis. Among them, (-)-epicatechin, nudiposide, lyoniside, and scopoletin had significant neuroprotective activities against glutamate-injured neurotoxicity in HT22 cells. Conclusion: These results demonstrated that compound two, three, four, and five have a pronounced protective effect against glutamate-induced neurotoxicity in HT22 cells. PMID:26664019

  6. Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ25-35 peptide-induced toxicity in vitro and in vivo in mice

    PubMed Central

    Villard, Vanessa; Alméras, Marion; Krishnan, Kathiresan; Covey, Douglas F.; Maurice, Tangui; Akwa, Yvette

    2014-01-01

    Rationale PREGS and DHEAS are pro-mnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer's disease (AD) patient brains, their low concentrations are correlated with high levels of Aβ and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents. We investigated here whether ent-PREGS and ent-DHEAS could be neuroprotective in AD models. Objective The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against Aβ25-35 peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice. Methods B104 cells pretreated with the steroids before Aβ25-35 were analyzed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with Aβ25-35 and the steroids, were analyzed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured. Results ent-PREGS and PREGS significantly attenuated the Aβ25-35-induced decrease in cell viability. Both steroids prevented the Aβ25-35-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the Aβ25-35-induced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite outgrowth per se and prevented the Aβ25-35-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the Aβ25-35-induced decrease in memory (spontaneous alternation and passive avoidance) and an increase in lipid peroxidation levels. In contrast to the natural steroids, both enantiomers prevented amnesia when injected 6 h before Aβ25-35 in contrast to the natural steroids. Conclusion The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD. PMID:24481566

  7. Neuroprotective effects of lotus seedpod procyanidins on extremely low frequency electromagnetic field-induced neurotoxicity in primary cultured hippocampal neurons.

    PubMed

    Yin, Chunchun; Luo, Xiaoping; Duan, Yuqing; Duan, Wenyi; Zhang, Haihui; He, Yuanqing; Sun, Guibo; Sun, Xiaobo

    2016-08-01

    The present study investigated the protective effects of lotus seedpod procyanidins (LSPCs) on extremely low frequency electromagnetic field (ELF-EMF)-induced neurotoxicity in primary cultured rat hippocampal neurons and the underlying molecular mechanism. The results of MTT, morphological observation, superoxide dismutase (SOD) and malondialdehyde (MDA) assays showed that compared with control, incubating neurons under ELF-EMF exposure significantly decreased cell viability and increased the number of apoptotic cells, whereas LSPCs evidently protected the hippocampal neurons against ELF-EMF-induced cell damage. Moreover, a certain concentration of LSPCs inhibited the elevation of intracellular reactive oxygen species (ROS) and Ca(2+) level, as well as prevented the disruption of mitochondrial membrane potential induced by ELF-EMF exposure. In addition, supplementation with LSPCs could alleviate DNA damage, block cell cycle arrest at S phase, and inhibit apoptosis and necrosis of hippocampal neurons under ELF-EMF exposure. Further study demonstrated that LSPCs up-regulated the activations of Bcl-2, Bcl-xl proteins and suppressed the expressions of Bad, Bax proteins caused by ELF-EMF exposure. In conclusion, these findings revealed that LSPCs protected against ELF-EMF-induced neurotoxicity through inhibiting oxidative stress and mitochondrial apoptotic pathway. PMID:27470406

  8. New Real-Time PCR Assays for Detection of Inducible and Acquired Clarithromycin Resistance in the Mycobacterium abscessus Group

    PubMed Central

    Shallom, Shamira J.; Moura, Natalia S.; Olivier, Kenneth N.; Sampaio, Elizabeth P.; Holland, Steven M.

    2015-01-01

    Members of the Mycobacterium abscessus group (MAG) cause lung, soft tissue, and disseminated infections. The oral macrolides clarithromycin and azithromycin are commonly used for treatment. MAG can display clarithromycin resistance through the inducible erm(41) gene or via acquired mutations in the rrl (23S rRNA) gene. Strains harboring a truncation or a T28C substitution in erm(41) lose the inducible resistance trait. Phenotypic detection of clarithromycin resistance requires extended incubation (14 days), highlighting the need for faster methods to detect resistance. Two real-time PCR-based assays were developed to assess inducible and acquired clarithromycin resistance and tested on a total of 90 clinical and reference strains. A SYBR green assay was designed to distinguish between a full-length and truncated erm(41) gene by temperature shift in melting curve analysis. Single nucleotide polymorphism (SNP) allele discrimination assays were developed to distinguish T or C at position 28 of erm(41) and 23S rRNA rrl gene mutations at position 2058 and/or 2059. Truncated and full-size erm(41) genes were detected in 21/90 and 69/90 strains, respectively, with 64/69 displaying T at nucleotide position 28 and 5/69 containing C at that position. Fifteen isolates showed rrl mutations conferring clarithromycin resistance, including A2058G (11 isolates), A2058C (3 isolates), and A2059G (1 isolate). Targeted sequencing and phenotypic assessment of resistance concurred with molecular assay results. Interestingly, we also noted cooccurring strains harboring an active erm(41), inactive erm(41), and/or acquired mutational resistance, as well as slowly growing MAG strains and also strains displaying an inducible resistance phenotype within 5 days, long before the recommended 14-day extended incubation. PMID:26269619

  9. ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC.

    PubMed

    Cheng, Qijian; Zhou, Ling; Zhou, Jianping; Wan, Huanying; Li, Qingyun; Feng, Yun

    2016-09-01

    Angiotensin II (AngII) is a multifunctional bioactive peptide in the renin-angiotensin system (RAS). Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of RAS. We previously reported that ACE2 overexpression may inhibit cell growth and vascular endothelial growth factor (VEGF) production in vitro and in vivo. In the present study, we investigated the effect of ACE2 on tumor-associated angiogen-esis after the development of acquired platinum resistance in non-small cell lung cancer (NSCLC). Four NSCLC cell lines, A549, LLC, A549-DDP and LLC-DDP, were used in vitro, while A549 and A549-DDP cells were used in vivo. A549-DDP and LLC-DDP cells were newly established at our institution as acquired platinum-resistant sublines by culturing the former parent cells in cisplatin (CDDP)-containing conditioned medium for 6 months. These platinum-resistant cells showed significantly higher angiotensin II type 1 receptor (AT1R), ACE and VEGF production and lower ACE2 expression than their corresponding parent cells. We showed that ACE2 overexpression inhibited the production of VEGF in vitro and in vivo compared to their corresponding parent cells. We also found that ACE2 overexpression reduced the expression of AT1R and ACE. Additionally, we confirmed that ACE2 overexpres-sion inhibited cell growth and VEGF production while simultaneously suppressing ACE and AT1R expression in human lung cancer xenografts. Our findings indicate that ACE2 overexpression may potentially suppress angiogenesis in NSCLC after the development of acquired platinum resistance. PMID:27460845

  10. Neuroprotective effects of xanthone derivative of Garcinia mangostana against lead-induced acetylcholinesterase dysfunction and cognitive impairment.

    PubMed

    Phyu, Moe Pwint; Tangpong, Jitbanjong

    2014-08-01

    Lead poisoning is a common environmental toxicity and low level of lead exposure is responsible for neurobehavioral or intelligence defects. This study was designed to investigate the protective effect of a xanthone derivative of Garcinia mangostana against lead-induced acetycholinesterase (AChE) dysfunction and cognitive impairment in mice. ICR mice were exposed to lead acetate (Pb) in drinking water (1%) with or without xanthone co-administration (100 and 200mg/kgBW/day) for 38days. Xanthone possesses a high phenolic content, which is positive correlation with its antioxidant activity (R(2)=0.98). The IC50 of xanthone on scavenging free radical activities, hydroxyl radical, superoxide radical, hydrogen peroxide and nitric oxide in cell-free system were 0.48±0.08, 1.88±0.09, 2.20±0.03 and 0.98±0.40mg/mL, respectively. We found that Pb induced AChE dysfunction and memory deficit in a dose dependent manner, indicated by in vitro and in vivo studies. However, xanthone significantly restored AChE activity in the blood and brains of mice and prevented Pb-induced neurobehavioral defect indicators with Forced Swimming and Morris water maze tests. Xanthone treatment improved all indicators compared to the Pb-treated group. In conclusion, xanthone alleviates Pb-induced neurotoxicity, in part, by suppression of oxidative damage and reversing AChE activity with a reduction in learning deficit and memory loss. PMID:24795231

  11. Neuroprotection of Ischemic Preconditioning is Mediated by Anti-inflammatory, Not Pro-inflammatory, Cytokines in the Gerbil Hippocampus Induced by a Subsequent Lethal Transient Cerebral Ischemia.

    PubMed

    Kim, Dong Won; Lee, Jae-Chul; Cho, Jeong-Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Tae, Hyun-Jin; Seo, Jeong Yeol; Cho, Jun Hwi; Kang, Il Jun; Hong, Seongkweon; Kim, Young-Myeong; Won, Moo-Ho; Kim, In Hye

    2015-09-01

    Ischemic preconditioning (IPC) induced by sublethal transient cerebral ischemia could reduce neuronal damage/death following a subsequent lethal transient cerebral ischemia. We, in this study, compared expressions of interleukin (IL)-2 and tumor necrosis factor (TNF)-α as pro-inflammatory cytokines, and IL-4 and IL-13 as anti-inflammatory cytokines in the gerbil hippocampal CA1 region between animals with lethal ischemia and ones with IPC followed by lethal ischemia. In the animals with lethal ischemia, pyramidal neurons in the stratum pyramidale (SP) of the hippocampal CA1 region were dead at 5 days post-ischemia; however, IPC protected the CA1 pyramidal neurons from lethal ischemic injury. Expressions of all cytokines were significantly decreased in the SP after lethal ischemia and hardly detected in the SP at 5 days post-ischemia because the CA1 pyramidal neurons were dead. IPC increased expressions of anti-inflammatory cytokines (IL-4 and IL-13) in the stratum pyramidale of the CA1 region following no lethal ischemia (sham-operation), and the increased expressions of IL-4 and IL-13 by IPC were continuously maintained is the SP of the CA1 region after lethal ischemia. However, pro-inflammatory cytokines (IL-2 and TNF-α) in the SP of the CA1 region were similar those in the sham-operated animals with IPC, and the IL-4 and IL-13 expressions in the SP were maintained after lethal ischemia. In conclusion, this study shows that anti-inflammatory cytokines significantly increased and longer maintained by IPC and this might be closely associated with neuroprotection after lethal transient cerebral ischemia. PMID:26290267

  12. Dopamine as a potent inducer of cellular glutathione and NAD(P)H:quinone oxidoreductase 1 in PC12 neuronal cells: a potential adaptive mechanism for dopaminergic neuroprotection.

    PubMed

    Jia, Zhenquan; Zhu, Hong; Misra, Bhaba R; Li, Yunbo; Misra, Hara P

    2008-11-01

    Dopamine auto-oxidation and the consequent formation of reactive oxygen species and electrophilic quinone molecules have been implicated in dopaminergic neuronal cell death in Parkinson's disease. We reported here that in PC12 dopaminergic neuronal cells dopamine at noncytotoxic concentrations (50-150 muM) potently induced cellular glutathione (GSH) and the phase 2 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), two critical cellular defenses in detoxification of ROS and electrophilic quinone molecules. Incubation of PC12 cells with dopamine also led to a marked increase in the mRNA levels for gamma-glutamylcysteine ligase catalytic subunit (GCLC) and NQO1. In addition, treatment of PC12 cells with dopamine resulted in a significant elevation of GSH content in the mitochondrial compartment. To determine whether treatment with dopamine at noncytotoxic concentrations, which upregulated the cellular defenses could protect the neuronal cells against subsequent lethal oxidative and electrophilic injury, PC12 cells were pretreated with dopamine (150 muM) for 24 h and then exposed to various cytotoxic concentrations of dopamine or 6-hydroxydopamine (6-OHDA). We found that pretreatment of PC12 cells with dopamine at a noncytotoxic concentration led to a remarkable protection against cytotoxicity caused by dopamine or 6-OHDA at lethal concentrations, as detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium reduction assay. In view of the critical roles of GSH and NQO1 in protecting against dopaminergic neuron degeneration, the above findings implicate that upregulation of both GSH and NQO1 by dopamine at noncytotoxic concentrations may serve as an important adaptive mechanism for dopaminergic neuroprotection. PMID:18368484

  13. Neuroprotective flavonoids from Flemingia macrophylla.

    PubMed

    Shiao, Young-Ji; Wang, Chuen-Neu; Wang, Wan-Yu; Lin, Yun-Lian

    2005-09-01

    Using an Abeta-induced neurotoxicity blocking assay to direct fractionation, three new flavonoids, fleminginin (1), flemingichromone (2), and flemingichalcone (3), and twenty known compounds were isolated from the active fractions of the aerial parts of Flemingia macrophylla. The structures of 1 - 3 were elucidated on the basis of spectroscopic data. When tested for neuroprotective activity, compound 2, osajin ( 4), 5,7,4'-trihydroxy-6,8-diprenylisoflavone (5), 5,7,4'-trihydroxy-6,3'-diprenylisoflavone (6), and aureole (7) protected neuronal cells from Abeta-induced damage with EC50 values of 31.43 +/- 3.16, 5.01 +/- 1.28, 11.25 +/-1.51, 4.47 +/- 0.65, 12.09 +/- 2.55 microM, respectively. PMID:16206038

  14. Neuroprotective and antioxidant activities of bamboo salt soy sauce against H2O2-induced oxidative stress in rat cortical neurons

    PubMed Central

    JEONG, JONG HEE; NOH, MIN-YOUNG; CHOI, JAE-HYEOK; LEE, HAIWON; KIM, SEUNG HYUN

    2016-01-01

    Bamboo salt (BS) and soy sauce (SS) are traditional foods in Asia, which contain antioxidants that have cytoprotective effects on the body. The majority of SS products contain high levels of common salt, consumption of which has been associated with numerous detrimental effects on the body. However, BS may be considered a healthier substitute to common salt. The present study hypothesized that SS made from BS, known as bamboo salt soy sauce (BSSS), may possess enhanced cytoprotective properties; this was evaluated using a hydrogen peroxide (H2O2)-induced neuronal cell death rat model. Rat neuronal cells were pretreated with various concentrations (0.001, 0.01, 0.1, 1 and 10%) of BSSS, traditional soy sauce (TRSS) and brewed soy sauce (BRSS), and were subsequently exposed to H2O2 (100 µM). The viability of neuronal cells, and the occurrence of DNA fragmentation, was subsequently examined. Pretreatment of neuronal cells with TRSS and BRSS reduced cell viability in a concentration-dependent manner, whereas neuronal cells pretreated with BSSS exhibited increased cell viability, as compared with non-treated neuronal cells. Furthermore, neuronal cells pretreated with 0.01% BSSS exhibited the greatest increase in viability. Exposure of neuronal cells to H2O2 significantly increased the levels of reactive oxygen species (ROS), B-cell lymphoma 2-associated X protein, poly (ADP-ribose), cleaved poly (ADP-ribose) polymerase, cytochrome c, apoptosis-inducing factor, cleaved caspase-9 and cleaved caspase-3, in all cases. Pretreatment of neuronal cells with BSSS significantly reduced the levels of ROS generated by H2O2, and increased the levels of phosphorylated AKT and phosphorylated glycogen synthase kinase-3β. Furthermore, the observed effects of BSSS could be blocked by administration of 10 µM LY294002, a phosphatidylinositol 3-kinase inhibitor. The results of the present study suggested that BSSS may exert positive neuroprotective effects against H2O2-induced cell death

  15. Inducible lymphoid clusters, iSALTs, in contact dermatitis: a new concept of acquired cutaneous immune responses.

    PubMed

    Natsuaki, Yohei; Kabashima, Kenji

    2016-09-01

    Antigen presentation to peripheral memory T cells is a key step in the prompt elicitation of acquired immune responses. In the mucosa, specific sentinel lymphoid tissues called mucosa-associated lymphoid tissue serve as antigen presentation sites. Correspondingly, the concept of skin-associated lymphoid tissue (SALT) has been proposed in the 1980s. However, the details of SALT have not been clarified so far. Recently, the live imaging analysis using two photon microscopes are developed. Here, we have identified inducible lymphoid clusters in the skin, we called it inducible SALTs (iSALTs), using a murine contact hypersensitivity model. In the elicitation phase, dendritic cells (DCs) formed clusters and interacted for several hours with effector memory T cells in the dermis. This interaction was essential for proliferation and activation of effector memory T cells in situ in an antigen dependent manner. Interestingly, DC clusters were abrogated by depletion of skin macrophages. Furthermore, IL-1 treatment induced CXCL2 production from macrophages and DC clusters were suppressed with the blockade of IL-1R or CXCR2. Taken together, this sustained conjugation between DCs and memory T cells, iSALTs, is essential for establishment of the effector phase in acquired cutaneous immunity. PMID:26941109

  16. Neuroprotective Effect of a DJ-1 Based Peptide in a Toxin Induced Mouse Model of Multiple System Atrophy

    PubMed Central

    Glat, Micaela Johanna; Ben-Zur, Tali; Barhum, Yael; Offen, Daniel

    2016-01-01

    Multiple System Atrophy (MSA) is a sporadic neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and dysautonomia, in various combinations. In MSA with parkinsonism (MSA-P), the degeneration is mainly restricted to the substantia nigra pars compacta and putamen. Studies have identified alterations in DJ-1 (PARK7), a key component of the anti-oxidative stress response, in Parkinson’s disease (PD) and MSA patients. Previously we have shown that a short DJ-1-based peptide named ND-13, protected cultured cells against neurotoxic insults and improved behavioral outcome in animal models of Parkinson’s disease (PD). In this study, we used the 3-Nitropropionic acid (3-NP)-induced mouse model of MSA and treated the animals with ND-13 in order to evaluate its therapeutic effects. Our results show that ND-13 protects cultured cells against oxidative stress generated by the mitochondrial inhibitor, 3-NP. Moreover, we show that ND-13 attenuates nigrostriatal degeneration and improves performance in motor-related behavioral tasks in 3-NP-treated mice. Our findings suggest a rationale for using ND-13 as a promising therapeutic approach for treatment of MSA. PMID:26901405

  17. Acquired coagulant factor VIII deficiency induced by Bacillus anthracis lethal toxin in mice

    PubMed Central

    Sun, Der-Shan; Lee, Po-Chien; Kau, Jyh-Hwa; Shih, Yung-Luen; Huang, Hsin-Hsien; Li, Chen-Ru; Lee, Chin-Cheng; Wu, Yu-Ping; Chen, Kuo-Ching; Chang, Hsin-Hou

    2015-01-01

    Mice treated with anthrax lethal toxin (LT) exhibit hemorrhage caused by unknown mechanisms. Moreover, LT treatment in mice induced liver damage. In this study, we hypothesized that a suppressed coagulation function may be associated with liver damage, because the liver is the major producing source of coagulation factors. The hepatic expression of coagulant factors and the survival rates were analyzed after cultured cells or mice were exposed to LT. In agreement with our hypothesis, LT induces cytotoxicity against hepatic cells in vitro. In addition, suppressed expression of coagulation factor VIII (FVIII) in the liver is associated with a prolonged plasma clotting time in LT-treated mice, suggesting a suppressive role of LT in coagulation. Accordingly, we further hypothesized that a loss-of-function approach involving treatments of an anticoagulant should exacerbate LT-induced abnormalities, whereas a gain-of-function approach involving injections of recombinant FVIII to complement the coagulation deficiency should ameliorate the pathogenesis. As expected, a sublethal dose of LT caused mortality in the mice that were non-lethally pretreated with an anticoagulant (warfarin). By contrast, treatments of recombinant FVIII reduced the mortality from a lethal dose of LT in mice. Our results indicated that LT-induced deficiency of FVIII is involved in LT-mediated pathogenesis. Using recombinant FVIII to correct the coagulant defect may enable developing a new strategy to treat anthrax. PMID:25906166

  18. Acquired coagulant factor VIII deficiency induced by Bacillus anthracis lethal toxin in mice.

    PubMed

    Sun, Der-Shan; Lee, Po-Chien; Kau, Jyh-Hwa; Shih, Yung-Luen; Huang, Hsin-Hsien; Li, Chen-Ru; Lee, Chin-Cheng; Wu, Yu-Ping; Chen, Kuo-Ching; Chang, Hsin-Hou

    2015-01-01

    Mice treated with anthrax lethal toxin (LT) exhibit hemorrhage caused by unknown mechanisms. Moreover, LT treatment in mice induced liver damage. In this study, we hypothesized that a suppressed coagulation function may be associated with liver damage, because the liver is the major producing source of coagulation factors. The hepatic expression of coagulant factors and the survival rates were analyzed after cultured cells or mice were exposed to LT. In agreement with our hypothesis, LT induces cytotoxicity against hepatic cells in vitro. In addition, suppressed expression of coagulation factor VIII (FVIII) in the liver is associated with a prolonged plasma clotting time in LT-treated mice, suggesting a suppressive role of LT in coagulation. Accordingly, we further hypothesized that a loss-of-function approach involving treatments of an anticoagulant should exacerbate LT-induced abnormalities, whereas a gain-of-function approach involving injections of recombinant FVIII to complement the coagulation deficiency should ameliorate the pathogenesis. As expected, a sublethal dose of LT caused mortality in the mice that were non-lethally pretreated with an anticoagulant (warfarin). By contrast, treatments of recombinant FVIII reduced the mortality from a lethal dose of LT in mice. Our results indicated that LT-induced deficiency of FVIII is involved in LT-mediated pathogenesis. Using recombinant FVIII to correct the coagulant defect may enable developing a new strategy to treat anthrax. PMID:25906166

  19. Neuroprotection in glaucoma

    PubMed Central

    Vasudevan, Sushil K; Gupta, Viney; Crowston, Jonathan G

    2011-01-01

    Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells and their axons. Recent evidence suggests that intraocular pressure (IOP) is only one of the many risk factors for this disease. Current treatment options for this disease have been limited to the reduction of IOP; however, it is clear now that the disease progression continues in many patients despite effective lowering of IOP. In the search for newer modalities in treating this disease, much data have emerged from experimental research the world over, suggesting various pathological processes involved in this disease and newer possible strategies to treat it. This review article looks into the current understanding of the pathophysiology of glaucoma, the importance of neuroprotection, the various possible pharmacological approaches for neuroprotection and evidence of current available medications. PMID:21150020

  20. Neuroprotective effect of ginsenoside Rg1 prevents cognitive impairment induced by isoflurane anesthesia in aged rats via antioxidant, anti-inflammatory and anti-apoptotic effects mediated by the PI3K/AKT/GSK-3β pathway.

    PubMed

    Zhang, Yini; Zhang, Zhao; Wang, Haitang; Cai, Nan; Zhou, Shuang; Zhao, Yaoping; Chen, Xue; Zheng, Shaoqiang; Si, Qi; Zhang, Wei

    2016-09-01

    Ginsenoside Rg1 is the primary active substance in ginseng, and it has multiple pharmacological actions. Investigations on the pharmacologic action of ginsenoside Rg1 have developed, with a particular focus on the regulation of metabolism. The present study hypothesized that the neuroprotective effects of ginsenoside Rg1 prevent cognitive impairment induced by isoflurane anesthesia via antioxidant, anti‑inflammatory and anti‑apoptotic effects, mediated by the phosphoinositide 3‑kinase (PI3K)/AKT/glycogen synthase kinase‑3β (GSK‑3β) pathway in aged rats. Sprague‑Dawley rats were divided into isoflurane and ginsenoside Rg1 groups and were treated with 20 mg/kg ginsenoside Rg1 for 7 days. Morris water maze was performed to analyze the cognitive function of the rats. Enzyme‑linked immunosorbent assays were used to analyze the levels of malondialdehyde, glutathione, interleukin (IL)‑1β, IL‑6 and caspase 3. The protein expression levels of AKT, GSK 3β, p21WAF1/CIP1 and p53 were measured using western blot analysis. Ginsenoside Rg1 significantly improved cognitive function, and exhibited antioxidant and anti‑inflammatory effects, demonstrating the neuroprotective effects of ginsenoside Rg1 against the effect of isoflurane anesthesia in the rats. In addition, ginsenoside Rg1 significantly reduced caspase‑3 activity, upregulated the expression of PI3K/AKT/GSK‑3β and downregulated the mRNA expression levels of p21WAF1/CIP1 and p53 in the aged rats exposed to isoflurane anesthesia. The data obtained in the present study provided evidence that the neuroprotective effects of ginsenoside Rg1 prevented the cognitive impairment induced by isoflurane anesthesia via antioxidant, anti‑inflammatory and anti‑apoptotic effects, mediated by the PI3K/AKT/GSK‑3β pathway. PMID:27485139

  1. A novel elicitor protein from Phytophthora parasitica induces plant basal immunity and systemic acquired resistance.

    PubMed

    Chang, Yi-Hsuan; Yan, Hao-Zhi; Liou, Ruey-Fen

    2015-02-01

    The interaction between Phytophthora pathogens and host plants involves the exchange of complex molecular signals from both sides. Recent studies of Phytophthora have led to the identification of various apoplastic elicitors known to trigger plant immunity. Here, we provide evidence that the protein encoded by OPEL of Phytophthora parasitica is a novel elicitor. Homologues of OPEL were identified only in oomycetes, but not in fungi and other organisms. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) revealed that OPEL is expressed throughout the development of P. parasitica and is especially highly induced after plant infection. Infiltration of OPEL recombinant protein from Escherichia coli into leaves of Nicotiana tabacum (cv. Samsun NN) resulted in cell death, callose deposition, the production of reactive oxygen species and induced expression of pathogen-associated molecular pattern (PAMP)-triggered immunity markers and salicylic acid-responsive defence genes. Moreover, the infiltration conferred systemic resistance against a broad spectrum of pathogens, including Tobacco mosaic virus, the bacteria wilt pathogen Ralstonia solanacearum and P. parasitica. In addition to the signal peptide, OPEL contains three conserved domains: a thaumatin-like domain, a glycine-rich protein domain and a glycosyl hydrolase (GH) domain. Intriguingly, mutation of a putative laminarinase active site motif in the predicted GH domain abolished its elicitor activity, which suggests enzymatic activity of OPEL in triggering the defence response. PMID:24965864

  2. Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders

    PubMed Central

    Ye, Zhaohui; Zhan, Huichun; Mali, Prashant; Dowey, Sarah; Williams, Donna M.; Jang, Yoon-Young; Dang, Chi V.; Spivak, Jerry L.; Moliterno, Alison R.

    2009-01-01

    Human induced pluripotent stem (iPS) cells derived from somatic cells hold promise to develop novel patient-specific cell therapies and research models for inherited and acquired diseases. We and others previously reprogrammed human adherent cells, such as postnatal fibroblasts to iPS cells, which resemble adherent embryonic stem cells. Here we report derivation of iPS cells from postnatal human blood cells and the potential of these pluripotent cells for disease modeling. Multiple human iPS cell lines were generated from previously frozen cord blood or adult CD34+ cells of healthy donors, and could be redirected to hematopoietic differentiation. Multiple iPS cell lines were also generated from peripheral blood CD34+ cells of 2 patients with myeloproliferative disorders (MPDs) who acquired the JAK2-V617F somatic mutation in their blood cells. The MPD-derived iPS cells containing the mutation appeared normal in phenotypes, karyotype, and pluripotency. After directed hematopoietic differentiation, the MPD-iPS cell-derived hematopoietic progenitor (CD34+CD45+) cells showed the increased erythropoiesis and gene expression of specific genes, recapitulating features of the primary CD34+ cells of the corresponding patient from whom the iPS cells were derived. These iPS cells provide a renewable cell source and a prospective hematopoiesis model for investigating MPD pathogenesis. PMID:19797525

  3. Benzoylsalicylic acid isolated from seed coats of Givotia rottleriformis induces systemic acquired resistance in tobacco and Arabidopsis.

    PubMed

    Kamatham, Samuel; Neela, Kishore Babu; Pasupulati, Anil Kumar; Pallu, Reddanna; Singh, Surya Satyanarayana; Gudipalli, Padmaja

    2016-06-01

    Systemic acquired resistance (SAR), a whole plant defense response to a broad spectrum of pathogens, is characterized by a coordinated expression of a large number of defense genes. Plants synthesize a variety of secondary metabolites to protect themselves from the invading microbial pathogens. Several studies have shown that salicylic acid (SA) is a key endogenous component of local and systemic disease resistance in plants. Although SA is a critical signal for SAR, accumulation of endogenous SA levels alone is insufficient to establish SAR. Here, we have identified a new acyl derivative of SA, the benzoylsalicylic acid (BzSA) also known as 2-(benzoyloxy) benzoic acid from the seed coats of Givotia rottleriformis and investigated its role in inducing SAR in tobacco and Arabidopsis. Interestingly, exogenous BzSA treatment induced the expression of NPR1 (Non-expressor of pathogenesis-related gene-1) and pathogenesis related (PR) genes. BzSA enhanced the expression of hypersensitivity related (HSR), mitogen activated protein kinase (MAPK) and WRKY genes in tobacco. Moreover, Arabidopsis NahG plants that were treated with BzSA showed enhanced resistance to tobacco mosaic virus (TMV) as evidenced by reduced leaf necrosis and TMV-coat protein levels in systemic leaves. We, therefore, conclude that BzSA, hitherto unknown natural plant product, is a new SAR inducer in plants. PMID:26988727

  4. Inclusion body disease of cranes: comparison of pathologic findings in cranes with acquired vs. experimentally induced disease

    USGS Publications Warehouse

    Schuh, J.C.; Sileo, L.; Siegfried, L.M.; Yuill, Thomas M.

    1986-01-01

    Inclusion body disease of cranes was the cause of death in 17 immature and mature cranes of 5 different species in Wisconsin. A herpesvirus of unknown origin was the apparent cause. An isolate of this herpesvirus was used to experimentally infect 3 species of cranes. Macroscopic and microscopic lesions associated with naturally acquired and experimentally induced disease were essentially identical. Multifocal hepatic and splenic necrosis was found in all cranes evaluated. Necrosis of the gastrointestinal tract, thymus, and bursa of Fabricius also was seen in some of the cranes. Eosinophilic intranuclear inclusion bodies often were commonly associated with hepatic lesions, sometimes with the splenic lesions, and rarely with the thymic or gastrointestinal tract lesions. The lesions of this inclusion body disease were similar to those reported for cranes in Austria from which a crane herpesvirus was isolated.

  5. Neuroprotective effects of donepezil against Aβ42-induced neuronal toxicity are mediated through not only enhancing PP2A activity but also regulating GSK-3β and nAChRs activity.

    PubMed

    Noh, Min-Young; Koh, Seong H; Kim, Sung-Min; Maurice, Tangui; Ku, Sae-Kwang; Kim, Seung H

    2013-11-01

    The main purpose of this study was to evaluate whether donepezil, acetylcholinesterase inhibitor, shown to play a protective role through inhibiting glycogen synthesis kinase-3β (GSK-3β) activity, could also exert neuroprotective effects by stimulating protein phosphatase 2A (PP2A) activity in the amyloid-beta (Aβ)42-induced neuronal toxicity model of Alzheimer's disease. In Aβ42-induced toxic conditions, each PP2A and GSK-3β activity measured at different times showed time-dependent reverse pattern toward the direction of accelerating neuronal deaths with the passage of time. In addition, donepezil pre-treatment showed dose-dependent stepwise increase of neuronal viability and stimulation of PP2A activity. However, such effects on them were significantly reduced through the depletion of PP2A activity with either okadaic acid or PP2Ac siRNA. In spite of blocked PP2A activity in this Aβ42 insult, however, donepezil pretreatment showed additional significant recovering effect on neuronal viability when compared to the value without donepezil. Moreover, donepezil partially recovered its dephosphorylating effect on hyperphosphorylated tau induced by Aβ42. This observation led us to assume that additional mechanisms of donepezil, including its inhibitory effect on GSK-3β activity and/or the activation role of nicotinic acetylcholine receptors (nAChRs), might be involved. Taken together, our results suggest that the neuroprotective effects of donepezil against Aβ42-induced neurotoxicity are mediated through activation of PP2A, but its additional mechanisms including regulation of GSK-3β and nAChRs activity would partially contribute to its effects. We investigated neuroprotective mechanisms of donepezil against Aβ42 toxicity: Donepezil increased neuronal viability with reduced p-tau by enhancing PP2A activity. Despite of blocked PP2A activity, donepezil showed additional recovering effect on neuronal viability, which findings led us to assume that additional

  6. The Neuroprotective Effects of Justicidin A on Amyloid Beta25-35-Induced Neuronal Cell Death Through Inhibition of Tau Hyperphosphorylation and Induction of Autophagy in SH-SY5Y Cells.

    PubMed

    Gu, Ming-Yao; Kim, Joonki; Yang, Hyun Ok

    2016-06-01

    Justicidin A is a structurally defined arylnaphthalide lignan, which has been shown anti-cancer activity; however, the neuroprotective effect of justicidin A is still untested. In this study, we investigated the action of justicidin A on amyloid beta (Aβ)25-35-induced neuronal cell death via inhibition of the hyperphosphorylation of tau and induction of autophagy in SH-SY5Y cells. Pretreatment with justicidin A significantly elevated cell viability in cells treated with Aβ25-35. Western blot data demonstrated that justicidin A inhibited the Aβ25-35-induced up-regulation the levels of hyperphosphorylation of tau in SH-SY5Y cells. In addition, treatment with justicidin A significantly induced autophagy as measured by the increasing LC3 II/I ratio, an important autophagy marker. These studies showed that justicidin A inhibited activity of glycogen synthase kinase-3beta (GSK-3β), which is an important kinase in up-stream signaling pathways; inhibited hyperphosphorylation of tau in AD; and enhanced activity of AMP-activated protein kinase (AMPK), which is the key molecule for both hyperphosphorylation of tau and induction of autophagy. These data provide the first evidence that justicidin A protects SH-SY5Y cells from Aβ25-35-induced neuronal cell death through inhibition of hyperphosphorylation of tau and induction of autophagy via regulation the activity of GSK-3β and AMPK, and they also provide some insights into the relationship between tau protein hyperphosphorylation and autophagy. Thus, we conclude that justicidin A may have a potential role for neuroprotection and, therefore, may be used as a therapeutic agent for AD. PMID:26887582

  7. Neuroprotective Actions of Neurosteroids

    PubMed Central

    Borowicz, Kinga K.; Piskorska, Barbara; Banach, Monika; Czuczwar, Stanislaw J.

    2011-01-01

    Neurosteroids were initially defined as steroid hormones locally synthesized within the nervous tissue. Subsequently, they were described as steroid hormone derivatives that devoid hormonal action but still affect neuronal excitability through modulation of ionotropic receptors. Neurosteroids are further subdivided into natural (produced in the brain) and synthetic. Some authors distinguish between hormonal and regular neurosteroids in the group of natural ones. The latter group, including hormone metabolites like allopregnanolone or tetrahydrodeoxycorticosterone, is devoid of hormonal activity. Both hormones and their derivatives share, however, most of the physiological functions. It is usually very difficult to distinguish the effects of hormones and their metabolites. All these substances may influence seizure phenomena and exhibit neuroprotective effects. Neuroprotection offered by steroid hormones may be realized in both genomic and non-genomic mechanisms and involve regulation of the pro- and anti-apoptotic factors expression, intracellular signaling pathways, neurotransmission, oxidative, and inflammatory processes. Since regular neurosteroids show no affinity for steroid receptors, they may act only in a non-genomic mode. Multiple studies have been conducted so far to show efficacy of neurosteroids in the treatment of the central and peripheral nervous system injury, ischemia, neurodegenerative diseases, or seizures. In this review we focused primarily on neurosteroid mechanisms of action and their role in the process of neurodegeneration. Most of the data refers to results obtained in experimental studies. However, it should be realized that knowledge about neuroactive steroids remains still incomplete and requires confirmation in clinical conditions. PMID:22649375

  8. Neuroprotection in Preterm Infants

    PubMed Central

    Berger, R.; Söder, S.

    2015-01-01

    Preterm infants born before the 30th week of pregnancy are especially at risk of perinatal brain damage which is usually a result of cerebral ischemia or an ascending intrauterine infection. Prevention of preterm birth and early intervention given signs of imminent intrauterine infection can reduce the incidence of perinatal cerebral injury. It has been shown that administering magnesium intravenously to women at imminent risk of a preterm birth leads to a significant reduction in the likelihood of the infant developing cerebral palsy and motor skill dysfunction. It has also been demonstrated that delayed clamping of the umbilical cord after birth reduces the rate of brain hemorrhage among preterm infants by up to 50%. In addition, mesenchymal stem cells seem to have significant neuroprotective potential in animal experiments, as they increase the rate of regeneration of the damaged cerebral area. Clinical tests of these types of therapeutic intervention measures appear to be imminent. In the last trimester of pregnancy, the serum concentrations of estradiol and progesterone increase significantly. Preterm infants are removed abruptly from this estradiol and progesterone rich environment. It has been demonstrated in animal experiments that estradiol and progesterone protect the immature brain from hypoxic-ischemic lesions. However, this neuroprotective strategy has unfortunately not yet been subject to sufficient clinical investigation. PMID:25650134

  9. Human Umbilical Cord Blood Cells Induce Neuroprotective Change in Gene Expression Profile in Neurons After Ischemia Through Activation of Akt Pathway

    PubMed Central

    Shahaduzzaman, M. D.; Mehta, Vijay; Golden, Jason E.; Rowe, Derrick D.; Green, Suzanne; Tadinada, Ramya; Foran, Elspeth A.; Sanberg, Paul R.; Pennypacker, Keith R.; Willing, Alison E.

    2016-01-01

    Human umbilical cord blood (HUCB) cell therapies have shown promising results in reducing brain infarct volume and most importantly in improving neurobehavioral function in rat permanent middle cerebral artery occlusion, a model of stroke. In this study, we examined the gene expression profile in neurons subjected to oxygen-glucose deprivation (OGD) with or without HUCB treatment and identified signaling pathways (Akt/MAPK) important in eliciting HUCB-mediated neuroprotective responses. Gene chip microarray analysis was performed using RNA samples extracted from the neuronal cell cultures from four experimental groups: normoxia, normoxia + HUCB, OGD, and OGD + HUCB. Both quantitative RT-PCR and immunohistochemistry were carried out to verify the microarray results. Using the Genomatix software program, promoter regions of selected genes were compared to reveal common transcription factor-binding sites and, subsequently, signal transduction pathways. Under OGD condition, HUCB cells significantly reduced neuronal loss from 68% to 44% [one-way ANOVA, F(3, 16) = 11, p = 0.0003]. Microarray analysis identified mRNA expression of Prdx5, Vcam1, CCL20, Alcam, and Pax6 as being significantly altered by HUCB cell treatment. Inhibition of the Akt pathway significantly abolished the neuroprotective effect of HUCB cells [one-way ANOVA, F(3, 11) = 8.663, p = 0.0031]. Our observations show that HUCB neuroprotection is dependent on the activation of the Akt signaling pathway that increases transcription of the Prdx5 gene. We concluded that HUCB cell therapy would be a promising treatment for stroke and other forms of brain injury by modifying acute gene expression to promote neural cell protection. PMID:25413246

  10. Calcium preconditioning triggers neuroprotection in retinal ganglion cells

    PubMed Central

    Brandt, Sean K.; Weatherly, Monique E.; Ware, Lillian; Linn, David M.; Linn, Cindy L.

    2010-01-01

    In the mammalian retina, excitotoxicity has been shown to be involved in apoptotic retinal ganglion cell (RGC) death and is associated with certain retinal disease states including glaucoma, diabetic retinopathy and retinal ischemia. Previous studies from this lab (Wehrwein et al., 2004) have demonstrated that acetylcholine (ACh) and nicotine protects against glutamate-induced excitotoxicity in isolated adult pig RGCs through nicotinic acetylcholine receptors (nAChRs). Activation of nAChRs in these RGCs triggers cell survival signaling pathways and inhibits apoptotic enzymes (Asomugha et al., 2010). However, the link between binding of nAChRs and activation of neuroprotective pathways is unknown. In this study, we examine the hypothesis that calcium permeation through nAChR channels is required for ACh-induced neuroprotection against glutamate-induced excitotoxicity in isolated pig RGCs. RGCs were isolated from other retinal tissue using a two step panning technique and cultured for 3 days under different conditions. In some studies, calcium imaging experiments were performed using the fluorescent calcium indicator, fluo-4, and demonstrated that calcium permeates the nAChR channels located on pig RGCs. In other studies, the extracellular calcium concentration was altered to determine the effect on nicotine-induced neuroprotection. Results support the hypothesis that calcium is required for nicotine-induced neuroprotection in isolated pig RGCs. Lastly, studies were performed to analyze the effects of preconditioning on glutamate-induced excitotoxicity and neuroprotection. In these studies, a preconditioning dose of calcium was introduced to cells using a variety of mechanisms before a large glutamate insult was applied to cells. Results from these studies support the hypothesis that preconditioning cells with a relatively low level of calcium before an excitotoxic insult leads to neuroprotection. In the future, these results could provide important information

  11. A Combination of Remote Ischemic Perconditioning and Cerebral Ischemic Postconditioning Inhibits Autophagy to Attenuate Plasma HMGB1 and Induce Neuroprotection Against Stroke in Rat.

    PubMed

    Wang, Jue; Han, Dong; Sun, Miao; Feng, Juan

    2016-04-01

    Remote ischemic perconditioning (RIPerC) and ischemic postconditioning (IPOC) are well-acknowledged neuroprotective procedures during ischemic injury. The present study established a combined RIPerC and IPOC (RIPerC + IPOC) model in rats and studied how it would regulate the autophagy process and affect HMGB1 levels in a rat model of middle cerebral artery occlusion (MCAO). Rats with MCAO were treated with RIPerC by fastening and release of the left hind limb to achieve 4 cycles of 5 min remote ischemia reperfusion, 40 min prior to cerebral reperfusion, and then treated with IPOC by exposing the cerebral middle artery to 3 cycles of 30 s reperfusion/30 s occlusion at the onset of cerebral reperfusion. Infarction volumes, neurological deficits, and pathological changes were assessed 24 h after ischemia. The autophagy activator rapamycin (RAP) and the autophagy inhibitor 3-methyladenine (3-MA) were administrated for further mechanism. The expression and location of HMGB1 and the autophagy-related proteins like LC3, Beclin1, and P62 as well as plasma HMGB1 levels were measured. Our results suggested that RIPerC + IPOC attenuated plasma HMGB1 levels to intensify its neuroprotective effect against cerebral ischemic reperfusion injury via inhibiting the autophagy process. PMID:26852332

  12. Functional Identification of Neuroprotective Molecules

    PubMed Central

    Dai, Cheng; Liang, Dong; Li, Huiwu; Sasaki, Masayuki; Dawson, Ted M.; Dawson, Valina L.

    2010-01-01

    The central nervous system has the capacity to activate profound neuroprotection following sub-lethal stress in a process termed preconditioning. To gain insight into this potent survival response we developed a functional cloning strategy that identified 31 putative neuroprotective genes of which 28 were confirmed to provide protection against oxygen-glucose deprivation (OGD) or excitotoxic exposure to N-methyl-D-aspartate (NMDA) in primary rat cortical neurons. These results reveal that the brain possesses a wide and diverse repertoire of neuroprotective genes. Further characterization of these and other protective signals could provide new treatment opportunities for neurological injury from ischemia or neurodegenerative disease. PMID:21124846

  13. Schistosoma mansoni: is acquired immunity induced by highly x-irradiated cercariae dependent on the size of the challenging dose

    SciTech Connect

    Hsue, S.Y.; Hsue, H.F.; Osborne, J.W.; Johnson, S.C.

    1982-04-01

    A high degree of immunity, as shown by a 91% reduction of the number of worms recovered was found in five groups of mice that were immunized five times with highly X-irradiated cercariae and then challenged with 10, 20, 50, 100, or 500 normal Schistosoma mansoni cercariae. The results indicated that there were no significant differences in worm reduction in immunized mice challenged with different numbers of cercariae; consequently the immunity induced by this immunization method did not appear to be challenge-dose-dependent. However, the results also showed that when immunized mice were challenged with 500, 100, 50, 20, and 10 cercariae, 0, 13, 26, 56, and 68%, respectively, of the experimental animals were free of worms. Thus, the percentage of worm-negative cases increased as the number of challenge cercariae decreased. When viewed in this manner, the acquired immunity may be considered challenge-dose-dependent as well. If this method of vaccination is used for schistosomiasis control, we may anticipate that in both hypo- and hyperendemic areas, the intensity of infection and the severity of the disease will be reduced owing to a reduction in worms burdens, and in hypoendemic areas, there will be a number of worm-free cases.

  14. Neuroprotection and antioxidants

    PubMed Central

    Lalkovičová, Maria; Danielisová, Viera

    2016-01-01

    Ischemia as a serious neurodegenerative disorder causes together with reperfusion injury many changes in nervous tissue. Most of the neuronal damage is caused by complex of biochemical reactions and substantial processes, such as protein agregation, reactions of free radicals, insufficient blood supply, glutamate excitotoxicity, and oxidative stress. The result of these processes can be apoptotic or necrotic cell death and it can lead to an irreversible damage. Therefore, neuroprotection and prevention of the neurodegeneration are highly important topics to study. There are several approaches to prevent the ischemic damage. Use of many modern therapeutical methods and the incorporation of several substances into the diet of patients is possible to stimulate the endogenous protective mechanisms and improve the life quality. PMID:27482198

  15. Therapeutic Hypothermia for Neuroprotection

    PubMed Central

    Karnatovskaia, Lioudmila V.; Wartenberg, Katja E.

    2014-01-01

    The earliest recorded application of therapeutic hypothermia in medicine spans about 5000 years; however, its use has become widespread since 2002, following the demonstration of both safety and efficacy of regimens requiring only a mild (32°C-35°C) degree of cooling after cardiac arrest. We review the mechanisms by which hypothermia confers neuroprotection as well as its physiological effects by body system and its associated risks. With regard to clinical applications, we present evidence on the role of hypothermia in traumatic brain injury, intracranial pressure elevation, stroke, subarachnoid hemorrhage, spinal cord injury, hepatic encephalopathy, and neonatal peripartum encephalopathy. Based on the current knowledge and areas undergoing or in need of further exploration, we feel that therapeutic hypothermia holds promise in the treatment of patients with various forms of neurologic injury; however, additional quality studies are needed before its true role is fully known. PMID:24982721

  16. Neuroprotection and antioxidants.

    PubMed

    Lalkovičová, Maria; Danielisová, Viera

    2016-06-01

    Ischemia as a serious neurodegenerative disorder causes together with reperfusion injury many changes in nervous tissue. Most of the neuronal damage is caused by complex of biochemical reactions and substantial processes, such as protein agregation, reactions of free radicals, insufficient blood supply, glutamate excitotoxicity, and oxidative stress. The result of these processes can be apoptotic or necrotic cell death and it can lead to an irreversible damage. Therefore, neuroprotection and prevention of the neurodegeneration are highly important topics to study. There are several approaches to prevent the ischemic damage. Use of many modern therapeutical methods and the incorporation of several substances into the diet of patients is possible to stimulate the endogenous protective mechanisms and improve the life quality. PMID:27482198

  17. Neuroprotective potential of phytochemicals.

    PubMed

    Kumar, G Phani; Khanum, Farhath

    2012-07-01

    Cognitive dysfunction is a major health problem in the 21st century, and many neuropsychiatric disorders and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer's Disease dementia, cerebrovascular impairment, seizure disorders, head injury and Parkinsonism, can be severly functionally debilitating in nature. In course of time, a number of neurotransmitters and signaling molecules have been identified which have been considered as therapeutic targets. Conventional as well newer molecules have been tried against these targets. Phytochemicals from medicinal plants play a vital role in maintaining the brain's chemical balance by influencing the function of receptors for the major inhibitory neurotransmitters. In traditional practice of medicine, several plants have been reported to treat cognitive disorders. In this review paper, we attempt to throw some light on the use of medicinal herbs to treat cognitive disorders. In this review, we briefly deal with some medicinal herbs focusing on their neuroprotective active phytochemical substances like fatty acids, phenols, alkaloids, flavonoids, saponins, terpenes etc. The resistance of neurons to various stressors by activating specific signal transduction pathways and transcription factors are also discussed. It was observed in the review that a number of herbal medicines used in Ayurvedic practices as well Chinese medicines contain multiple compounds and phytochemicals that may have a neuroprotective effect which may prove beneficial in different neuropsychiatric and neurodegenerative disorders. Though the presence of receptors or transporters for polyphenols or other phytochemicals of the herbal preparations, in brain tissues remains to be ascertained, compounds with multiple targets appear as a potential and promising class of therapeutics for the treatment of diseases with a multifactorial etiology. PMID:23055633

  18. Neuroprotective potential of phytochemicals

    PubMed Central

    Kumar, G. Phani; Khanum, Farhath

    2012-01-01

    Cognitive dysfunction is a major health problem in the 21st century, and many neuropsychiatric disorders and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer's Disease dementia, cerebrovascular impairment, seizure disorders, head injury and Parkinsonism, can be severly functionally debilitating in nature. In course of time, a number of neurotransmitters and signaling molecules have been identified which have been considered as therapeutic targets. Conventional as well newer molecules have been tried against these targets. Phytochemicals from medicinal plants play a vital role in maintaining the brain's chemical balance by influencing the function of receptors for the major inhibitory neurotransmitters. In traditional practice of medicine, several plants have been reported to treat cognitive disorders. In this review paper, we attempt to throw some light on the use of medicinal herbs to treat cognitive disorders. In this review, we briefly deal with some medicinal herbs focusing on their neuroprotective active phytochemical substances like fatty acids, phenols, alkaloids, flavonoids, saponins, terpenes etc. The resistance of neurons to various stressors by activating specific signal transduction pathways and transcription factors are also discussed. It was observed in the review that a number of herbal medicines used in Ayurvedic practices as well Chinese medicines contain multiple compounds and phytochemicals that may have a neuroprotective effect which may prove beneficial in different neuropsychiatric and neurodegenerative disorders. Though the presence of receptors or transporters for polyphenols or other phytochemicals of the herbal preparations, in brain tissues remains to be ascertained, compounds with multiple targets appear as a potential and promising class of therapeutics for the treatment of diseases with a multifactorial etiology. PMID:23055633

  19. Mechanism of neuroprotection by donepezil pretreatment in rat cortical neurons chronically treated with donepezil.

    PubMed

    Takada-Takatori, Yuki; Kume, Toshiaki; Ohgi, Yuta; Izumi, Yasuhiko; Niidome, Tetsuhiro; Fujii, Takeshi; Sugimoto, Hachiro; Akaike, Akinori

    2008-12-01

    Previously, we showed that in rat cortical neurons, chronic donepezil treatment (10 microM, 4 days) up-regulates nicotinic receptors (nAChR) and makes neurons more sensitive to the neuroprotective effect of donepezil. Here we examined the mechanism of donepezil-induced neuroprotection in neurons chronically treated with donepezil. The mechanism of neuroprotection was examined under different conditions of exposure to glutamate, acute and moderate, that induce cell death associated with necrotic and apoptotic cell death, respectively. Concomitant treatment with antagonists of nAChRs but not muscarinic receptors inhibited donepezil pretreatment-induced neuroprotection against acute glutamate treatment-induced death. Donepezil pretreatment prevented acute glutamate- and ionomycin-induced neurotoxicity, but not S-nitrosocysteine-induced neurotoxicity, suggesting that donepezil protects neurons via nAChR at levels before nitric oxide synthase activation against acute glutamate neurotoxicity. Concomitant treatment with antagonists of nAChR or phosphatidylinositol 3-kinase (PI3K) signaling inhibitors significantly inhibited neuroprotection against moderate glutamate neurotoxicity and decreased the phosphorylation level of Akt. Neuroprotection was also inhibited by treatment with inhibitor of mitogen-activated protein kinase (MAPK) kinase. These results suggest that donepezil protects neurons against moderate glutamate neurotoxicity via nAChR-PI3K-Akt and MAPK signaling pathways. This study provides novel insight into the mechanism of donepezil-induced neuroprotection that involves nAChR up-regulation. PMID:18655200

  20. Insulin Neuroprotection and the Mechanisms

    PubMed Central

    Yu, Li-Yun; Pei, Yu

    2015-01-01

    Objective: To analyze the mechanism of neuroprotection of insulin and which blood glucose range was benefit for insulin exerting neuroprotective action. Data Sources: The study is based on the data from PubMed. Study Selection: Articles were selected with the search terms “insulin”, “blood glucose”, “neuroprotection”, “brain”, “glycogen”, “cerebral ischemia”, “neuronal necrosis”, “glutamate”, “γ-aminobutyric acid”. Results: Insulin has neuroprotection. The mechanisms include the regulation of neurotransmitter, promoting glycogen synthesis, and inhibition of neuronal necrosis and apoptosis. Insulin could play its role in neuroprotection by avoiding hypoglycemia and hyperglycemia. Conclusions: Intermittent and long-term infusion insulin may be a benefit for patients with ischemic brain damage at blood glucose 6–9 mmol/L. PMID:25836621

  1. Nucleotides in neuroregeneration and neuroprotection.

    PubMed

    Miras-Portugal, M Teresa; Gomez-Villafuertes, Rosa; Gualix, Javier; Diaz-Hernandez, Juan Ignacio; Artalejo, Antonio R; Ortega, Felipe; Delicado, Esmerilda G; Perez-Sen, Raquel

    2016-05-01

    Brain injury generates the release of a multitude of factors including extracellular nucleotides, which exhibit bi-functional properties and contribute to both detrimental actions in the acute phase and also protective and reparative actions in the later recovery phase to allow neuroregeneration. A promising strategy toward restoration of neuronal function is based on activation of endogenous adult neural stem/progenitor cells. The implication of purinergic signaling in stem cell biology, including regulation of proliferation, differentiation, and cell death has become evident in the last decade. In this regard, current strategies of acute transplantation of ependymal stem/progenitor cells after spinal cord injury restore altered expression of P2X4 and P2X7 receptors and improve functional locomotor recovery. The expression of both receptors is transcriptionally regulated by Sp1 factor, which plays a key role in the startup of the transcription machinery to induce regeneration-associated genes expression. Finally, general signaling pathways triggered by nucleotide receptors in neuronal populations converge on several intracellular kinases, such as PI3K/Akt, GSK3 and ERK1,2, as well as the Nrf-2/heme oxigenase-1 axis, which specifically link them to neuroprotection. In this regard, regulation of dual specificity protein phosphatases can become novel mechanism of actions for nucleotide receptors that associate them to cell homeostasis regulation. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID:26359530

  2. α-Linolenic Acid, A Nutraceutical with Pleiotropic Properties That Targets Endogenous Neuroprotective Pathways to Protect against Organophosphate Nerve Agent-Induced Neuropathology.

    PubMed

    Piermartiri, Tetsade; Pan, Hongna; Figueiredo, Taiza H; Marini, Ann M

    2015-01-01

    α-Linolenic acid (ALA) is a nutraceutical found in vegetable products such as flax and walnuts. The pleiotropic properties of ALA target endogenous neuroprotective and neurorestorative pathways in brain and involve the transcription factor nuclear factor kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), a major neuroprotective protein in brain, and downstream signaling pathways likely mediated via activation of TrkB, the cognate receptor of BDNF. In this review, we discuss possible mechanisms of ALA efficacy against the highly toxic OP nerve agent soman. Organophosphate (OP) nerve agents are highly toxic chemical warfare agents and a threat to military and civilian populations. Once considered only for battlefield use, these agents are now used by terrorists to inflict mass casualties. OP nerve agents inhibit the critical enzyme acetylcholinesterase (AChE) that rapidly leads to a cholinergic crisis involving multiple organs. Status epilepticus results from the excessive accumulation of synaptic acetylcholine which in turn leads to the overactivation of muscarinic receptors; prolonged seizures cause the neuropathology and long-term consequences in survivors. Current countermeasures mitigate symptoms and signs as well as reduce brain damage, but must be given within minutes after exposure to OP nerve agents supporting interest in newer and more effective therapies. The pleiotropic properties of ALA result in a coordinated molecular and cellular program to restore neuronal networks and improve cognitive function in soman-exposed animals. Collectively, ALA should be brought to the clinic to treat the long-term consequences of nerve agents in survivors. ALA may be an effective therapy for other acute and chronic neurodegenerative disorders. PMID:26569216

  3. The Microglial α7-Acetylcholine Nicotinic Receptor Is a Key Element in Promoting Neuroprotection by Inducing Heme Oxygenase-1 via Nuclear Factor Erythroid-2-Related Factor 2

    PubMed Central

    Parada, Esther; Egea, Javier; Buendia, Izaskun; Negredo, Pilar; Cunha, Ana C.; Cardoso, Silvia; Soares, Miguel P.

    2013-01-01

    Abstract Aims: We asked whether the neuroprotective effect of cholinergic microglial stimulation during an ischemic event acts via a mechanism involving the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) and/or the expression of its target cytoprotective gene, heme oxygenase-1 (HO-1). Specifically, the protective effect of the pharmacologic alpha-7 nicotinic acetylcholine receptor (α7 nAChR) agonist PNU282987 was analyzed in organotypic hippocampal cultures (OHCs) subjected to oxygen and glucose deprivation (OGD) in vitro as well as in photothrombotic stroke in vivo. Results: OHCs exposed to OGD followed by reoxygenation elicited cell death, measured by propidium iodide and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide staining. Activation of α7 nAChR by PNU282987, after OGD, reduced cell death, reactive oxygen species production, and tumor necrosis factor release. This was associated with induction of HO-1 expression, an effect reversed by α-bungarotoxin and by tin–protoporphyrin IX. The protective effect of PNU282987 was lost in microglial-depleted OHCs as well as in OHCs from Nrf2-deficient-versus-wild-type mice, an effect associated with suppression of HO-1 expression in microglia. Administration of PNU282987 1 h after induction of photothrombotic stroke in vivo reduced the infarct size and improved motor skills in Hmox1lox/lox mice that express normal levels of HO-1, but not in LysMCreHmox1Δ/Δ in which HO-1 expression is inhibited in myeloid cells, including the microglia. Innovation: This study suggests the participation of the microglial α7 nAChR in the brain cholinergic anti-inflammatory pathway. Conclusion: Activation of the α7 nAChR/Nrf2/HO-1 axis in microglia regulates neuroinflammation and oxidative stress, affording neuroprotection under brain ischemic conditions. Antioxid. Redox Signal. 19, 1135–1148. PMID:23311871

  4. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis.

    PubMed

    Gintant, G A; Limberis, J T; McDermott, J S; Wegner, C D; Cox, B F

    2001-05-01

    Torsade de pointes is a rare but potentially fatal ventricular arrhythmia associated with drug-induced delayed repolarization and prolongation of the QT interval. To determine if the arrhythmogenic potential of noncardiac drugs can be assessed in vitro, we evaluated the effects of 12 drugs on the action potential duration (APD) of cardiac Purkinje fibers and compared results with clinical observations. APD changes in canine and porcine fibers were evaluated under physiologic conditions (37 degrees C, [K+]0 = 4 mM) using standard microelectrode techniques. Six of seven drugs associated with QT prolongation or torsade de pointes in man (cisapride, erythromycin, grepafloxacin, moxifloxacin, sertindole, and sotalol) affected concentration-dependent prolongation of the APD in canine fibers during slow stimulation (2-s basic cycle length), attaining greater than 15% prolongation at high concentrations (> or = 10-fold clinically encountered plasma levels). Each of five drugs not linked clinically to QT prolongation and torsade de pointes (azithromycin, enalaprilat, fluoxetine, indomethacin, and pinacidil) failed to attain 15% prolongation, with fluoxetine, indomethacin, and pinacidil abbreviating the APD. Drugs eliciting the greatest prolongation also demonstrated prominent reverse rate-dependent effects. The antihistamine terfenadine (linked to dose-dependent QT prolongation and torsade de pointes clinically) only minimally prolonged the APD in canine and porcine fibers (and exerted no effect on midmyocardial fibers from left ventricular free wall) at supratherapeutic concentrations. On the basis of concentration-dependent APD prolongation and reverse rate-dependent effects, this Purkinje fiber model detects six of seven drugs linked clinically to acquired long QT syndrome and torsade de pointes, and clears each of five drugs not associated with repolarization abnormalities (overall 92% accuracy), validating the utility of this Purkinje fiber model in the preclinical

  5. Systemic acquired resistance in Cavendish banana induced by infection with an incompatible strain of Fusarium oxysporum f. sp. cubense.

    PubMed

    Wu, Yuanli; Yi, Ganjun; Peng, Xinxiang; Huang, Bingzhi; Liu, Ee; Zhang, Jianjun

    2013-07-15

    Fusarium wilt of banana is caused by the soil-borne fungus Fusarium oxysporum f. sp. cubense (Foc). The fact that there are no economically viable biological, chemical, or cultural measures of controlling the disease in an infected field leads to search for alternative strategies involving activation of the plant's innate defense system. The mechanisms underlying systemic acquired resistance (SAR) are much less understood in monocots than in dicots. Since systemic protection of plants by attenuated or avirulent pathogens is a typical SAR response, the establishment of a biologically induced SAR model in banana is helpful to investigate the mechanism of SAR to Fusarium wilt. This paper described one such model using incompatible Foc race 1 to induce resistance against Foc tropical race 4 in an in vitro pathosystem. Consistent with the observation that the SAR provided the highest level of protection when the time interval between primary infection and challenge inoculation was 10d, the activities of defense-related enzymes such as phenylalanine ammonia lyase (PAL, EC 4.3.1.5), peroxidase (POD, EC 1.11.1.7), polyphenol oxidase (PPO, EC 1.14.18.1), and superoxide dismutase (SOD, EC 1.15.1.1) in systemic tissues also reached the maximum level and were 2.00-2.43 times higher than that of the corresponding controls on the tenth day. The total salicylic acid (SA) content in roots of banana plantlets increased from about 1 to more than 5 μg g⁻¹ FW after the second leaf being inoculated with Foc race 1. The systemic up-regulation of MaNPR1A and MaNPR1B was followed by the second up-regulation of PR-1 and PR-3. Although SA and jasmonic acid (JA)/ethylene (ET) signaling are mostly antagonistic, systemic expression of PR genes regulated by different signaling pathways were simultaneously up-regulated after primary infection, indicating that both pathways are involved in the activation of the SAR. PMID:23702248

  6. Microglia and neuroprotection.

    PubMed

    Chen, Zhihong; Trapp, Bruce D

    2016-01-01

    Microglia were first identified over a century ago, but our knowledge about their ontogeny and functions has significantly expanded only recently. Microglia colonize the central nervous system (CNS) in utero and play essential roles in brain development. Once neural development is completed, microglia function as the resident innate immune cells of the CNS by surveying their microenvironment and becoming activated when the CNS is challenged by infection, injury, or disease. Despite the traditional view of microglia as being destructive in neurological diseases, recent studies have shown that microglia maintain CNS homeostasis and protect the CNS under various pathological conditions. Microglia can be prophylactically activated by modeling infection with systemic lipopolysaccharide injections and these activated microglia can protect the brain from traumatic injury through modulation of neuronal synapses. Microglia can also protect the CNS by promoting neurogenesis, clearing debris, and suppressing inflammation in diseases such as stroke, autism, and Alzheimer's. Microglia are the resident innate immune cells of the CNS. Despite the traditional view of microglia as being destructive in neurological diseases, recent studies have shown that they maintain tissue homeostasis and protect the CNS under various pathological conditions. They achieve so by clearing debris, promoting neurogenesis, suppressing inflammation and stripping inhibitory synapses. This review summarizes recent advances of our understanding on the multi-dimensional neuroprotective roles of microglia. PMID:25693054

  7. The Neuro-Protective Effect of the Methanolic Extract of Perilla frutescens var. japonica and Rosmarinic Acid against H2O2-Induced Oxidative Stress in C6 Glial Cells

    PubMed Central

    Lee, Ah Young; Wu, Ting Ting; Hwang, Bo Ra; Lee, Jaemin; Lee, Myoung-Hee; Lee, Sanghyun; Cho, Eun Ju

    2016-01-01

    Neurodegenerative diseases are often associated with oxidative damage in neuronal cells. This study was conducted to investigate the neuro-protective effect of methanolic (MeOH) extract of Perilla frutescens var. japonica and its one of the major compounds, rosmarinic acid, under oxidative stress induced by hydrogen peroxide (H2O2) in C6 glial cells. Exposure of C6 glial cells to H2O2 enhanced oxidative damage as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and thiobarbituric acid-reactive substance assays. The MeOH extract and rosmarinic acid prevented oxidative stress by increasing cell viability and inhibiting cellular lipid peroxidation. In addition, the MeOH extract and rosmarinic acid reduced H2O2-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the transcriptional level. Moreover, iNOS and COX-2 protein expression was down-regulated in H2O2-indcued C6 glial cells treated with the MeOH extract and rosmarinic acid. These findings suggest that P. frutescens var. japonica and rosmarinic acid could prevent the progression of neurodegenerative diseases through attenuation of neuronal oxidative stress. PMID:27133263

  8. Gas1 Knockdown Increases the Neuroprotective Effect of Glial Cell-Derived Neurotrophic Factor Against Glutamate-Induced Cell Injury in Human SH-SY5Y Neuroblastoma Cells.

    PubMed

    Wang, Ke; Zhu, Xue; Zhang, Kai; Zhou, Fanfan; Zhu, Ling

    2016-05-01

    Growth arrest-specific 1 (Gas1) protein acts as an inhibitor of cell growth and a mediator of cell death in nervous system during development and is also re-expressed in adult neurons during excitotoxic insult. Due to its structural similarity to the glial cell-derived neurotrophic factor family receptors α (GFRα), Gas1 is likely to interfere with the neuroprotective effect of GDNF. In the present study, we investigated the expression profile of Gas1 during glutamate insults in human SH-SY5Y neuroblastoma cells as well as the influence of Gas1 inhibition on the protective effect of GDNF against glutamate-induced cell injury. Our data showed that Gas1 expression was significantly increased with the treatment of glutamate in SH-SY5Y cells. The silencing of Gas1 by small interfering RNA promoted the protective effect of GDNF against glutamate-induced cytotoxicity as well as cell apoptosis, which effect was likely mediated through activating Akt/PI3 K-dependent cell survival signaling pathway and inhibiting mitochondrial-dependent cell apoptosis signaling pathway via Bad dephosphorylation blockade. In summary, this study showed the synergistic effect of Gas1 inhibition and GDNF against glutamate-induced cell injury in human SH-SY5Y neuroblastoma cells, which information might significantly contribute to better understanding the function of Gas1 in neuronal cells and form the basis of the therapeutic development of GDNF in treating human neurodegenerative diseases in the future. PMID:26215053

  9. The Neuroprotective Functions of Transforming Growth Factor Beta Proteins

    PubMed Central

    Dobolyi, Arpád; Vincze, Csilla; Pál, Gabriella; Lovas, Gábor

    2012-01-01

    Transforming growth factor beta (TGF-β) proteins are multifunctional cytokines whose neural functions are increasingly recognized. The machinery of TGF-β signaling, including the serine kinase type transmembrane receptors, is present in the central nervous system. However, the 3 mammalian TGF-β subtypes have distinct distributions in the brain suggesting different neural functions. Evidence of their involvement in the development and plasticity of the nervous system as well as their functions in peripheral organs suggested that they also exhibit neuroprotective functions. Indeed, TGF-β expression is induced following a variety of types of brain tissue injury. The neuroprotective function of TGF-βs is most established following brain ischemia. Damage in experimental animal models of global and focal ischemia was shown to be attenuated by TGF-βs. In addition, support for their neuroprotective actions following trauma, sclerosis multiplex, neurodegenerative diseases, infections, and brain tumors is also accumulating. The review will also describe the potential mechanisms of neuroprotection exerted by TGF-βs including anti-inflammatory, -apoptotic, -excitotoxic actions as well as the promotion of scar formation, angiogenesis, and neuroregeneration. The participation of these mechanisms in the neuroprotective effects of TGF-βs during different brain lesions will also be discussed. PMID:22942700

  10. Neuroprotective Strategies for Traumatic Brain Injury: Improving Clinical Translation

    PubMed Central

    Kabadi, Shruti V.; Faden, Alan I.

    2014-01-01

    Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed. In part, these failures likely reflect methodological differences between the clinical and animal studies, as well as inadequate pre-clinical evaluation and/or trial design problems. However, recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation. Here we critically analyze the current limitations and translational opportunities for developing successful neuroprotective therapies for TBI. PMID:24445258

  11. Is longer sevoflurane preconditioning neuroprotective in permanent focal cerebral ischemia?

    PubMed

    Qiu, Caiwei; Sheng, Bo; Wang, Shurong; Liu, Jin

    2013-08-15

    Sevoflurane preconditioning has neuroprotective effects in the cerebral ischemia/reperfusion model. However, its influence on permanent cerebral ischemia remains unclear. In the present study, the rats were exposed to sevoflurane for 15, 30, 60, and 120 minutes, followed by induction of permanent cerebral ischemia. Results demonstrated that 30- and 60-minute sevoflurane preconditioning significantly reduced the infarct volume at 24 hours after cerebral ischemia, and 60-minute lurane preconditioning additionally reduced the number of TUNEL- and caspase-3-positive cells in the ischemic penumbra. However, 120-minute sevoflurane preconditioning did not show evident neuroprotective effects. Moreover, 60-minute sevoflurane preconditioning significantly attenuated neurological deficits and infarct volume in rats at 4 days after cerebral ischemia. These findings indicated that 60-minute sevoflurane preconditioning can induce the best neuroprotective effects in rats with permanent cerebral ischemia through the inhibition of apoptosis. PMID:25206521

  12. Poly-arginine and arginine-rich peptides are neuroprotective in stroke models.

    PubMed

    Meloni, Bruno P; Brookes, Laura M; Clark, Vince W; Cross, Jane L; Edwards, Adam B; Anderton, Ryan S; Hopkins, Richard M; Hoffmann, Katrin; Knuckey, Neville W

    2015-06-01

    Using cortical neuronal cultures and glutamic acid excitotoxicity and oxygen-glucose deprivation (OGD) stroke models, we demonstrated that poly-arginine and arginine-rich cell-penetrating peptides (CPPs), are highly neuroprotective, with efficacy increasing with increasing arginine content, have the capacity to reduce glutamic acid-induced neuronal calcium influx and require heparan sulfate preotoglycan-mediated endocytosis to induce a neuroprotective effect. Furthermore, neuroprotection could be induced with immediate peptide treatment or treatment up to 2 to 4 hours before glutamic acid excitotoxicity or OGD, and with poly-arginine-9 (R9) when administered intravenously after stroke onset in a rat model. In contrast, the JNKI-1 peptide when fused to the (non-arginine) kFGF CPP, which does not rely on endocytosis for uptake, was not neuroprotective in the glutamic acid model; the kFGF peptide was also ineffective. Similarly, positively charged poly-lysine-10 (K10) and R9 fused to the negatively charged poly-glutamic acid-9 (E9) peptide (R9/E9) displayed minimal neuroprotection after excitotoxicity. These results indicate that peptide positive charge and arginine residues are critical for neuroprotection, and have led us to hypothesize that peptide-induced endocytic internalization of ion channels is a potential mechanism of action. The findings also question the mode of action of different neuroprotective peptides fused to arginine-rich CPPs. PMID:25669902

  13. Poly-arginine and arginine-rich peptides are neuroprotective in stroke models

    PubMed Central

    Meloni, Bruno P; Brookes, Laura M; Clark, Vince W; Cross, Jane L; Edwards, Adam B; Anderton, Ryan S; Hopkins, Richard M; Hoffmann, Katrin; Knuckey, Neville W

    2015-01-01

    Using cortical neuronal cultures and glutamic acid excitotoxicity and oxygen-glucose deprivation (OGD) stroke models, we demonstrated that poly-arginine and arginine-rich cell-penetrating peptides (CPPs), are highly neuroprotective, with efficacy increasing with increasing arginine content, have the capacity to reduce glutamic acid-induced neuronal calcium influx and require heparan sulfate preotoglycan-mediated endocytosis to induce a neuroprotective effect. Furthermore, neuroprotection could be induced with immediate peptide treatment or treatment up to 2 to 4 hours before glutamic acid excitotoxicity or OGD, and with poly-arginine-9 (R9) when administered intravenously after stroke onset in a rat model. In contrast, the JNKI-1 peptide when fused to the (non-arginine) kFGF CPP, which does not rely on endocytosis for uptake, was not neuroprotective in the glutamic acid model; the kFGF peptide was also ineffective. Similarly, positively charged poly-lysine-10 (K10) and R9 fused to the negatively charged poly-glutamic acid-9 (E9) peptide (R9/E9) displayed minimal neuroprotection after excitotoxicity. These results indicate that peptide positive charge and arginine residues are critical for neuroprotection, and have led us to hypothesize that peptide-induced endocytic internalization of ion channels is a potential mechanism of action. The findings also question the mode of action of different neuroprotective peptides fused to arginine-rich CPPs. PMID:25669902

  14. Exercise-Induced Neuroprotection of Hippocampus in APP/PS1 Transgenic Mice via Upregulation of Mitochondrial 8-Oxoguanine DNA Glycosylase

    PubMed Central

    Kang, Weimin; Jiang, Ning; Wang, Xun; Zhang, Yong; Ji, Li Li

    2014-01-01

    Improving mitochondrial function has been proposed as a reasonable therapeutic strategy to reduce amyloid-β (Aβ) load and to modify the progression of Alzheimer's disease (AD). However, the relationship between mitochondrial adaptation and brain neuroprotection caused by physical exercise in AD is poorly understood. This study was undertaken to investigate the effects of long-term treadmill exercise on mitochondrial 8-oxoguanine DNA glycosylase-1 (OGG1) level, mtDNA oxidative damage, and mitochondrial function in the hippocampus of APP/PS1 transgenic mouse model of AD. In the present study, twenty weeks of treadmill training significantly improved the cognitive function and reduced the expression of Aβ-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase activities, whereas it attenuated ROS generation and mtDNA oxidative damage in Tg mice. Furthermore, the impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in Tg mice after exercise training, in parallel with increased level of SIRT3. These findings suggest that exercise training could increase mtDNA repair capacity in the mouse hippocampus, which in turn would result in protection against AD-related mitochondrial dysfunction and phenotypic deterioration. PMID:25538817

  15. [Effect of the novel nootropic and neuroprotective dipeptide noopept on the streptozotocin-induced model of sporadic Alzheimer disease in rats].

    PubMed

    Ostrovskaia, R U; Tsaplina, A P; Vakhitova, Iu V; Salimgareeva, M Kh; Iamidanov, R S

    2010-01-01

    Streptozotocin-intracerebroventricularly treated rats are proposed as an experimental model of sporadic Alzheimer disease (AD). Diabetogenic toxin streptozotocin (STZ) administered in both cerebral ventricles in a dose of 3 mg/kg decreases the expression of NGF and BDNF mainly in the hippocampus and increases the content of malonic dialdehyde (MDA)--a product of lipid peroxidation--in the brain tissues. These metabolic changes are accompanied by a pronounced cognitive deficiency, which is manifested by long-term memory deterioration in the passive avoidance test. These manifestations of pathology are not accompanied by hyperglycemia in the case of intraventricular STZ administration, in contrast to the systemic (in particular, intraperitoneal) route of introduction that causes a pronounced increase in the blood glucose level. These results are consistent with the existing notions that (i) STZ administered intraventricularly provokes a complex of changes imitating the sporadic AD and (ii) this disease can be considered as a manifestation of type-III diabetes. The new original cognition enhancing and neuroprotective dipeptide noopept decreases the aforementioned metabolic changes and the accompanying long-term deterioration of the memory. Previously, this systemically active dipeptide was shown to be capable of increasing expression of NGF and BDNF in the hippocampus, stimulating the antibody production to beta-amyloid, inhibiting the lipid peroxidation, activating the endogenous antioxidant systems, and decreasing the rate of glutamate release (cholinopositive effect). Taken together, these data indicate that noopept can be considered as a multipotent substance acting upon several important pathogenic chainsof the sporadic AD. PMID:20184279

  16. Exercise-induced neuroprotection of hippocampus in APP/PS1 transgenic mice via upregulation of mitochondrial 8-oxoguanine DNA glycosylase.

    PubMed

    Bo, Hai; Kang, Weimin; Jiang, Ning; Wang, Xun; Zhang, Yong; Ji, Li Li

    2014-01-01

    Improving mitochondrial function has been proposed as a reasonable therapeutic strategy to reduce amyloid-β (Aβ) load and to modify the progression of Alzheimer's disease (AD). However, the relationship between mitochondrial adaptation and brain neuroprotection caused by physical exercise in AD is poorly understood. This study was undertaken to investigate the effects of long-term treadmill exercise on mitochondrial 8-oxoguanine DNA glycosylase-1 (OGG1) level, mtDNA oxidative damage, and mitochondrial function in the hippocampus of APP/PS1 transgenic mouse model of AD. In the present study, twenty weeks of treadmill training significantly improved the cognitive function and reduced the expression of Aβ-42 in APP/PS1 transgenic (Tg) mice. Training also ameliorated mitochondrial respiratory function by increasing the complexes I, and IV and ATP synthase activities, whereas it attenuated ROS generation and mtDNA oxidative damage in Tg mice. Furthermore, the impaired mitochondrial antioxidant enzymes and mitochondrial OGG1 activities seen in Tg mice were restored with training. Acetylation level of mitochondrial OGG1 and MnSOD was markedly suppressed in Tg mice after exercise training, in parallel with increased level of SIRT3. These findings suggest that exercise training could increase mtDNA repair capacity in the mouse hippocampus, which in turn would result in protection against AD-related mitochondrial dysfunction and phenotypic deterioration. PMID:25538817

  17. Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron.

    PubMed

    Sharma, Aruna; Muresanu, Dafin F; Lafuente, José V; Patnaik, Ranjana; Tian, Z Ryan; Buzoianu, Anca D; Sharma, Hari S

    2015-10-01

    Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB

  18. Impaired acquired resistance of mice to Klebsiella pneumoniae infection induced by acute NO/sub 2/ exposure

    SciTech Connect

    Bouley, G.; Azoulay-Dupuis, E.; Gaudebout, C.

    1985-12-01

    The natural resistance of nonimmunized C57B1/6 mice to an intraperitoneal Klebsiella pneumoniae challenge was not significantly affected by prior continuous exposure to 20 ppm NO/sub 2/ for 4 days. In contrast, the acquired resistance of mice immunized just before and infected just after NO/sub 2/ exposure was seriously impaired. This could not be explained by the loss of appetite (about 30%) observed in NO/sub 2/ treated mice, for neither the natural nor acquired resistance of control air exposure mice given approximately 70% ad libitum food and water were significantly modified.

  19. Neuroprotective action of cycloheximide involves induction of bcl-2 and antioxidant pathways.

    PubMed

    Furukawa, K; Estus, S; Fu, W; Mark, R J; Mattson, M P

    1997-03-10

    The ability of the protein synthesis inhibitor cycloheximide (CHX) to prevent neuronal death in different paradigms has been interpreted to indicate that the cell death process requires synthesis of "killer" proteins. On the other hand, data indicate that neurotrophic factors protect neurons in the same death paradigms by inducing expression of neuroprotective gene products. We now provide evidence that in embryonic rat hippocampal cell cultures, CHX protects neurons against oxidative insults by a mechanism involving induction of neuroprotective gene products including the antiapoptotic gene bcl-2 and antioxidant enzymes. Neuronal survival after exposure to glutamate, FeSO4, and amyloid beta-peptide was increased in cultures pretreated with CHX at concentrations of 50-500 nM; higher and lower concentrations were ineffective. Neuroprotective concentrations of CHX caused only a moderate (20-40%) reduction in overall protein synthesis, and induced an increase in c-fos, c-jun, and bcl-2 mRNAs and protein levels as determined by reverse transcription-PCR analysis and immunocytochemistry, respectively. At neuroprotective CHX concentrations, levels of c-fos heteronuclear RNA increased in parallel with c-fos mRNA, indicating that CHX acts by inducing transcription. Neuroprotective concentrations of CHX suppressed accumulation of H2O2 induced by FeSO4, suggesting activation of antioxidant pathways. Treatment of cultures with an antisense oligodeoxynucleotide directed against bcl-2 mRNA decreased Bcl-2 protein levels and significantly reduced the neuroprotective action of CHX, suggesting that induction of Bcl-2 expression was mechanistically involved in the neuroprotective actions of CHX. In addition, activity levels of the antioxidant enzymes Cu/Zn-superoxide dismutase, Mn-superoxide dismutase, and catalase were significantly increased in cultures exposed to neuroprotective levels of CHX. Our data suggest that low concentrations of CHX can promote neuron survival by

  20. Neuroprotective effects of Arctium lappa L. roots against glutamate-induced oxidative stress by inhibiting phosphorylation of p38, JNK and ERK 1/2 MAPKs in PC12 cells.

    PubMed

    Tian, Xing; Sui, Shuang; Huang, Jin; Bai, Jun-Peng; Ren, Tian-Shu; Zhao, Qing-Chun

    2014-07-01

    Many studies have shown that glutamate-induced oxidative stress can lead to neuronal cell death involved in the development of neurodegenerative diseases. In this work, protective effects of ethyl acetate extract (EAE) of Arctium lappa L. roots against glutamate-induced oxidative stress in PC12 cells were evaluated. Also, the effects of EAE on antioxidant system, mitochondrial pathway, and signal transduction pathway were explored. Pretreatment with EAE significantly increased cell viability, activities of GSH-Px and SOD, mitochondrial membrane potential and reduced LDH leakage, ROS formation, and nuclear condensation in a dose-dependent manner. Furthermore, western blot results revealed that EAE increased the Bcl-2/Bax ratio, and inhibited the up-regulation of caspase-3, release of cytochrome c, phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). Therefore, our results indicate that EAE may be a promising neuroprotective agent for the prevention and treatment of neurodegenerative diseases implicated with oxidative stress. PMID:24956398

  1. Hypothermia as a clinical neuroprotectant.

    PubMed

    Sherman, Andrew L; Wang, Michael Y

    2014-08-01

    Applying therapeutic hypothermia (TH) for the purposes of neuroprotection, originally termed "hibernation," started nearly 100 years ago. Because TH cooling systems have improved to the point where it is practical and safe for general application, interest in providing such treatment in conditions such as spinal cord injury, traumatic brain injury, stroke, and cardiac arrest has increased. This article reviews the mechanisms by which TH mitigates secondary neurologic injury, the clinical scenarios where TH is being applied, and reviews selected published studies using TH for central nervous system neuroprotection. PMID:25064786

  2. Saccharin-induced systemic acquired resistance against rust (Phakopsora pachyrhizi) infection in soybean: Effects on growth and development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We examined the effect of saccharin on the systemic acquired resistance (SAR) response of soybean to the fungus Phakopsora pachyrhizi, the causal agent of soybean rust. Plants were grown hydroponically in half-strength Hoagland’s solution and were challenged with the pathogen 1, 5, 10 and 15 days af...

  3. Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease.

    PubMed

    Bayliss, Jacqueline A; Lemus, Moyra B; Stark, Romana; Santos, Vanessa V; Thompson, Aiysha; Rees, Daniel J; Galic, Sandra; Elsworth, John D; Kemp, Bruce E; Davies, Jeffrey S; Andrews, Zane B

    2016-03-01

    Calorie restriction (CR) is neuroprotective in Parkinson's disease (PD) although the mechanisms are unknown. In this study we hypothesized that elevated ghrelin, a gut hormone with neuroprotective properties, during CR prevents neurodegeneration in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. CR attenuated the MPTP-induced loss of substantia nigra (SN) dopamine neurons and striatal dopamine turnover in ghrelin WT but not KO mice, demonstrating that ghrelin mediates CR's neuroprotective effect. CR elevated phosphorylated AMPK and ACC levels in the striatum of WT but not KO mice suggesting that AMPK is a target for ghrelin-induced neuroprotection. Indeed, exogenous ghrelin significantly increased pAMPK in the SN. Genetic deletion of AMPKβ1 and 2 subunits only in dopamine neurons prevented ghrelin-induced AMPK phosphorylation and neuroprotection. Hence, ghrelin signaling through AMPK in SN dopamine neurons mediates CR's neuroprotective effects. We consider targeting AMPK in dopamine neurons may recapitulate neuroprotective effects of CR without requiring dietary intervention. PMID:26961958

  4. An Analog of Thyrotropin-Releasing Hormone (TRH) is Neuroprotective Against Glutamate-Induced Toxicity In Fetal Rat Hippocampal Neurons In Vitro

    PubMed Central

    Veronesi, Michael C.; Yard, Michael; Jackson, James; Lahiri, Debomoy K.; Kubek, Michael J.

    2007-01-01

    TRH has been found to be efficacious in treating certain neurodegenerative disorders such as epilepsy, Alzheimer’s disease, neurotrauma and depression, however, its mechanism of action is poorly understood. Since Glutamate (Glu) toxicity has been implicated in these disorders, we utilized primary enriched cultures of rat fetal (E 17) hippocampal neurons to test the hypothesis that an analog of TRH, 3-Methyl-Histidine TRH (3Me-H TRH), given concurrently with Glu would protect such neurons against cell damage and cell death. Cell viability was assessed via Trypan Blue exclusion cell counts and neuronal damage was determined by assaying lactic acid dehydrogenase (LDH) released in the conditioned media. Fetal hippocampal neurons were cultured in neurobasal media for 7 days. On day 7, neurons (106/well) were treated with: control media, 10 μM 3Me-H TRH, 500 μM Glu, or 500 μM Glu with either 10, 1, 0.1, 0.01 or 0.001 μM 3Me-H TRH. Both media and neurons were harvested 16 hr after treatment. Prolonged exposure to 10 μM 3Me-H TRH was not toxic to the cells, whereas, neurons exposed to 500 μM Glu resulted in maximal cell death. Notably, 10, 1 and 0.1 μM 3Me-H TRH, when co-treated with 500 μM Glu protected fetal neurons against cell death in a concentration-dependent manner. These results provide support for an important neuroprotective effect of TRH/analogs against glutamate toxicity in primary hippocampal neuronal culture, and implicate a potentially beneficial role of TRH/analogs in neurodegenerative diseases. PMID:17125753

  5. Attenuating effect of Acorus calamus extract in chronic constriction injury induced neuropathic pain in rats: an evidence of anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory effects

    PubMed Central

    2011-01-01

    Background Acorus calamus (family: Araceae), is an indigenous plant, traditionally it is used as an ingredient of various cocktail preparations and for the management of severe inflammatory disorders in Indian system of medicine. Present study investigated the attenuating role of Acorus calamus plant extract in chronic constriction injury (CCI) of sciatic nerve induced peripheral neuropathy in rats. Methods Hot plate, plantar, Randall Selitto, Von Frey Hair, pin prick, acetone drop, photoactometer and rota-rod tests were performed to assess degree of thermal, radiant, mechanical, chemical sensation, spontaneous motor activity and motor co-ordination changes respectively, at different time intervals i.e., day 0, 1, 3, 6, 9, 12, 15, 18 and 21. Tissue myeloperoxidase, superoxide anion and total calcium levels were determined after 21st day to assess biochemical alterations. Histopathological evaluations were also performed. Hydroalcoholic extract of Acorus calamus (HAE-AC, 100 and 200 mg/kg, p.o.) and pregabalin (10 mg/kg, p.o.) were administered from the day of surgery for 14 days. Results CCI of sciatic nerve significantly induced thermal, radiant, mechanical hyperalgesia and thermal, chemical, tactile allodynia, along with increase in the levels of superoxide anion, total calcium and myeloperoxidase activity. Moreover significant histological changes were also observed. HAE-AC attenuated CCI induced development of painful behavioural, biochemical and histological changes in a dose dependent manner similar to that of pregabalin serving as positive control. Conclusions Acorus calamus prevented CCI induced neuropathy which may be attributed to its multiple actions including anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory actions. PMID:21426568

  6. Neuroprotective oleanane triterpenes from the roots of Bupleurum chinense.

    PubMed

    Li, Dan-Qi; Zhou, Le; Wang, Di; Wu, Jie; Li, Ling-Zhi; Huang, Xiao-Xiao; Liu, Qing-Bo; Wu, Ying-Ying; Lin, Song; Yang, Jing-Yu; Song, Shao-Jiang; Wu, Chun-Fu

    2016-03-15

    The discovery of new natural compounds with pharmacological properties is an increasingly important field, and a continuous phytochemical investigation of the roots of Bupleurum chinense D.C. has led to the isolation of 17 triterpenoids, including three new oleanane triterpenes (1-3) together with 14 known ones. Their structures were determined on the basis of 1D and 2D NMR spectra as well as HR-ESI-MS data. The cytotoxicities of all compounds against five selected human cancer cell lines were assayed. Only compounds 9 and 14 exhibited moderate activities. Recently, a number of investigations have focused on the neuroprotective properties of triterpenoids in B. chinense. In order to expand our knowledge about this herb, the neuroprotective effects of compounds 1-17 against hydrogen peroxide (H2O2)-induced neuronal cell damage in human neuroblastoma SH-SY5Y cells were evaluated. Compounds 1-3, 6-7 showed significant neuroprotective effects against H2O2-induced SH-SY5Y cell death. Preliminary structure-activity relationships (SARs) between neuroprotective effects and the isolates were also discussed. PMID:26883148

  7. Clinical trials for neuroprotection in ALS.

    PubMed

    Siciliano, G; Carlesi, C; Pasquali, L; Piazza, S; Pietracupa, S; Fornai, F; Ruggieri, S; Murri, L

    2010-07-01

    Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies. PMID:20406180

  8. Neuroprotective Mechanisms Mediated by CDK5 Inhibition.

    PubMed

    Mushtaq, Gohar; Greig, Nigel H; Anwar, Firoz; Al-Abbasi, Fahad A; Zamzami, Mazin A; Al-Talhi, Hasan A; Kamal, Mohammad A

    2016-01-01

    Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not wellunderstood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine- induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke. PMID:26601962

  9. Neuroprotective Mechanisms Mediated by CDK5 Inhibition

    PubMed Central

    Mushtaq, Gohar; Greig, Nigel H.; Anwar, Firoz; Al-Abbasi, Fahad A.; Zamzami, Mazin A.; Al-Talhi, Hasan A.; Kamal, Mohammad A.

    2016-01-01

    Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not well-understood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine-induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer’s disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke. PMID:26601962

  10. Calcium preconditioning triggers neuroprotection in retinal ganglion cells.

    PubMed

    Brandt, S K; Weatherly, M E; Ware, L; Linn, D M; Linn, C L

    2011-01-13

    In the mammalian retina, excitotoxicity has been shown to be involved in apoptotic retinal ganglion cell (RGC) death and is associated with certain retinal disease states including glaucoma, diabetic retinopathy and retinal ischemia. Previous studies from this lab [Wehrwein E, Thompson SA, Coulibaly SF, Linn DM, Linn CL (2004) Invest Ophthalmol Vis Sci 45:1531-1543] have demonstrated that acetylcholine (ACh) and nicotine protects against glutamate-induced excitotoxicity in isolated adult pig RGCs through nicotinic acetylcholine receptors (nAChRs). Activation of nAChRs in these RGCs triggers cell survival signaling pathways and inhibits apoptotic enzymes [Asomugha CO, Linn DM, Linn CL (2010) J Neurochem 112:214-226]. However, the link between binding of nAChRs and activation of neuroprotective pathways is unknown. In this study, we examine the hypothesis that calcium permeation through nAChR channels is required for ACh-induced neuroprotection against glutamate-induced excitotoxicity in isolated pig RGCs. RGCs were isolated from other retinal tissue using a two step panning technique and cultured for 3 days under different conditions. In some studies, calcium imaging experiments were performed using the fluorescent calcium indicator, fluo-4, and demonstrated that calcium permeates the nAChR channels located on pig RGCs. In other studies, the extracellular calcium concentration was altered to determine the effect on nicotine-induced neuroprotection. Results support the hypothesis that calcium is required for nicotine-induced neuroprotection in isolated pig RGCs. Lastly, studies were performed to analyze the effects of preconditioning on glutamate-induced excitotoxicity and neuroprotection. In these studies, a preconditioning dose of calcium was introduced to cells using a variety of mechanisms before a large glutamate insult was applied to cells. Results from these studies support the hypothesis that preconditioning cells with a relatively low level of calcium before

  11. The retina as an early biomarker of neurodegeneration in a rotenone-induced model of Parkinson's disease: evidence for a neuroprotective effect of rosiglitazone in the eye and brain.

    PubMed

    Normando, Eduardo Maria; Davis, Benjamin Michael; De Groef, Lies; Nizari, Shereen; Turner, Lisa A; Ravindran, Nivedita; Pahlitzsch, Milena; Brenton, Jonathan; Malaguarnera, Giulia; Guo, Li; Somavarapu, Satyanarayana; Cordeiro, Maria Francesca

    2016-01-01

    Parkinson's Disease (PD) is the second most common neurodegenerative disease worldwide, affecting 1 % of the population over 65 years of age. Dopaminergic cell death in the substantia nigra and accumulation of Lewy bodies are the defining neuropathological hallmarks of the disease. Neuronal death and dysfunction have been reported in other central nervous system regions, including the retina. Symptoms of PD typically manifest only when more than 70 % of dopaminergic cells are lost, and the definitive diagnosis of PD can only be made histologically at post-mortem, with few biomarkers available.In this study, a rotenone-induced rodent model of PD was employed to investigate retinal manifestations in PD and their usefulness in assessing the efficacy of a novel therapeutic intervention with a liposomal formulation of the PPAR-γ (Peroxisome proliferator-activated receptor gamma) agonist rosiglitazone.Retinal assessment was performed using longitudinal in vivo imaging with DARC (detection of apoptosing retinal cells) and OCT (optical coherence tomography) technologies and revealed increased RGCs (Retinal Ganglion Cells) apoptosis and a transient swelling of the retinal layers at day 20 of the rotenone insult. Follow-up of this model demonstrated characteristic histological neurodegenerative changes in the substantia nigra and striatum by day 60, suggesting that retinal changes precede the "traditional" pathological manifestations of PD. The therapeutic effect of systemic administration of different formulations of rosiglitazone was then evaluated, both in the retina and the brain. Of all treatment regimen tested, sustained release administration of liposome-encapsulated rosiglitazone proved to be the most potent therapeutic strategy, as evidenced by its significant neuroprotective effect on retinal neurons at day 20, and on nigrostriatal neurons at day 60, provided convincing evidence for its potential as a treatment for PD.Our results demonstrate significant retinal

  12. In contrast to its anti-inflammatory and anti-apoptotic peripheral effect, levosimendan failed to induce a long-term neuroprotective effect in a rat model of mild septic encephalopathy: a pilot study.

    PubMed

    Plaschke, Konstanze; Bent, Franziska; Wagner, Sören; Zorn, Markus; Kopitz, Jürgen

    2014-02-01

    Levosimendan shows protective myocardial characteristics and is administered to enhance cardiac contractility in patients. However, currently little is known about levosimendan's effect on brain. The aim of this pilot study was to investigate the long-term effect of levosimendan on brain and during mild rat sepsis in comparison to its peripheral mode of action. Adult rats (n=40) were divided into four groups with n=10 per group: (I) sham, (II) levosimendan (283 μg/kg body weight i.v.), (III) lipopolysaccharide (LPS, 8 mg/kg body weight i.p.), and (IV) LPS+levosimendan. Levosimendan was given 24h after injecting LPS. Psychometric investigations were conducted using a Morris water maze (MWM) and a holeboard test. In cerebral and splenic tissue, IL-1β, Il-6, TNFalpha levels, and apoptosis were determined; cerebral tissue corticosterone concentration was measured 6 days after injecting LPS. Blood cytokine concentrations were determined 1 day and 6 days after injecting LPS. Rats that received an LPS injection spent more time in the outer zone of the MWM according to increased cerebral corticosterone levels, and showed decreased cognitive abilities. LPS induced a reduction in body weight, increased splenic apoptosis and blood cytokine level. Levosimendan showed anti-inflammatory and anti-apoptotic properties in spleen but failed to show a long-term neuroprotective effect. PMID:24361133

  13. Treatment with MOG-DNA vaccines induces CD4+CD25+FoxP3+ regulatory T cells and up-regulates genes with neuroprotective functions in experimental autoimmune encephalomyelitis

    PubMed Central

    2012-01-01

    Background DNA vaccines represent promising therapeutic strategies in autoimmune disorders such as multiple sclerosis (MS). However, the precise mechanisms by which DNA vaccines induce immune regulation remain largely unknown. Here, we aimed to expand previous knowledge existing on the mechanisms of action of DNA vaccines in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), by treating EAE mice with a DNA vaccine encoding the myelin oligodendrocyte glycoprotein (MOG), and exploring the therapeutic effects on the disease-induced inflammatory and neurodegenerative changes. Methods EAE was induced in C57BL6/J mice by immunization with MOG35-55 peptide. Mice were intramuscularly treated with a MOG-DNA vaccine or vehicle in prophylactic and therapeutic approaches. Histological studies were performed in central nervous system (CNS) tissue. Cytokine production and regulatory T cell (Treg) quantification were achieved by flow cytometry. Gene expression patterns were determined using microarrays, and the main findings were validated by real-time PCR. Results MOG-DNA treatment reduced the clinical and histopathological signs of EAE when administered in both prophylactic and therapeutic settings. Suppression of clinical EAE was associated with dampening of antigen (Ag)-specific proinflammatory Th1 and Th17 immune responses and, interestingly, expansion of Treg in the periphery and upregulation in the CNS of genes encoding neurotrophic factors and proteins involved in remyelination. Conclusions These results suggest for the first time that the beneficial effects of DNA vaccines in EAE are not limited to anti-inflammatory mechanisms, and DNA vaccines may also exert positive effects through hitherto unknown neuroprotective mechanisms. PMID:22727044

  14. Plasmodesmata-located protein overexpression negatively impacts the manifestation of systemic acquired resistance and the long-distance movement of Defective in Induced Resistance1 in Arabidopsis.

    PubMed

    Carella, P; Isaacs, M; Cameron, R K

    2015-03-01

    Systemic acquired resistance (SAR) is a plant defence response that provides immunity to distant uninfected leaves after an initial localised infection. The lipid transfer protein (LTP) Defective in Induced Resistance1 (DIR1) is an essential component of SAR that moves from induced to distant leaves following a SAR-inducing local infection. To understand how DIR1 is transported to distant leaves during SAR, we analysed DIR1 movement in transgenic Arabidopsis lines with reduced cell-to-cell movement caused by the overexpression of Plasmodesmata-Located Proteins PDLP1 and PDLP5. These PDLP-overexpressing lines were defective for SAR, and DIR1 antibody signals were not observed in phloem sap-enriched petiole exudates collected from distant leaves. Our data support the idea that cell-to-cell movement of DIR1 through plasmodesmata is important during long-distance SAR signalling in Arabidopsis. PMID:25296648

  15. Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-β 1-42 induced neurotoxicity and memory impairment.

    PubMed

    Bellozi, Paula Maria Quaglio; Lima, Isabel Vieira de Assis; Dória, Juliana Guimarães; Vieira, Érica Leandro Marciano; Campos, Alline Cristina; Candelario-Jalil, Eduardo; Reis, Helton José; Teixeira, Antônio Lúcio; Ribeiro, Fabíola Mara; de Oliveira, Antônio Carlos Pinheiro

    2016-01-01

    Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the main cause of dementia. Substantial evidences indicate that there is over-activation of the PI3K/Akt/mTOR axis in AD. Therefore, the aim of the present study was to investigate the effects of NVP-BEZ235 (BEZ; dactolisib), a dual PI3K/mTOR inhibitor that is under phase I/II clinical trials for the treatment of some types of cancer, in hippocampal neuronal cultures stimulated with amyloid-β (Aβ) 1-42 and in mice injected with Aβ 1-42 in the hippocampus. In cell cultures, BEZ reduced neuronal death induced by Aβ. BEZ, but not rapamycin, a mTOR inhibitor, or LY294002, a PI3K inhibitor that also inhibits mTOR, reduced the memory impairment induced by Aβ. The effect induced by Aβ was also prevented in PI3Kγ(-/-) mice. Neuronal death and microgliosis induced by Aβ were reduced by BEZ. In addition, the compound increased IL-10 and TNF-α levels in the hippocampus. Finally, BEZ did not change the phosphorylation of Akt and p70s6K, suggesting that the involvement of PI3K and mTOR in the effects induced by BEZ remains controversial. Therefore, BEZ represents a potential strategy to prevent the pathological outcomes induced by Aβ and should be investigated in other models of neurodegenerative conditions. PMID:27142962

  16. Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-β 1–42 induced neurotoxicity and memory impairment

    PubMed Central

    Bellozi, Paula Maria Quaglio; Lima, Isabel Vieira de Assis; Dória, Juliana Guimarães; Vieira, Érica Leandro Marciano; Campos, Alline Cristina; Candelario-Jalil, Eduardo; Reis, Helton José; Teixeira, Antônio Lúcio; Ribeiro, Fabíola Mara; de Oliveira, Antônio Carlos Pinheiro

    2016-01-01

    Alzheimer’s Disease (AD) is a progressive neurodegenerative disease and the main cause of dementia. Substantial evidences indicate that there is over-activation of the PI3K/Akt/mTOR axis in AD. Therefore, the aim of the present study was to investigate the effects of NVP-BEZ235 (BEZ; dactolisib), a dual PI3K/mTOR inhibitor that is under phase I/II clinical trials for the treatment of some types of cancer, in hippocampal neuronal cultures stimulated with amyloid-β (Aβ) 1–42 and in mice injected with Aβ 1–42 in the hippocampus. In cell cultures, BEZ reduced neuronal death induced by Aβ. BEZ, but not rapamycin, a mTOR inhibitor, or LY294002, a PI3K inhibitor that also inhibits mTOR, reduced the memory impairment induced by Aβ. The effect induced by Aβ was also prevented in PI3Kγ−/− mice. Neuronal death and microgliosis induced by Aβ were reduced by BEZ. In addition, the compound increased IL-10 and TNF-α levels in the hippocampus. Finally, BEZ did not change the phosphorylation of Akt and p70s6K, suggesting that the involvement of PI3K and mTOR in the effects induced by BEZ remains controversial. Therefore, BEZ represents a potential strategy to prevent the pathological outcomes induced by Aβ and should be investigated in other models of neurodegenerative conditions. PMID:27142962

  17. Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective.

    PubMed

    Bruno, V; Ksiazek, I; Battaglia, G; Lukic, S; Leonhardt, T; Sauer, D; Gasparini, F; Kuhn, R; Nicoletti, F; Flor, P J

    2000-09-01

    We have used potent and selective non-competitive antagonists of metabotropic glutamate receptor subtype 5 (mGlu5) -- 2-methyl-6-phenylethynylpyridine (MPEP), [6-methyl-2-(phenylazo)-3-pyridinol] (SIB-1757) and [(E)-2-methyl-6-(2-phenylethenyl)pyridine] (SIB-1893) - to examine whether endogenous activation of this particular metabotropic glutamate receptor subtype contributes to neuronal degeneration. In cortical cultures challenged with N-methyl-D-aspartate (NMDA), all three mGlu5 receptor antagonists were neuroprotective. The effect of MPEP was highly specific because the close analogue, 3-methyl-6-phenylethynylpyridine (iso-MPEP), which did not antagonize heterologously expressed mGlu5 receptors, was devoid of activity on NMDA toxicity. Neuroprotection by mGlu5 receptor antagonists was also observed in cortical cultures challenged with a toxic concentration of beta-amyloid peptide. We have also examined the effect of mGlu5 receptor antagonists in in vivo models of excitotoxic degeneration. MPEP and SIB-1893 were neuroprotective against neuronal damage induced by intrastriatal injection of NMDA or quinolinic acid. These results indicate that mGlu5 receptors represent a suitable target for novel neuroprotective agents of potential application in neurodegenerative disorders. PMID:10974306

  18. Resveratrol Neuroprotection in a Chronic Mouse Model of Multiple Sclerosis

    PubMed Central

    Fonseca-Kelly, Zoe; Nassrallah, Mayssa; Uribe, Jorge; Khan, Reas S.; Dine, Kimberly; Dutt, Mahasweta; Shindler, Kenneth S.

    2012-01-01

    Resveratrol is a naturally occurring polyphenol that activates SIRT1, an NAD-dependent deacetylase. SRT501, a pharmaceutical formulation of resveratrol with enhanced systemic absorption, prevents neuronal loss without suppressing inflammation in mice with relapsing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). In contrast, resveratrol has been reported to suppress inflammation in chronic EAE, although neuroprotective effects were not evaluated. The current studies examine potential neuroprotective and immunomodulatory effects of resveratrol in chronic EAE induced by immunization with myelin oligodendroglial glycoprotein peptide in C57/Bl6 mice. Effects of two distinct formulations of resveratrol administered daily orally were compared. Resveratrol delayed the onset of EAE compared to vehicle-treated EAE mice, but did not prevent or alter the phenotype of inflammation in spinal cords or optic nerves. Significant neuroprotective effects were observed, with higher numbers of retinal ganglion cells found in eyes of resveratrol-treated EAE mice with optic nerve inflammation. Results demonstrate that resveratrol prevents neuronal loss in this chronic demyelinating disease model, similar to its effects in relapsing EAE. Differences in immunosuppression compared with prior studies suggest that immunomodulatory effects may be limited and may depend on specific immunization parameters or timing of treatment. Importantly, neuroprotective effects can occur without immunosuppression, suggesting a potential additive benefit of resveratrol in combination with anti-inflammatory therapies for MS. PMID:22654783

  19. Acquired amegakaryocytic thrombocytopenic purpura induced by percutaneous ethanol injection during treatment of hepatocellular carcinoma: A case report

    PubMed Central

    AI, DING-LUN; LI, BO-TAO; PENG, XIAO-MING; ZHANG, LIN-ZHI; WANG, JING-YAN; ZHAO, YUN; YANG, BIN; YU, QIANG; LIU, CHUN-ZI; YANG, NING; WANG, HUA-MING; ZHOU, LIN

    2016-01-01

    Percutaneous ethanol injection is an important localized treatment method for patients presenting with hepatocellular carcinoma (HCC). Among the advantages of percutaneous ethanol injection are its minimal invasiveness, simplicity, low cost and low risk of complications. However, the increasing popularity of percutaneous ethanol injection has resulted in serious adverse effects attributed to individual variations. The present study describes the case of a patient who exhibited acquired amegakaryocytic thrombocytopenic purpura, caused by percutaneous ethanol injection treatment for HCC. This complication was promptly identified, and platelet transfusion and injection of recombinant human interleukin-11 resulted in a rapid recovery of the patient's platelet count. Attention should be given to this rare complication in patients administered percutaneous ethanol injection treatment for HCC. PMID:26870287

  20. A craniocervical injury-induced syringomyelia caused by central canal dilation secondary to acquired tonsillar herniation. Case report.

    PubMed

    Takamura, Y; Kawasaki, T; Takahashi, A; Nunomura, K; Tiba, K; Hasunuma, M; Itou, T

    2001-07-01

    The authors report on a 19-year-old man with an acquired tonsillar herniation caused by a craniocervical junction injury in which serial magnetic resonance (MR) images demonstrated patent and isolated segments of the central canal participating in the dilation and then formation of a cervical syrinx. The patient was involved in a motor vehicle accident; he developed tonsillar herniation as a complication of subarachnoid and epidural hemorrhage, predominantly observed around the cisterna magna and upper cervical canal. Repeated MR images obtained over an 11-month period indicated the for mation and acute enlargement of the syrinx. Ten months after the accident, the patient presented with sensory disturbance in both upper extremities and spasticity due to syringomyelia. He underwent craniocervical decompressive surgery and doraplasty, which reduced the size of syringomyelia. The authors postulate that the patent central canal may play a role in determining the location of a syrinx remote from a focus of cerebrospinal fluid obstruction. PMID:11453413

  1. Neuroprotective dibenzylbutyrolactone lignans of Torreya nucifera.

    PubMed

    Jang, Y P; Kim, S R; Kim, Y C

    2001-07-01

    The methanolic extract of the bark of Torreya nucifera Sieb. et Zucc. (Taxaceae) significantly protected primary cultures of rat cortical cells exposed to the excitotoxic amino acid, L-glutamate. (-)-Arctigenin (1), (-)-traxillagenin (2), arctiin (4), traxillaside (5), and a newly-reported compound 3 (-)-4'-demethyltraxillagenin [(2R,3R)-2-(4''-hydroxy-3''-methoxybenzyl)-3-(4'-hydroxy-3',5'-dimethoxybenzyl)-butyrolactone] were isolated by bioactivity-guided fractionation and further separation using chromatographic techniques. These lignans and their glycosides had significant neuroprotective activities against glutamate-induced toxicity in primary cultures of rat cortical cells at concentrations ranging from 0.01 microM to 10.0 microM. PMID:11488466

  2. TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition.

    PubMed

    Raninga, Prahlad V; Di Trapani, Giovanna; Vuckovic, Slavica; Tonissen, Kathryn F

    2016-02-16

    Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxic-myeloma cells to bortezomib. Hypoxia increased NF-кβ subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-кβ p65 protein levels in the nucleus and reduced the expression of NF-кβ-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the naïve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-кβ-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-кβ signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomib-resistance and improve survival outcomes of MM patients. PMID:26743692

  3. Duality of Antidepressants and Neuroprotectants.

    PubMed

    Tizabi, Yousef

    2016-07-01

    The co-morbidity of neuropsychiatric disorders, particularly major depressive disorder (MDD) with neurodegenerative diseases, in particular Parkinson's disease (PD) is now well recognized. Indeed, it is suggested that depressive disorders, especially in late life, may be an indication of latent neurodegeneration. Thus, it is not unreasonable to expect that deterrents of MDD may also deter the onset and/or progression of the neurodegenerative diseases including PD. In this review, examples of neuroprotective efficacy of established as well as prospective antidepressants are provided. Conversely, mood-regulating effects of some neuroprotective drugs are also presented. Thus, in addition to currently used antidepressants, ketamine, nicotine, curcumin, and resveratrol are discussed for their dual efficacy. In addition, potential neurobiological substrates for their actions are presented. It is concluded that pharmacological developments of mood-regulating or neuroprotective drugs can have cross benefit in co-morbid conditions of neuropsychiatric and neurodegenerative disorders and that inflammatory and neurotrophic factors play important roles in both conditions. PMID:26613895

  4. Glucocorticoid receptor is involved in the neuroprotective effect of ginsenoside Rg1 against inflammation-induced dopaminergic neuronal degeneration in substantia nigra.

    PubMed

    Sun, Xian-Chang; Ren, Xiao-Fan; Chen, Lei; Gao, Xian-Qi; Xie, Jun-Xia; Chen, Wen-Fang

    2016-01-01

    Accumulating clinical and experimental evidence suggests that chronic neuroinflammation is associated with dopaminergic neuronal death in Parkinson's disease (PD). Ginsenoside Rg1, the most active components of ginseng, possesses a variety of biological effects on the central nervous system, cardiovascular system and immune system. The present study aimed to evaluate the protective effects of ginsenoside Rg1 on lipopolysaccharide (LPS)-induced microglia activation and dopaminergic neuronal degeneration in rat substantia nigra (SN) and its potential mechanisms. Treatment with Rg1 could ameliorate the apomorphine-induced rotational behavior in LPS-lesioned rats. GR antagonist RU486 partly abolished the protective effect of Rg1. Rg1 treatment significantly attenuated LPS-induced loss of tyrosin hydroxlase (TH) positive neurons in substantial nigra par compacta (SNpc) and decreased content of dopamine (DA) and its metabolites in striatum of the lesioned side. Meanwhile, Rg1 significantly inhibited LPS-induced microglial activation and production of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and nitric oxide (NO). These effects were abolished by co-treatment with RU486. In addition, Rg1 treatment significantly inhibited the LPS-induced phosphorylation of IκB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) in the lesioned side of substantial nigra. These effect could be also partly blocked by RU486. Taken together, these data indicate that Rg1 has protective effects on mesencephalic dopaminergic neurons from LPS-induced microglia inflammation. GR signaling pathway might be involved in the anti-inflammatory effect of Rg1. PMID:26455404

  5. Neuroprotective Effects of Alpha-Mangostin on MPP+-Induced Apoptotic Cell Death in Neuroblastoma SH-SY5Y Cells

    PubMed Central

    Janhom, Prachya; Dharmasaroja, Permphan

    2015-01-01

    In vitro studies have shown that extracts from mangosteen (Garcinia mangostana Linn.) act as antioxidants and cytoprotective agents against oxidative damage. The protective effect of alpha-mangostin, the major xanthone found in the pericarp of the mangosteen, in cellular models of Parkinson's disease (PD), has not been investigated. This study aims to investigate whether alpha-mangostin could protect SH-SY5Y neuroblastoma cells from MPP+-induced apoptosis. The effects of alpha-mangostin on MPP+-induced cell death were evaluated with a cell viability assay, staining for nuclear DNA morphology, flow cytometry for apoptotic cells and reactive oxygen species (ROS) production, quantitative real-time PCR for the expression of p53, Bax, and Bcl-2, and western blot analysis for cleaved caspase-3. Concomitant treatment with alpha-mangostin attenuated the effect of MPP+ on cell viability and apoptotic cell death. Alpha-mangostin reduced ROS formation induced by MPP+. Bax/Bcl-2 expression ratio and expression of p53 were significantly lower in cells cocultured with alpha-mangostin and MPP+. The cotreated cells showed a significant decrease in activated caspase-3 compared with MPP+ treatment alone. Our data suggest that cytoprotection of alpha-mangostin against MPP+-induced apoptosis may be associated with the reduction of ROS production, modulating the balance of pro- and antiapoptotic genes, and suppression of caspase-3 activation. PMID:26357513

  6. Neuroprotective Effects of Alpha-Mangostin on MPP(+)-Induced Apoptotic Cell Death in Neuroblastoma SH-SY5Y Cells.

    PubMed

    Janhom, Prachya; Dharmasaroja, Permphan

    2015-01-01

    In vitro studies have shown that extracts from mangosteen (Garcinia mangostana Linn.) act as antioxidants and cytoprotective agents against oxidative damage. The protective effect of alpha-mangostin, the major xanthone found in the pericarp of the mangosteen, in cellular models of Parkinson's disease (PD), has not been investigated. This study aims to investigate whether alpha-mangostin could protect SH-SY5Y neuroblastoma cells from MPP(+)-induced apoptosis. The effects of alpha-mangostin on MPP(+)-induced cell death were evaluated with a cell viability assay, staining for nuclear DNA morphology, flow cytometry for apoptotic cells and reactive oxygen species (ROS) production, quantitative real-time PCR for the expression of p53, Bax, and Bcl-2, and western blot analysis for cleaved caspase-3. Concomitant treatment with alpha-mangostin attenuated the effect of MPP(+) on cell viability and apoptotic cell death. Alpha-mangostin reduced ROS formation induced by MPP(+). Bax/Bcl-2 expression ratio and expression of p53 were significantly lower in cells cocultured with alpha-mangostin and MPP(+). The cotreated cells showed a significant decrease in activated caspase-3 compared with MPP(+) treatment alone. Our data suggest that cytoprotection of alpha-mangostin against MPP(+)-induced apoptosis may be associated with the reduction of ROS production, modulating the balance of pro- and antiapoptotic genes, and suppression of caspase-3 activation. PMID:26357513

  7. Neuroprotective effect of Citrus unshiu immature peel and nobiletin inhibiting hydrogen peroxide-induced oxidative stress in HT22 murine hippocampal neuronal cells

    PubMed Central

    Cho, Hyun Woo; Jung, Su Young; Lee, Gyeong Hwan; Cho, Jung Hee; Choi, In Young

    2015-01-01

    Background: Oxidative stress-induced cell damage is common in the etiology of several neurobiological disorders, including Alzheimer's disease and Parkinson's disease. In a case study, nobiletin-rich Citrus reticulata peels could prevent the progression of cognitive impairment in donepezil-preadministered Alzheimer's disease patients. Objective: In this study, we investigated the effects and underlying mechanism of nobiletin and Citrus unshiu immature peel (CUIP) water extract, which contains nobiletin as a major compound, on hydrogen peroxide-induced oxidative stress in HT22 cells, a murine hippocampal neuronal model. Materials and Methods: HT22 cells were treated with hydrogen peroxide in the presence or absence of various concentrations of CUIP and nobiletin. Cytotoxicity and apoptotic protein levels were measured by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and Western blotting. Results: Pretreatment with CUIP and nobiletin inhibited cell death due to hydrogen peroxide. Hydrogen peroxide-induced the expression of phospho-Jun N-terminal kinases (p-JNK) and p-p38 proteins in HT22 cells; however CUIP and nobiletin suppressed p-JNK and p-p38 without changing JNK or p38. Regarding apoptosis, caspase 3, B-cell lymphoma 2 (Bcl-2), and Bax protein expression was determined. CUIP and nobiletin suppressed caspase 3 and Bax expression, but they induced Bcl-2 expression in HT22 cells. Conclusion: These results show that CUIP and nobiletin can protect against hydrogen peroxide-induced cell death in HT22 neurons via mitogen-activated protein kinases and apoptotic pathways. PMID:26664016

  8. Bacillus cereus AR156 activates PAMP-triggered immunity and induces a systemic acquired resistance through a NPR1-and SA-dependent signaling pathway.

    PubMed

    Niu, Dongdong; Wang, Xiujuan; Wang, Yanru; Song, Xiaoou; Wang, Jiansheng; Guo, Jianhua; Zhao, Hongwei

    2016-01-01

    Induced resistance responses play a potent role in plant defense system against pathogen attack. Bacillus cereus AR156 is a plant growth promoting rhizobacterium (PGPR) that installs induced systemic resistance (ISR) to Pseudomonas syringae pv. tomato (Pst) in Arabidopsis. Here, we show that AR156 leaf infiltration enhances disease resistance in Arabidopsis through the activation of a systemic acquired resistance (SAR). PR1 protein expression and reactive oxygen species (ROS) burst are strongly induced in plants treated with AR156 and inoculated with Pst than that in plants inoculated with Pst only. Moreover, AR156 can trigger SAR in jar1 or ein2 mutants, but not in the NahG transgenic and NPR1 mutant plants. Our results indicate that AR156-induced SAR depends on SA-signaling pathway and NPR1, but not JA and ET. Also, AR156-treated plants are able to rapidly activate MAPK signaling and FRK1 gene expression, which are involved in pathogen associated molecular pattern (PAMP)-triggered immunity (PTI). Altogether, our results indicate that AR156 can induce SAR by the SA-signaling pathways in an NPR1-dependent manner and involves multiple PTI components. PMID:26616055

  9. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induced cell-specific drug transporters with acquired cisplatin resistance in cisplatin sensitive cancer cells.

    PubMed

    Gotovdorj, Tuvshinjargal; Lee, Eunil; Lim, Yongchul; Cha, Eun Jeong; Kwon, Daeho; Hong, Eunyoung; Kim, YunJeong; Oh, Min-Yeong

    2014-09-01

    2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce drug transporter genes such as the ATP-binding cassette G member 2 (ABCG2), which contributes to multidrug resistance. We investigated the effect of TCDD pretreatment on drug transporters induction from cancer cells of various origins. Cell viabilities after treatment of cisplatin were measured to evaluate acquiring cisplatin resistance by TCDD. Acquring cisplatin resistance was found only in cisplatin senstivie cancer cells including gastric SNU601, colon LS180, brain CRT-MG and lymphoma Jurkat cells which showed a significant increase in cell viability after combined treatment with TCDD and cisplatin. High increase of ABCG2 gene expression was found in SNU601 and LS180 cells with a mild increase in the expression of the ABCC3, ABCC5,and SLC29A2 genes in SNU601 cells, and of major vault protein (MVP) in LS180 cells. The AhR inhibitor kaempferol suppressed the upregulation of ABCG2 expression and reversed the TCDD-induced increase in cell viability in LS180 cells. However, in CRT-MG cells, other transporter genes including ABCC1, ABCC5, ABCA3, ABCA2, ABCB4, ABCG1, and SLC29A1 were up-regulated. These findings suggested the acquiring cisplatin resistance by TCDD associated with cancer cell-type-specific induction of drug transporters. PMID:25246735

  10. Neuroprotective 2-(2-phenylethyl)chromones of Imperata cylindrica.

    PubMed

    Yoon, Jeong Seon; Lee, Mi Kyeong; Sung, Sang Hyun; Kim, Young Choong

    2006-02-01

    Bioactivity-guided fractionation of the methanolic extract of the rhizomes of Imperata cylindrica afforded a new compound, 5-hydroxy-2-(2-phenylethyl)chromone (1), together with three known compounds, 5-hydroxy-2-[2-(2-hydroxyphenyl)ethyl]chromone (2), flidersiachromone (3), and 5-hydroxy-2-styrylchromone (4). Among these four compounds, 1 and 2 showed significant neuroprotective activity against glutamate-induced neurotoxicity in primary cultures of rat cortical cells. PMID:16499335

  11. Neuroprotective effects of piperine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mouse model.

    PubMed

    Yang, Wei; Chen, Yu-Hua; Liu, Hao; Qu, Hong-Dang

    2015-11-01

    Parkinson's disease (PD) is second only to Alzheimer's disease as the most common and debilitating age-associated neurodegenerative disorder. Currently, no therapy has been shown to unequivocally retard or arrest the progression of the disease. The aim of the present study was to investigate the protective effect of piperine on the 1-methyl-4-phenyl-1,2,3,6‑tetrahydropyridine (MPTP)-induced Parkinson's mouse model. For MPTP treatment, the animals received repeated intraperitoneal injections (i.p.) of MPTP (30 mg/kg) solution for 7 days. Piperine (10 mg/kg) was administered orally for 15 days including 8 days of pretreatment. Motor behavior analysis was conducted with the rotarod test. The Morris water maze (MWM) was used to assess the cognitive learning ability of the mice. A histological examination was subsequently conducted. The results ddemonstrate that piperine treatment attenuated MPTP-induced deficits in motor coordination and cognitive functioning. Piperine also prevented MPTP-induced decreases in the number of tyrosine hydroxylase-positive cells in the substantia nigra. Additionally, piperine reduced the number of activated microglia, expression of cytokine IL-1β, and oxidative stress following MPTP treatment. An anti-apoptotic property of piperine was identified by maintaining the balance of Bcl-2/Bax. In conclusion, the results show that piperine exerts a protective effect on dopaminergic neurons via antioxidant, anti-apoptotic, and anti-inflammatory mechanisms in an MPTP-induced mouse model of PD. Thus, piperine is a potential therapeutic treatment for PD. PMID:26648012

  12. Neuroprotective Role of L-NG-Nitroarginine Methyl Ester (L-NAME) against Chronic Hypobaric Hypoxia with Crowding Stress (CHC) Induced Depression-Like Behaviour

    PubMed Central

    Deep, Satya Narayan; Baitharu, Iswar; Sharma, Apurva; Gurjar, Anoop Kishor Singh; Prasad, Dipti; Singh, Shashi Bala

    2016-01-01

    Improper neuroimmune responses following chronic stress exposure have been reported to cause neuronal dysfunctions leading to memory impairment, anxiety and depression like behaviours. Though several factors affecting microglial activation and consequent alteration in neuro-inflammatory responses have been well studied, role of NO and its association with microglia in stress induced depression model is yet to be explored. In the present study, we validated combination of chronic hypobaric hypoxia and crowding (CHC) as a stress model for depression and investigated the role of chronic stress induced elevated nitric oxide (NO) level in microglia activation and its effect on neuro-inflammatory responses in brain. Further, we evaluated the ameliorative effect of L-NG-Nitroarginine Methyl Ester (L-NAME) to reverse the stress induced depressive mood state. Four groups of male Sprague Dawley rat were taken and divided into control and CHC stress exposed group with and without treatment of L-NAME. Depression like behaviour and anhedonia in rats were assessed by Forced Swim Test (FST) and Sucrose Preference Test (SPT). Microglial activation was evaluated using Iba-1 immunohistochemistry and proinflammatory cytokines were assessed in the hippocampal region. Our result showed that exposure to CHC stress increased the number of active microglia with corresponding increase in inflammatory cytokines and altered behavioural responses. The inhibition of NO synthesis by L-NAME during CHC exposure decreased the number of active microglia in hippocampus as evident from decreased Iba-1 positive cells. Further, L-NAME administration decreased pro-inflammatory cytokines in hippocampus and improved behaviour of rats. Our study demonstrate that stress induced elevation of NO plays pivotal role in altered microglial activation and consequent neurodegenerative processes leading to depression like behaviour in rat. PMID:27082990

  13. Neuroprotective Role of L-NG-Nitroarginine Methyl Ester (L-NAME) against Chronic Hypobaric Hypoxia with Crowding Stress (CHC) Induced Depression-Like Behaviour.

    PubMed

    Deep, Satya Narayan; Baitharu, Iswar; Sharma, Apurva; Gurjar, Anoop Kishor Singh; Prasad, Dipti; Singh, Shashi Bala

    2016-01-01

    Improper neuroimmune responses following chronic stress exposure have been reported to cause neuronal dysfunctions leading to memory impairment, anxiety and depression like behaviours. Though several factors affecting microglial activation and consequent alteration in neuro-inflammatory responses have been well studied, role of NO and its association with microglia in stress induced depression model is yet to be explored. In the present study, we validated combination of chronic hypobaric hypoxia and crowding (CHC) as a stress model for depression and investigated the role of chronic stress induced elevated nitric oxide (NO) level in microglia activation and its effect on neuro-inflammatory responses in brain. Further, we evaluated the ameliorative effect of L-NG-Nitroarginine Methyl Ester (L-NAME) to reverse the stress induced depressive mood state. Four groups of male Sprague Dawley rat were taken and divided into control and CHC stress exposed group with and without treatment of L-NAME. Depression like behaviour and anhedonia in rats were assessed by Forced Swim Test (FST) and Sucrose Preference Test (SPT). Microglial activation was evaluated using Iba-1 immunohistochemistry and proinflammatory cytokines were assessed in the hippocampal region. Our result showed that exposure to CHC stress increased the number of active microglia with corresponding increase in inflammatory cytokines and altered behavioural responses. The inhibition of NO synthesis by L-NAME during CHC exposure decreased the number of active microglia in hippocampus as evident from decreased Iba-1 positive cells. Further, L-NAME administration decreased pro-inflammatory cytokines in hippocampus and improved behaviour of rats. Our study demonstrate that stress induced elevation of NO plays pivotal role in altered microglial activation and consequent neurodegenerative processes leading to depression like behaviour in rat. PMID:27082990

  14. Inhibition of Endoplasmic Reticulum Stress is Involved in the Neuroprotective Effect of bFGF in the 6-OHDA-Induced Parkinson’s Disease Model

    PubMed Central

    Cai, Pingtao; Ye, Jingjing; Zhu, Jingjing; Liu, Dan; Chen, Daqing; Wei, Xiaojie; Johnson, Noah R.; Wang, Zhouguang; Zhang, Hongyu; Cao, Guodong; Xiao, Jian; Ye, Junming; Lin, Li

    2016-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder with complicated pathophysiologic mechanisms. Endoplasmic reticulum (ER) stress appears to play a critical role in the progression of PD. We demonstrated that basic fibroblast growth factor (bFGF), as a neurotropic factor, inhibited ER stress-induced neuronal cell apoptosis and that 6-hydroxydopamine (6-OHDA)-induced ER stress was involved in the progression of PD in rats. bFGF administration improved motor function recovery, increased tyrosine hydroxylase (TH)-positive neuron survival, and upregulated the levels of neurotransmitters in PD rats. The 6-OHDA-induced ER stress response proteins were inhibited by bFGF treatment. Meanwhile, bFGF also increased expression of TH. The administration of bFGF activated the downstream signals PI3K/Akt and Erk1/2 in vivo and in vitro. Inhibition of the PI3K/Akt and Erk1/2 pathways by specific inhibitors partially reduced the protective effect of bFGF. This study provides new insight towards bFGF translational drug development for PD involving the regulation of ER stress. PMID:27493838

  15. Neuroprotective Effects of Engineered Polymeric Nasal Microspheres Containing Hydroxypropyl-β-cyclodextrin on β-Amyloid (1-42)-Induced Toxicity.

    PubMed

    Yalcin, Ayfer; Soddu, Elena; Turunc Bayrakdar, Ezgi; Uyanikgil, Yigit; Kanit, Lutfiye; Armagan, Guliz; Rassu, Giovanna; Gavini, Elisabetta; Giunchedi, Paolo

    2016-08-01

    β-Amyloid (Aβ) plaques are the key neurotoxic assemblies in Alzheimer disease. It has been suggested that an interaction occurs between membrane cholesterol and Aβ aggregation in the brain. Cyclodextrins can remove cholesterol from cell membranes and change receptor function. This study aimed to investigate the effect of hydroxypropyl-β-cyclodextrin (HP-CD) polymeric microspheres, based on chitosan or sodium alginate, on the levels of lipid peroxidation, reactive oxygen species production, and mitochondrial function in brain synaptosomes. The effect of microspheres on DNA fragmentation, the expression of Bcl-2, Bax, and Apex1 mRNAs in rat hippocampus after Aβ(1-42) peptide-induced neurotoxicity was also evaluated. Comparison with HP-CD raw material was performed. Aβ(1-42) treatment significantly decreased the mitochondrial activity of Apex1 and Bcl-2 mRNAs, induced DNA fragmentation, and increased mRNA levels of Bax. Treatment with HP-CD microspheres against Aβ(1-42) significantly reduced DNA fragmentation and increased the Bcl-2/Bax mRNA ratio and mitochondrial function. In addition, HP-CD microspheres used against Aβ(1-42) decreased the levels of lipid peroxidation and reactive oxygen species production. These results indicate that nasally administered spray-dried HP-CD microspheres are able to provide protection against Aβ(1-42)-induced neurotoxicity, due to the suppressed levels of oxidative stress and apoptotic signals in the rat hippocampus. PMID:27353207

  16. Inhibition of Endoplasmic Reticulum Stress is Involved in the Neuroprotective Effect of bFGF in the 6-OHDA-Induced Parkinson's Disease Model.

    PubMed

    Cai, Pingtao; Ye, Jingjing; Zhu, Jingjing; Liu, Dan; Chen, Daqing; Wei, Xiaojie; Johnson, Noah R; Wang, Zhouguang; Zhang, Hongyu; Cao, Guodong; Xiao, Jian; Ye, Junming; Lin, Li

    2016-08-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder with complicated pathophysiologic mechanisms. Endoplasmic reticulum (ER) stress appears to play a critical role in the progression of PD. We demonstrated that basic fibroblast growth factor (bFGF), as a neurotropic factor, inhibited ER stress-induced neuronal cell apoptosis and that 6-hydroxydopamine (6-OHDA)-induced ER stress was involved in the progression of PD in rats. bFGF administration improved motor function recovery, increased tyrosine hydroxylase (TH)-positive neuron survival, and upregulated the levels of neurotransmitters in PD rats. The 6-OHDA-induced ER stress response proteins were inhibited by bFGF treatment. Meanwhile, bFGF also increased expression of TH. The administration of bFGF activated the downstream signals PI3K/Akt and Erk1/2 in vivo and in vitro. Inhibition of the PI3K/Akt and Erk1/2 pathways by specific inhibitors partially reduced the protective effect of bFGF. This study provides new insight towards bFGF translational drug development for PD involving the regulation of ER stress. PMID:27493838

  17. STATINS AND NEUROPROTECTION: A PRESCRIPTION TO MOVE THE FIELD FORWARD

    PubMed Central

    Wood, W. Gibson; Eckert, Gunter P.; Igbavboa, Urule; Müller, Walter E.

    2009-01-01

    There is growing interest in the use of statins, HMG-CoA reductase inhibitors, for treating specific neurodegenerative diseases (cerebrovascular disease, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis) and possibly traumatic brain injury. Neither is there is a consensus on the efficacy of statins in treating the aforementioned diseases nor are the mechanisms of the purported statin-induced neuroprotection well-understood. Part of the support for statin-induced neuroprotection comes from studies using animal models and cell culture. Important information has resulted from that work but there continues to be a lack of progress on basic issues pertaining to statins and brain which impedes advancement in understanding how statins alter brain function. For example, there are scant data on the pharmacokinetics of lipophilic and hydrophilic statins in brain, statin-induced neuroprotection versus cell death and statins and brain isoprenoids. The purpose of this mini-review will be to examine those aforementioned issues and to identify directions of future research. PMID:20633110

  18. Neuroprotection: lessons from hibernators.

    PubMed

    Dave, Kunjan R; Christian, Sherri L; Perez-Pinzon, Miguel A; Drew, Kelly L

    2012-05-01

    Mammals that hibernate experience extreme metabolic states and body temperatures as they transition between euthermia, a state resembling typical warm blooded mammals, and prolonged torpor, a state of suspended animation where the brain receives as low as 10% of normal cerebral blood flow. Transitions into and out of torpor are more physiologically challenging than the extreme metabolic suppression and cold body temperatures of torpor per se. Mammals that hibernate show unprecedented capacities to tolerate cerebral ischemia, a decrease in blood flow to the brain caused by stroke, cardiac arrest or brain trauma. While cerebral ischemia often leads to death or disability in humans and most other mammals, hibernating mammals suffer no ill effects when blood flow to the brain is dramatically decreased during torpor or experimentally induced during euthermia. These animals, as adults, also display rapid and pronounced synaptic flexibility where synapses retract during torpor and rapidly re-emerge upon arousal. A variety of coordinated adaptations contribute to tolerance of cerebral ischemia in these animals. In this review we discuss adaptations in heterothermic mammals that may suggest novel therapeutic targets and strategies to protect the human brain against cerebral ischemic damage and neurodegenerative disease. PMID:22326449

  19. XENON in medical area: emphasis on neuroprotection in hypoxia and anesthesia

    PubMed Central

    2013-01-01

    Xenon is a medical gas capable of establishing neuroprotection, inducing anesthesia as well as serving in modern laser technology and nuclear medicine as a contrast agent. In spite of its high cost, its lack of side effects, safe cardiovascular and organoprotective profile and effective neuroprotective role after hypoxic-ischemic injury (HI) favor its applications in clinics. Xenon performs its anesthetic and neuroprotective functions through binding to glycine site of glutamatergic N-methyl-D-aspartate (NMDA) receptor competitively and blocking it. This blockage inhibits the overstimulation of NMDA receptors, thus preventing their following downstream calcium accumulating cascades. Xenon is also used in combination therapies together with hypothermia or sevoflurane. The neuroprotective effects of xenon and hypothermia cooperate synergistically whether they are applied synchronously or asynchronously. Distinguishing properties of Xenon promise for innovations in medical gas field once further studies are fulfilled and Xenon’s high cost is overcome. PMID:23369273

  20. Neuroprotective Effect of Portulaca oleraceae Ethanolic Extract Ameliorates Methylmercury Induced Cognitive Dysfunction and Oxidative Stress in Cerebellum and Cortex of Rat Brain.

    PubMed

    Sumathi, Thangarajan; Christinal, Johnson

    2016-07-01

    Methylmercury (MeHg) is highly toxic, and its principal target tissue in human is the nervous system, which has made MeHg intoxication a public health concern for many decades. Portulaca oleraceae (purslane), a member of the Portulacaceae family, is widespread as a weed and has been ranked the eighth most common plant in the world. In this study, we sought for potential beneficial effects of Portulaca oleracea ethanolic extract (POEE) against the neurotoxicity induced by MeHg in cerebellum and cortex of rats. Male Wistar rats were administered with MeHg orally at a dose of 5 mg/kg b.w. for 21 days. Experimental rats were given MeHg and also administered with POEE (4 mg/kg, orally) 1 h prior to the administration of MeHg for 21 days. After MeHg exposure, we determine the mercury concentration by atomic absorption spectroscopy (AAS); mercury content was observed high in MeHg-induced group. POEE reduced the mercury content. We also observed that the activities of catalase, superoxide dismutase, glutathione peroxidase, and the level of glutathione were reduced. The levels of glutathione reductase and thiobarbituric acid reactive substance were found to be increased. The above biochemical changes were found to be reversed with POEE. Behavioral changes like decrease tail flick response, longer immobility time, and decreased motor activity were noted down during MeHg exposure. POEE pretreatment offered protection from these behavioral changes. MeHg intoxication also caused histopathological changes in cerebellum and cortex, which was found to be normalized by treatment with POEE. The present results indicate that POEE has protective effect against MeHg-induced neurotoxicity. PMID:26563420

  1. Progesterone receptor signalling in retinal photoreceptor neuroprotection.

    PubMed

    Jackson, Alice C Wyse; Roche, Sarah L; Byrne, Ashleigh M; Ruiz-Lopez, Ana M; Cotter, Thomas G

    2016-01-01

    'Norgestrel', a synthetic form of the female hormone progesterone has been identified as potential drug candidate for the treatment of the degenerative eye disease retinitis pigmentosa. However, to date, no work has looked at the compound's specific cellular target. Therefore, this study aimed to identify the receptor target of Norgestrel and begin to examine its potential mechanism of action in the retina. In this work, we identify and characterize the expression of progesterone receptors present in the C57 wild type and rd10 mouse model of retinitis pigmentosa. Classical progesterone receptors A and B (PR A/B), progesterone receptor membrane components 1 and 2 (PGRMC1, PGRMC2) and membrane progesterone receptors α, β and γ were found to be expressed. All receptors excluding PR A/B were also found in the 661W photoreceptor cell line. PGRMC1 is a key regulator of apoptosis and its expression is up-regulated in the degenerating rd10 mouse retina. Activated by Norgestrel through nuclear trafficking, siRNA knock down of PGRMC1 abrogated the protective properties of Norgestrel on damaged photoreceptors. Furthermore, specific inhibition of PGRMC1 by AG205 blocked Norgestrel-induced protection in stressed retinal explants. Therefore, we conclude that PGRMC1 is crucial to the neuroprotective effects of Norgestrel on stressed photoreceptors. The synthetic progestin 'Norgestrel' has been identified as a potential therapeutic for the treatment of Retinitis Pigmentosa, a degenerative eye disease. However, the mechanism behind this neuroprotection is currently unknown. In this work, we identify 'Progesterone Receptor Membrane Component 1' as the major progesterone receptor eliciting the protective effects of Norgestrel, both in vitro and ex vivo. This furthers our understanding of Norgestrel's molecular mechanism, which we hope will help bring Norgestrel one step closer to the clinic. PMID:26447367

  2. Radiation-induced cytochrome c release and the neuroprotective effects of the pan-caspase inhibitor z-VAD-fmk in the hypoglossal nucleus

    PubMed Central

    LI, JIANGUO; WANG, YAN; DU, LIQING; XU, CHANG; CAO, JIA; WANG, QIN; LIU, QIANG; FAN, FEIYUE

    2014-01-01

    Numerous studies have demonstrated that neuronal cell death occurs via extrinsic (death receptors) and intrinsic (mitochondria) pathways. Radiation induces caspase activation fundamentally via the mitochondrial pathway. To investigate the role of caspase, a cell permeable pan-caspase inhibitor, z-VAD-fmk [N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone], was used to investigate the effects of caspase blockade in vivo following irradiation. Adult male Sprague-Dawley rats (weight, 250–300 g) underwent irradiation at room temperature with a 4-Gy dose of radiation. Since z-VAD-fmk does not penetrate the blood-brain barrier, it was applied intracerebroventricularly via a bolus injection (0.2 μg/h for 1 h). Terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) demonstrated that z-VAD-fmk reduced the numbers of TUNEL-positive cells within the hypoglossal nucleus, suggesting that intervention in the caspase cascade following radiation may have therapeutic applications. The caspase inhibitor z-VAD-fmk reduced the expression and activation of caspase-3, caspase-8 and caspase-9 in the irradiated rats, indicating that caspase may be a potential therapeutic target in the treatment of brain radiation injury. Treatment with z-VAD-fmk also reduced the appearance of cytochrome c within the cytosolic fraction following radiation. The hypoglossal nucleus may be used as a model of radiation-induced injury in the central nervous system, providing visual information and displaying apoptotic nuclear morphology. PMID:24396410

  3. [Mechanisms of neuroprotective effects of therapeutic acetylcholinesterase inhibitors used in treatment of Alzheimer's disease].

    PubMed

    Takatori, Yuki

    2006-08-01

    Donepezil, galanthamine, and tacrine are therapeutic acetylcholinesterase (AChE) inhibitors used for the treatment of Alzheimer's disease. The aim of this paper is to review recent findings on their neuroprotective properties and the mechanisms of neuroprotection against glutamate neurotoxicity in rat cortical neurons. First, the hallmark of neurotoxicity induced by two different glutamate treatment conditions was examined, revealing that acute glutamate treatment (1 mM, 10 min) induces necrotic neuronal death and that moderate glutamate treatment (100 microM, 24 hr) induces apoptotic neuronal death. Next, we showed that therapeutic AChE inhibitors protect cortical neurons from glutamate neurotoxicity in a time- and concentration-dependent manner. We examined the mechanism of this neuroprotective effect and found that the neuroprotective effects against both acute and moderate glutamate treatments are mediated through nicotinic acetylcholine receptors (nAChRs), or more specifically, the effects of donepezil and galanthamine are mediated through alpha4- and alpha7-nAChR. We also showed that donepezil and galanthamine protect cortical neurons against acute glutamate treatment-induced neurotoxicity at steps before, and that tacrine protects at steps after, nitric oxide radical formation. On the other hand, the neuroprotective effects of donepezil and galanthamine, but not of tacrine, against neurotoxicity induced by moderate glutamate treatment were mediated through the phosphatidylinositol 3-kinase-Akt pathway. These findings unveiled the hitherto unknown neuroprotective effects of therapeutic AChE inhibitors and provided valuable insights into its neuroprotective mechanisms. They may very likely form the basis for a novel treatment strategy against Alzheimer's disease. PMID:16880719

  4. Neuroprotective effect of preoperatively induced mild hypothermia as determined by biomarkers and histopathological estimation in a rat subdural hematoma decompression model

    PubMed Central

    Yokobori, Shoji; Gajavelli, Shyam; Mondello, Stefania; Mo-Seaney, Jixiang; Hayes, Ronald L; Bramlett, Helen M.; Dietrich, W. Dalton; Bullock, M. Ross

    2016-01-01

    Object In traumatic brain injury (TBI) patients, hypothermia therapy has not shown efficacy in multicenter clinical trials. With the post-hoc data from the latest clinical trial (NABIS:H II), we hypothesized that hypothermia may be beneficial in the rat acute subdural hematoma (ASDH) model by blunting the effects of ischemic/ reperfusional (I/R) injury. The major aim of our study was to test the efficacy of temperature management in reducing brain damage after ASDH. Methods Rats were induced with ASDH and placed into (1) Normothermia group (37°C) (2) Early hypothermia group; head and body temperature reduced to 33°C at 30 minutes prior to craniotomy (3) Late hypothermia group; temperature was lowered to 33°C at 30 minutes after decompression (4) Sham group; no ASDH and underwent only craniotomy with normothermia. To assess of neuronal and glial cell damage, we analyzed microdialysate (MD ; using 100kD probe) concentrations of: glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1). Fluoro-Jade B (FJB) positive neurons and injury volume with 2,3,5-triphenyltetrazolium chloride (TTC) staining were also measured. Results In the early phase of reperfusion (30min- 2.5 hrs after decompression), extracellular UCH-L1 in the early hypothermia group was significantly lower than in the normothermia. (Early; 4.9±1.0 ng/dl, Late; 35.2±12.1 ng/dl, Normo; 50.20± 28.3 ng/dl, Sham; 3.1±1.3 ng/dl, Early vs Normo; p < 0.01, Sham vs Normo; p < 0.01, analyzed with ANOVA followed by a post-hoc Bonferroni’s test ). In the late phase of reperfusion (> 2.5hrs after decompression), extracellular GFAP in the early hypothermia group was also lower than in the normothermia and late hypothermia groups (Early; 5.5±2.9 ng/dl, Late; 7.4±3.4 ng/dl, Normo; 15.3±8.4 ng/dl, Sham; 3.3±1.0 ng/dl, Normo vs Sham; p < 0.01). The number of FJB positive cells in early hypothermia group was significantly smaller than in normothermia group (Normo vs Early: 774

  5. Neurotropic and neuroprotective activities of the earthworm peptide Lumbricusin

    SciTech Connect

    Kim, Dae Hong; Lee, Ik Hwan; Nam, Seung Taek; Hong, Ji; Zhang, Peng; Hwang, Jae Sam; Seok, Heon; Choi, Hyemin; Lee, Dong Gun; Kim, Jae Il; Kim, Ho

    2014-06-06

    Highlights: • 11-mer peptide Lumbricusin, a defensin like peptide, is isolated from earthworm. • We here demonstrated that Lumbricusin has neurotropic and neuroprotective effects. • p27 degradation by Lumbricusin mediates effects of Lumbricusin on neuronal cells. - Abstract: We recently isolated a polypeptide from the earthworm Lumbricus terrestris that is structurally similar to defensin, a well-known antibacterial peptide. An 11-mer antibacterial peptide (NH{sub 2}-RNRRWCIDQQA), designated Lumbricusin, was synthesized based on the amino acid sequence of the isolated polypeptide. Since we previously reported that CopA3, a dung beetle peptide, enhanced neuronal cell proliferation, we here examined whether Lumbricusin exerted neurotropic and/or neuroprotective effects. Lumbricusin treatment induced a time-dependent increase (∼51%) in the proliferation of human neuroblastoma SH-SY5Y cells. Lumbricusin also significantly inhibited the apoptosis and decreased viability induced by treatment with 6-hydroxy dopamine, a Parkinson’s disease-mimicking agent. Immunoblot analyses revealed that Lumbricusin treatment increased ubiquitination of p27{sup Kip1} protein, a negative regulator of cell-cycle progression, in SH-SY5Y cells, and markedly promoted its degradation. Notably, adenoviral-mediated over-expression of p27{sup Kip1} significantly blocked the antiapoptotic effect of Lumbricusin in 6-hydroxy dopamine-treated SH-SY5Y cells. These results suggest that promotion of p27{sup Kip1} degradation may be the main mechanism underlying the neuroprotective and neurotropic effects of Lumbricusin.

  6. Mitochondria: the missing link between preconditioning and neuroprotection.

    PubMed

    Correia, Sónia C; Santos, Renato X; Perry, George; Zhu, Xiongwei; Moreira, Paula I; Smith, Mark A

    2010-01-01

    The quote "what does not kill you makes you stronger" perfectly describes the preconditioning phenomenon - a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Over the last few decades, many attempts have been made to identify the molecular mechanisms involved in preconditioning-induced protective responses, and recent data suggests that many of these mechanisms converge on the mitochondria, positing mitochondria as master regulators of preconditioning-triggered endogenous neuroprotection. In this review, we critically discuss evidence for the involvement of mitochondria within the preconditioning paradigm. We will highlight the crucial targets and mediators by which mitochondria are integrated into neuroprotective signaling pathways that underlie preconditioning, putting focus on mitochondrial respiratory chain and mitochondrial reactive oxygen species, mitochondrial ATP-sensitive potassium channels, mitochondrial permeability transition pore, uncoupling proteins, and mitochondrial antioxidant enzyme manganese superoxide dismutase. We also discuss the role of mitochondria in the induction of hypoxia-inducible factor-1, a transcription factor engaged in preconditioning-mediated neuroprotective effects. The identification of intrinsic mitochondrial mechanisms involved in preconditioning will provide new insights which can be translated into potential pharmacological interventions aimed at counteracting neurodegeneration. PMID:20463394

  7. Antioxidant and neuroprotective activity of the extract from the seaweed, Halimeda incrassata (Ellis) Lamouroux, against in vitro and in vivo toxicity induced by methyl-mercury.

    PubMed

    Linares, Adyary Fallarero; Loikkanen, Jarkko; Jorge, Mancini-Filho; Soria, René Barro; Novoa, Alexis Vidal

    2004-02-01

    A growing body of evidence suggests oxidative stress as part of the toxicity mechanism of methyl-mercury (MeHg) in cell cultures and animal models and so justifies the use of natural antioxidants as therapeutic alternatives. This research examines the effect of an aqueous extract from the marine seaweed Halimeda incrassata (Hi) against the oxidative stress induced by MeHg on in vitro and in vivo models. In GT1-7 mouse hypothalamic cell cultures, the extract of Hi increased cell viability and reduced ROS production after 24-h exposure to MeHgCl. Wistar rats, acutely intoxicated with MeHgCl, had reduced levels of serum and brain thiobarbituric reactive substances when treated with the Hi extract. Similarly, animals exposed to repeated doses of MeHgCl were protected by the seaweed extract from variations in body weight, food consumption and the appearance of neurological effects. This research supports the notion that oxidative stress is directly involved in MeHg intoxication, so that natural antioxidants, particularly those in the extract of Hi, can be useful therapeutic alternatives. PMID:14748406

  8. Expression of the Homeobox Gene HOXA9 in Ovarian Cancer Induces Peritoneal Macrophages to Acquire an M2 Tumor-Promoting Phenotype

    PubMed Central

    Ko, Song Yi; Ladanyi, Andras; Lengyel, Ernst; Naora, Honami

    2015-01-01

    Tumor-associated macrophages (TAMs) exhibit an M2 macrophage phenotype that suppresses anti-tumor immune responses and often correlates with poor outcomes in patients with cancer. Patients with ovarian cancer frequently present with peritoneal carcinomatosis, but the mechanisms that induce naïve peritoneal macrophages into TAMs are poorly understood. In this study, we found an increased abundance of TAMs in mouse i.p. xenograft models of ovarian cancer that expressed HOXA9, a homeobox gene that is associated with poor prognosis in patients with ovarian cancer. HOXA9 expression in ovarian cancer cells stimulated chemotaxis of peritoneal macrophages and induced macrophages to acquire TAM-like features. These features included induction of the M2 markers, CD163 and CD206, and the immunosuppressive cytokines, IL-10 and chemokine ligand 17, and down-regulation of the immunostimulatory cytokine, IL-12. HOXA9-mediated induction of TAMs was primarily due to the combinatorial effects of HOXA9-induced, tumor-derived transforming growth factor-β2 and chemokine ligand 2 levels. High HOXA9 expression in clinical specimens of ovarian cancer was strongly associated with increased abundance of TAMs and intratumoral T-regulatory cells and decreased abundance of CD8+ tumor-infiltrating lymphocytes. Levels of immunosuppressive cytokines were also elevated in ascites fluid of patients with tumors that highly expressed HOXA9. HOXA9 may, therefore, stimulate ovarian cancer progression by promoting an immunosuppressive microenvironment via paracrine effects on peritoneal macrophages. PMID:24332016

  9. Neuroprotective effects of Rosa damascena extract on learning and memory in a rat model of amyloid-β-induced Alzheimer's disease

    PubMed Central

    Esfandiary, Ebrahim; Karimipour, Mohammad; Mardani, Mohammad; Ghanadian, Mustafa; Alaei, Hojjat Allah; Mohammadnejad, Daryoush; Esmaeili, Abolghasem

    2015-01-01

    Background: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease, which is characterized clinically by serious impairment in memory and cognition. Current medications only slow down the dementia progression and the present treatment one-drug one-target paradigm for anti-AD treatment appears to be clinically unsuccessful. Therefore, alternative therapeutic strategies are urgently needed. With respect to multifunctional and multitargeted characteristics of Rosa damascena via its effective flavonoids, we investigated the effects of R. damascena extract on behavioral functions in a rat model of amyloid-β (A-β)-induced Alzheimer's disease. Materials and Methods: After preparation of the methanolic extract of the R. damascena, HPLC analysis and toxicity studies, median lethal dose (LD50) and dose levels were determined. For evaluation of baseline training behavioral performance, Morris water maze and passive avoidance tests were used. A-β was injected bilaterally into CA1 area of the hippocampus. Twenty-one days after injection of A-β, the first probe trial of the behavioral tests were used to confirm learning and memory impairment. To examine the potential effects of the extract on behavioral tasks, the second probe trials were performed after one month administration of R. damasena extract. Results: Results showed that the R. damascena extract significantly improved the spatial and long-term memories in the extract- treated groups in a dose-dependent manner, as in the middle and high doses it had significant effect. Conclusion: According to these results, we concluded that R. damascena can reverse behavioral deficits caused by A-β, and may provide a new potential option for prevention and treatment of the cognitive dysfunction in Alzheimer's disease. PMID:26322279

  10. Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress

    PubMed Central

    Ruan, Kai; Zhu, Yi; Li, Chong; Brazill, Jennifer M.; Zhai, R. Grace

    2015-01-01

    Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved enzyme in the NAD synthetic pathway. It has also been identified as an effective and versatile neuroprotective factor. However, it remains unclear how healthy neurons regulate the dual functions of NMNAT and achieve self-protection under stress. Here we show that Drosophila Nmnat (DmNmnat) is alternatively spliced into two mRNA variants, RA and RB, which translate to protein isoforms with divergent neuroprotective capacities against spinocerebellar ataxia 1-induced neurodegeneration. Isoform PA/PC translated from RA is nuclear-localized with minimal neuroprotective ability, and isoform PB/PD translated from RB is cytoplasmic and has robust neuroprotective capacity. Under stress, RB is preferably spliced in neurons to produce the neuroprotective PB/PD isoforms. Our results indicate that alternative splicing functions as a switch that regulates the expression of functionally distinct DmNmnat variants. Neurons respond to stress by driving the splicing switch to produce the neuroprotective variant and therefore achieve self-protection. PMID:26616331

  11. Paracrine effect of carbon monoxide - astrocytes promote neuroprotection through purinergic signaling in mice.

    PubMed

    Queiroga, Cláudia S F; Alves, Raquel M A; Conde, Sílvia V; Alves, Paula M; Vieira, Helena L A

    2016-08-15

    The neuroprotective role of carbon monoxide (CO) has been studied in a cell-autonomous mode. Herein, a new concept is disclosed - CO affects astrocyte-neuron communication in a paracrine manner to promote neuroprotection. Neuronal survival was assessed when co-cultured with astrocytes that had been pre-treated or not with CO. The CO-pre-treated astrocytes reduced neuronal cell death, and the cellular mechanisms were investigated, focusing on purinergic signaling. CO modulates astrocytic metabolism and extracellular ATP content in the co-culture medium. Moreover, several antagonists of P1 adenosine and P2 ATP receptors partially reverted CO-induced neuroprotection through astrocytes. Likewise, knocking down expression of the neuronal P1 adenosine receptor A2A-R (encoded by Adora2a) reverted the neuroprotective effects of CO-exposed astrocytes. The neuroprotection of CO-treated astrocytes also decreased following prevention of ATP or adenosine release from astrocytic cells and inhibition of extracellular ATP metabolism into adenosine. Finally, the neuronal downstream event involves TrkB (also known as NTRK2) receptors and BDNF. Pharmacological and genetic inhibition of TrkB receptors reverts neuroprotection triggered by CO-treated astrocytes. Furthermore, the neuronal ratio of BDNF to pro-BDNF increased in the presence of CO-treated astrocytes and decreased whenever A2A-R expression was silenced. In summary, CO prevents neuronal cell death in a paracrine manner by targeting astrocytic metabolism through purinergic signaling. PMID:27383770

  12. Piperlonguminine is neuroprotective in experimental rat stroke.

    PubMed

    Yang, Tiansong; Sun, Shixiao; Wang, Tiegang; Tong, Xin; Bi, Junhui; Wang, Yulin; Sun, Zhongren

    2014-12-01

    Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Piperlonguminine (PE) has been proved to have anti-inflammatory actions. In this study, we investigated the effects of PE on cultured neuronal cell line, SH-SY5Y in vitro and experimental rat ischemic stroke in vivo. For oxygen-glucose deprivation (OGD) and tumor necrosis factor-α (TNF-α) stimulated SH-SY5Y cell line in vitro, SH-SY5Y cells were incubated with PE. In vivo, rats were subjected to middle cerebral artery occlusion (MACO) for 1h, followed by reperfusion for 23 h. The results of this study showed that treatment of SH-SY5Y cells with PE reduced the OGD-induced cytotoxicity and apoptosis and blocked TNF-α-induced activation of NF-κB and MAPK. Intraperitoneal injection of PE (2.4 mg/kg) produced a significant neuroprotective potential in rats with cerebral ischemia. PE attenuated neurological deficit scores, brain infarct volume and brain water content in rats, and inhibited activation of NF-κB and MAPK. These data show that PE protects the brain against ischemic cerebral injury via alleviating blood-brain barrier (BBB) breakdown, which may be mediated via inhibiting NF-κB and MAPK signaling pathways. PMID:25257731

  13. The Arabidopsis Mediator Complex Subunit16 Positively Regulates Salicylate-Mediated Systemic Acquired Resistance and Jasmonate/Ethylene-Induced Defense Pathways[W

    PubMed Central

    Zhang, Xudong; Wang, Chenggang; Zhang, Yanping; Sun, Yijun; Mou, Zhonglin

    2012-01-01

    Systemic acquired resistance (SAR) is a long-lasting plant immunity against a broad spectrum of pathogens. Biological induction of SAR requires the signal molecule salicylic acid (SA) and involves profound transcriptional changes that are largely controlled by the transcription coactivator NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (NPR1). However, it is unclear how SAR signals are transduced from the NPR1 signaling node to the general transcription machinery. Here, we report that the Arabidopsis thaliana Mediator subunit16 (MED16) is an essential positive regulator of SAR. Mutations in MED16 reduced NPR1 protein levels and completely compromised biological induction of SAR. These mutations also significantly suppressed SA-induced defense responses, altered the transcriptional changes induced by the avirulent bacterial pathogen Pseudomonas syringae pv tomato (Pst) DC3000/avrRpt2, and rendered plants susceptible to both Pst DC3000/avrRpt2 and Pst DC3000. In addition, mutations in MED16 blocked the induction of several jasmonic acid (JA)/ethylene (ET)–responsive genes and compromised resistance to the necrotrophic fungal pathogens Botrytis cinerea and Alternaria brassicicola. The Mediator complex acts as a bridge between specific transcriptional activators and the RNA polymerase II transcription machinery; therefore, our data suggest that MED16 may be a signaling component in the gap between the NPR1 signaling node and the general transcription machinery and may relay signals from both the SA and the JA/ET pathways. PMID:23064320

  14. Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease

    PubMed Central

    Naranjo, José R.; Zhang, Hongyu; Villar, Diego; González, Paz; Dopazo, Xose M.; Morón-Oset, Javier; Higueras, Elena; Oliveros, Juan C.; Arrabal, María D.; Prieto, Angela; Cercós, Pilar; González, Teresa; De la Cruz, Alicia; Casado-Vela, Juan; Rábano, Alberto; Valenzuela, Carmen; Gutierrez-Rodriguez, Marta; Li, Jia-Yi; Mellström, Britt

    2016-01-01

    Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD. PMID:26752648

  15. Creatinyl amino acids: new hybrid compounds with neuroprotective activity.

    PubMed

    Burov, Sergey; Leko, Maria; Dorosh, Marina; Dobrodumov, Anatoliy; Veselkina, Olga

    2011-09-01

    Prolonged oral creatine administration resulted in remarkable neuroprotection in experimental models of brain stroke. However, because of its polar nature creatine has poor ability to penetrate the blood-brain barrier (BBB) without specific creatine transporter (CRT). Thus, synthesis of hydrophobic derivatives capable of crossing the BBB by alternative pathway is of great importance for the treatment of acute and chronic neurological diseases including stroke, traumatic brain injury and hereditary CRT deficiency. Here we describe synthesis of new hybrid compounds-creatinyl amino acids, their neuroprotective activity in vivo and stability to degradation in different media. The title compounds were synthesized by guanidinylation of corresponding sarcosyl peptides or direct creatine attachment using isobutyl chloroformate method. Addition of lipophilic counterion (p-toluenesulfonate) ensures efficient creatine dissolution in DMF with simultaneous protection of guanidino group towards intramolecular cyclization. It excludes the application of expensive guanidinylating reagents, permits to simplify synthetic procedure and adapt it to large-scale production. The biological activity of creatinyl amino acids was tested in vivo on ischemic stroke and NaNO(2) -induced hypoxia models. One of the most effective compounds-creatinyl-glycine ethyl ester increases life span of experimental animals more than two times in hypoxia model and has neuroprotective action in brain stroke model when applied both before and after ischemia. These data evidenced that creatinyl amino acids can represent promising candidates for the development of new drugs useful in stroke treatment. PMID:21644247

  16. Stem Cell-Based Neuroprotective and Neurorestorative Strategies

    PubMed Central

    Hung, Chia-Wei; Liou, Ying-Jay; Lu, Shao-Wei; Tseng, Ling-Ming; Kao, Chung-Lan; Chen, Shih-Jen; Chiou, Shih-Hwa; Chang, Charn-Jung

    2010-01-01

    Stem cells, a special subset of cells derived from embryo or adult tissues, are known to present the characteristics of self-renewal, multiple lineages of differentiation, high plastic capability, and long-term maintenance. Recent reports have further suggested that neural stem cells (NSCs) derived from the adult hippocampal and subventricular regions possess the utilizing potential to develop the transplantation strategies and to screen the candidate agents for neurogenesis, neuroprotection, and neuroplasticity in neurodegenerative diseases. In this article, we review the roles of NSCs and other stem cells in neuroprotective and neurorestorative therapies for neurological and psychiatric diseases. We show the evidences that NSCs play the key roles involved in the pathogenesis of several neurodegenerative disorders, including depression, stroke and Parkinson’s disease. Moreover, the potential and possible utilities of induced pluripotent stem cells (iPS), reprogramming from adult fibroblasts with ectopic expression of four embryonic genes, are also reviewed and further discussed. An understanding of the biophysiology of stem cells could help us elucidate the pathogenicity and develop new treatments for neurodegenerative disorders. In contrast to cell transplantation therapies, the application of stem cells can further provide a platform for drug discovery and small molecular testing, including Chinese herbal medicines. In addition, the high-throughput stem cell-based systems can be used to elucidate the mechanisms of neuroprotective candidates in translation medical research for neurodegenerative diseases. PMID:20559500

  17. Neuroprotection and its molecular mechanism following spinal cord injury☆

    PubMed Central

    Liu, Nai-Kui; Xu, Xiao-Ming

    2012-01-01

    Acute spinal cord injury initiates a complex cascade of molecular events termed ‘secondary injury’, which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degeneration of intact white matter tracts, and, ultimately, expansion of the initial injury. These secondary injury processes include, but are not limited to, inflammation, free radical-induced cell death, glutamate excitotoxicity, phospholipase A2 activation, and induction of extrinsic and intrinsic apoptotic pathways, which are important targets in developing neuroprotective strategies for treatment of spinal cord injury. Recently, a number of studies have shown promising results on neuroprotection and recovery of function in rodent models of spinal cord injury using treatments that target secondary injury processes including inflammation, phospholipase A2 activation, and manipulation of the PTEN-Akt/mTOR signaling pathway. The present review outlines our ongoing research on the molecular mechanisms of neuroprotection in experimental spinal cord injury and briefly summarizes our earlier findings on the therapeutic potential of pharmacological treatments in spinal cord injury. PMID:25624837

  18. Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease.

    PubMed

    Naranjo, José R; Zhang, Hongyu; Villar, Diego; González, Paz; Dopazo, Xose M; Morón-Oset, Javier; Higueras, Elena; Oliveros, Juan C; Arrabal, María D; Prieto, Angela; Cercós, Pilar; González, Teresa; De la Cruz, Alicia; Casado-Vela, Juan; Rábano, Alberto; Valenzuela, Carmen; Gutierrez-Rodriguez, Marta; Li, Jia-Yi; Mellström, Britt

    2016-02-01

    Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD. PMID:26752648

  19. Erythropoietin as a Neuroprotectant for Neonatal Brain Injury: Animal Models

    PubMed Central

    Traudt, Christopher M.; Juul, Sandra E.

    2016-01-01

    Prematurity and perinatal hypoxia-ischemia are common problems that result in significant neurodevelopmental morbidity and high mortality worldwide. The Vannucci model of unilateral brain injury was developed to model perinatal brain injury due to hypoxia-ischemia. Because the rodent brain is altricial, i.e., it develops postnatally, investigators can model either preterm or term brain injury by varying the age at which injury is induced. This model has allowed investigators to better understand developmental changes that occur in susceptibility of the brain to injury, evolution of brain injury over time, and response to potential neuroprotective treatments. The Vannucci model combines unilateral common carotid artery ligation with a hypoxic insult. This produces injury of the cerebral cortex, basal ganglia, hippocampus, and periventricular white matter ipsilateral to the ligated artery. Varying degrees of injury can be obtained by varying the depth and duration of the hypoxic insult. This chapter details one approach to the Vannucci model and also reviews the neuroprotective effects of erythropoietin (Epo), a neuroprotective treatment that has been extensively investigated using this model and others. PMID:23456865

  20. Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More

    PubMed Central

    Costa, Lucio G.; Garrick, Jacqueline M.; Roquè, Pamela J.; Pellacani, Claudia

    2016-01-01

    Increasing interest has recently focused on determining whether several natural compounds, collectively referred to as nutraceuticals, may exert neuroprotective actions in the developing, adult, and aging nervous system. Quercetin, a polyphenol widely present in nature, has received the most attention in this regard. Several studies in vitro, in experimental animals and in humans, have provided supportive evidence for neuroprotective effects of quercetin, either against neurotoxic chemicals or in various models of neuronal injury and neurodegenerative diseases. The exact mechanisms of such protective effects remain elusive, though many hypotheses have been formulated. In addition to a possible direct antioxidant effect, quercetin may also act by stimulating cellular defenses against oxidative stress. Two such pathways include the induction of Nrf2-ARE and induction of the antioxidant/anti-inflammatory enzyme paraoxonase 2 (PON2). In addition, quercetin has been shown to activate sirtuins (SIRT1), to induce autophagy, and to act as a phytoestrogen, all mechanisms by which quercetin may provide its neuroprotection. PMID:26904161

  1. Neuroprotective effects of Lepidium meyenii (Maca).

    PubMed

    Pino-Figueroa, Alejandro; Nguyen, Diane; Maher, Timothy J

    2010-06-01

    The neuroprotective activity of the plant Lepidium meyenii (Maca) was studied in two experimental models: in vitro and in vivo. Crayfish neurons were pretreated with vehicle or the pentane extract from Maca, subjected to H(2)O(2), and their viability determined microscopically and chemically. A significant concentration-neuroprotective effect relationship was demonstrated. The pentane extract was then administered intravenously to rats prior to and following middle cerebral artery occlusion. While infarct volumes were decreased for the lower dose, higher doses increased infarct volumes compared to controls. These results suggest a potential application of Maca as a neuroprotectant. PMID:20633111

  2. Neurodegeneration and Neuroprotection in Glaucoma.

    PubMed

    Gauthier, Angela C; Liu, Ji

    2016-03-01

    Glaucoma is the principal cause of irreversible blindness in the world. The disease leads to progressive optic nerve degeneration with a gradual loss of retinal ganglion cells. Neurodegeneration in glaucoma extends beyond the eye into the lateral geniculate nucleus and visual cortex, and the disease even shares some characteristics with other central nervous system degenerative disorders. Glaucoma destroys neurons through oxidative stress, impairment in axonal transport, neuroinflammation, and excitotoxicity. Autophagy may promote or inhibit disease progression. Currently, lowering intraocular pressure is the only way proven to delay glaucoma advancement. However, many new therapies are being developed, including antioxidants, adenosine receptor antagonists, Rho-pathway inhibitors, stem cell therapy, and neurotrophic factors. These therapies focus on neuroprotection, and they may eventually halt glaucoma progression or reverse the process of the disease itself. PMID:27505018

  3. Neurodegeneration and Neuroprotection in Glaucoma

    PubMed Central

    Gauthier, Angela C.; Liu, Ji

    2016-01-01

    Glaucoma is the principal cause of irreversible blindness in the world. The disease leads to progressive optic nerve degeneration with a gradual loss of retinal ganglion cells. Neurodegeneration in glaucoma extends beyond the eye into the lateral geniculate nucleus and visual cortex, and the disease even shares some characteristics with other central nervous system degenerative disorders. Glaucoma destroys neurons through oxidative stress, impairment in axonal transport, neuroinflammation, and excitotoxicity. Autophagy may promote or inhibit disease progression. Currently, lowering intraocular pressure is the only way proven to delay glaucoma advancement. However, many new therapies are being developed, including antioxidants, adenosine receptor antagonists, Rho-pathway inhibitors, stem cell therapy, and neurotrophic factors. These therapies focus on neuroprotection, and they may eventually halt glaucoma progression or reverse the process of the disease itself.

  4. The acquired radioresistance in HeLa cells under conditions mimicking hypoxia was attenuated by a decreased expression of HIF subunit genes induced by RNA interference

    SciTech Connect

    Doi, Nobutaka; Ogawa, Ryohei; Cui, Zheng-Guo; Morii, Akihiro; Watanabe, Akihiko; Kanayama, Shinji; Yoneda, Yuko; Kondo, Takashi

    2015-05-01

    The cancer cells residing in the hypoxic layer are resistant to radiation and these are ones responsible for cancer recurrence after radiation therapy. One of the reasons why hypoxic cancer cells acquire radioresistance may be attributable to changes in the gene expression profile by the activation of hypoxia inducible factors (HIFs). However, the details underlying this process remain unknown. In this study, we investigated the effects of knockdown of HIF subunit genes to elucidate how HIF subunit genes may be involved in the radioresistance acquired by HeLa cells following exposure to a hypoxia mimic. Interestingly, HIF-1α and HIF-2α seemed mutually complementary for each other when either of them was suppressed. We thus suppressed the expression of both genes simultaneously. To do this, we developed a short hairpin RNA (shRNA) targeting a high homology region between HIF-1α and HIF-2α. It was shown that the expression of the shRNA effectively suppressed the acquisition of radioresistance following the hypoxia mimic. Moreover, it was confirmed that suppression of both subunits resulted in the downregulation of stem cell markers and the suppression of spheroid formation during the hypoxia mimicking-conditions. This shRNA-mediated knockdown method targeting a common region shared by a family of genes may offer a new candidate cancer treatment. - Highlights: • Incubation with CoCl{sub 2} confers radioresistance to HeLa cells. • Both HIF-1α and HIF-2α are involved in the acquisition of radioresistance. • An shRNA to a homology region of HIF-1α and HIF-2α suppressed the radioresistance. • The shRNA decreased cells with stem cell markers and a stem cell phenotype.

  5. [Evolution of the neuroprotection concept].

    PubMed

    Ostrovskaia, R U

    2003-01-01

    Although the modern concept of neuroprotection has been formulated quite recently, the basis of this approach was laid about four decades ago when Zakusov initiated the study of mechanisms involved in the neuroprotector action of GABA shunt metabolites (in particular, alpha-hydroxybutyric acid and succinic semialdehyde) during hypoxia. It was suggested to consider these agents as a system of endogenous neuroprotectors. The interest of Zakusov in endogenous regulators (including oligopeptides) had stimulated research in this direction and gave impact to the investigations of A. P. Skoldinov and T. A. Gudasheva initiated in the early 1980s. Proceeding from the original concept of the possibility of imitation of the action of neurotropic agents by their structural-conformational oligopeptide analogs, a number of biologically active stable dipeptides were obtained, based on pyroglutamate and proline, and high specific bioaccessibility of these dipeptides for the brain was established. Our investigations showed that these compounds not only possess nootropic activity (in a dose 1000 times lower than that of piracetam), but produce a pronounced neuroprotector action as well. Most thoroughly studied in this respect were substituted acyl-prolyl dipeptides, in particular, the drug noopept exhibiting a combined neuroprotector effect both in vitro and in vivo. Noopept decreases the extent of necrotic damage caused by photoinduced thrombosis of cortical blood vessels. It was established that the neuroprotector effect of noopept is related to its action upon the well-known "triad", whereby the drug reduces neurotoxic effects of excess extracellular calcium, glutamate, and free radicals. Two additional components of the neuroprotector action of noopept are related to the antiinflammatory and antithrombotic activity. The prospects of using direct and indirect action upon neurotrophin system for neuroprotection purposes are considered. Taking into account common secondary

  6. p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration.

    PubMed

    Turnquist, C; Horikawa, I; Foran, E; Major, E O; Vojtesek, B; Lane, D P; Lu, X; Harris, B T; Harris, C C

    2016-09-01

    Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases. PMID:27104929

  7. Neuroprotective and antioxidant lanostanoid triterpenes from the fruiting bodies of Ganoderma atrum.

    PubMed

    Qiu, Junming; Wang, Xiang; Song, Chengguang

    2016-03-01

    Five new lanostanoid triterpenes were isolated from the ethanol extract of the fruiting bodies of Ganoderma atrum. The structures of the isolated compounds were established based on 1D and 2D ((1)H-(1)H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated compounds were tested in vitro for neuroprotective activities against 6-OHDA-induced cell death in SH-SY5Y cells and radical scavenging activities. As a result, compounds 2 and 5 exhibited potent neuroprotective activity against 6-OHDA-induced cell death in SH-SY5Y cells with the lowest IC50 value (0.5 μM) while compounds 1, 3 and 4 possessed significant neuroprotective activity with IC50 value less than 10 μM. Additionally, all tested compounds 1-6 showed the comparable free radical scavenging activities with the standard drug trolox in both ABTS (+) and DPPH experiment. PMID:26709153

  8. Cognitive Enhancing and Neuroprotective Effect of the Embryo of the Nelumbo nucifera Seed

    PubMed Central

    Kim, Eun Sil; Weon, Jin Bae; Yun, Bo-Ra; Lee, Jiwoo; Eom, Min Rye; Oh, Kyoung-Hee; Ma, Choong Je

    2014-01-01

    The aim of the present study was to evaluate the effect of ENS on cognitive impairment induced by scopolamine and its potential neuroprotective effect against glutamate-induced cytotoxicity in HT22 cell and to investigate the underlying mechanisms. ENS (3, 10, 30, and 100 mg/kg), scopolamine (1 mg/kg), and donepezil (1 mg/kg) were administered to mice during a test period. Scopolamine impaired memory and learning in a water maze test and a passive avoidance test. The neuroprotective effect of ENS (10 and 100 μg/mL) was investigated on glutamate-induced cell death in HT22 cells by MTT assay. We investigated acetylcholinesterase inhibition in hippocampus and antioxidant activity, ROS levels, and Ca2+ influx in HT22 cells to elucidate the potential mechanisms of ENS. We found that ENS significantly ameliorated scopolamine-induced memory impairment and inhibited AChE activity in hippocampus. In vitro, ENS showed potent neuroprotective effects against glutamate-induced neurotoxicity in the HT22 cell. In addition, ENS induced a decrease in ROS production and intercellular Ca2+ accumulation and showed DPPH radical and H2O2 scavenging activity. In conclusion, ENS showed both a memory improving effect and a neuroprotective effect. Our results indicate that ENS may be of use in the treatment and prevention of neurodegenerative disorders. PMID:25610484

  9. Neuroprotective effects of nimodipine and nifedipine in the NGF-differentiated PC12 cells exposed to oxygen-glucose deprivation or trophic withdrawal.

    PubMed

    Lecht, Shimon; Rotfeld, Elena; Arien-Zakay, Hadar; Tabakman, Rinat; Matzner, Henry; Yaka, Rami; Lelkes, Peter I; Lazarovici, Philip

    2012-10-01

    The goal of this study was to compare the neuroprotective properties of the L-type Ca²⁺ channel blockers, nimodipine and nifedipine, using nerve growth factor (NGF)-differentiated PC12 neuronal cultures exposed to oxygen-glucose deprivation (OGD) and trophic withdrawal-induced cell death. Nimodipine (1-100 μM) conferred 65±13% neuroprotection upon exposure to OGD and 35±6% neuroprotection towards different trophic withdrawal-induced cell death measured by lactate dehydrogenase and caspase 3 activities. The time window of nimodipine conferred neuroprotection was detected during the first 5h but not at longer OGD exposures. Nifedipine (1-100 μM), to a lower potency than nimodipine, conferred 30-55±8% neuroprotection towards OGD in PC12 cells and 29±5% in rat hypocampal slices, and 10±3% neuroprotection at 100 μM towards trophic withdrawal-induced PC12 cell death. The ability to demonstrate that nimodipine conferred neuroprotection in a narrow therapeutic time-window indicates that the OGD PC12 model mimics the in vivo models and therefore suitable for neuroprotective drug discovery and development. PMID:22677442

  10. In vitro neuroprotective activities of compounds from Angelica shikokiana Makino.

    PubMed

    Mira, Amira; Yamashita, Shuntaro; Katakura, Yoshinori; Shimizu, Kuniyoshi

    2015-01-01

    Angelica shikokiana is widely marketed in Japan as a dietary food supplement. With a focus on neurodegenerative conditions such as Alzheimer's disease, the aerial part was extracted and through bio-guided fractionation, fifteen compounds [α-glutinol, β-amyrin, kaempferol, luteolin, quercetin, kaempferol-3-O-glucoside, kaempferol-3-O-rutinoside, methyl chlorogenate, chlorogenic acid, hyuganin E, 5-(hydroxymethyl)-2-furaldehyde, β-sitosterol-3-O-glucoside, adenosine (isolated for the first time from A. shikokiana), isoepoxypteryxin and isopteryxin] were isolated. Isolated compounds were evaluated for in vitro neuroprotection using acetylcholine esterase inhibitory, protection against hydrogen peroxide and amyloid β peptide (Aβ25-35)-induced neurotoxicity in neuro-2A cells, scavenging of hydroxyl radicals and intracellular reactive oxygen species and thioflavin T assays. Quercetin showed the strongest AChE inhibition (IC50 value = 35.5 µM) through binding to His-440 and Tyr-70 residues at the catalytic and anionic sites of acetylcholine esterase, respectively. Chlorogenic acid, its methyl ester, quercetin and luteolin could significantly protect neuro-2A cells against H2O2-induced neurotoxicity and scavenge hydroxyl radical and intracellular reactive oxygen species. Kaempferol-3-O-rutinoiside, hyuganin E and isoepoxypteryxin significantly decreased Aβ25-35-induced neurotoxicity and Th-T fluorescence. To the best of our knowledge, this is the first report about neuroprotection of hyuganin E and isoepoxypteryxin against Aβ25-35-induced neurotoxicity. PMID:25786165

  11. Methylene blue provides behavioral and metabolic neuroprotection against optic neuropathy.

    PubMed

    Rojas, Julio C; John, Joseph M; Lee, Jung; Gonzalez-Lima, F

    2009-04-01

    Methylene blue (MB) is a diaminophenothiazine with potent antioxidant and unique redox properties that prevent morphologic degenerative changes in the mouse retina induced by rotenone, a specific mitochondrial complex I inhibitor. This study evaluated pigmented rats to determine whether MB's neuroprotective effects against rotenone-mediated retinal neurotoxicity have functional relevance and whether these effects are mediated by an improvement in neuronal energy metabolism in vivo. Visual function was behaviorally assessed by determining differences in the illuminance sensitivity threshold pre- and post-bilateral intravitreal injection of rotenone (200 microg/kg) or rotenone plus MB (70 microg/kg). Retinal degeneration was morphologically studied using unbiased stereological tools. Changes in histochemically determined cytochrome oxidase activity in the visual pathway were used to evaluate the impact of treatments on neuronal energy metabolism. Rotenone induced a 1.4 log unit increase in the illumination threshold compared to baseline, as well as a 32% decrease in ganglion cell layer cell (GCL) density, and a 56% decrease in GCL layer + nerve fiber layer thickness. Co-administration of MB prevented the changes in visual function and the retinal histopathology. Furthermore, rotenone induced a functional deafferentation of the visual system, as revealed by decreases in the metabolic activity of the retina, superior colliculus, and visual cortex. These metabolic changes were also prevented by MB. The results provided the first demonstration of MB's behavioral and metabolic neuroprotection against optic neuropathy, and implicate MB as a candidate neuroprotective agent with metabolic-enhancing properties that may be used in the treatment of neurodegenerative diseases associated with mitochondrial dysfunction. PMID:19384599

  12. The neuroprotective effect of Activin A and B: implication for neurodegenerative diseases.

    PubMed

    Kupershmidt, Lana; Amit, Tamar; Bar-Am, Orit; Youdim, Moussa B H; Blumenfeld, Zeev

    2007-11-01

    Activin is a member of the transforming growth factor-beta superfamily which comprises a growing list of multifunctional proteins that function as modulators of cell proliferation, differentiation, hormone secretion and neuronal survival. This study examined the neuroprotective effect of both Activin A and B in serum withdrawal and oxidative stress apoptotic cellular models and investigated the expression of pro- and anti-apoptotic proteins, which may account for the mechanism of Activin-induced neuroprotection. Here, we report that recombinant Activin A and B are neuroprotective against serum deprivation- and toxin- [either the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA) or the peroxynitrite donor, 3-(4-morpholinyl) sydnonimine hydrochloride (SIN-1)] induced neuronal death in human SH-SY5Y neuroblastoma cells. Furthermore, we demonstrate for the first time that transient transfection with Activin betaA or betaB significantly protect SH-SY5Y and rat pheochromocytoma PC12 cells against serum withdrawal-induced apoptosis. This survival effect is mediated by the Bcl-2 family members and involves inhibition of caspase-3 activation; reduction of cleaved poly-ADP ribose polymerase and phosphorylated H2A.X protein levels and elevation of tyrosine hydroxylase expression. These results indicate that both Activin-A and -B share the potential to induce neuroprotective activity and thus may have positive impact on aging and neurodegenerative diseases to retard the accelerated rate of neuronal degeneration. PMID:17680997

  13. Limonoids with neuroprotective activity from the stems of Clausena emarginata.

    PubMed

    Ouyang, Guo-Qing; Li, Chuang-Jun; Yang, Jing-Zhi; Ma, Jie; Li, Li; Peng, Ying; Wang, Xiao-Liang; Zhang, Dong-Ming

    2016-10-01

    Two new limonoids, clauemargines M-N (1-2), together with five known compounds (3-7), were isolated from the stems of Clausena emarginata, and compounds 6 and 7 were gained from this plant for the first time. Their structures were established and elucidated on the basis of comprehensive spectroscopic analysis. The absolute configurations of 1-2 were further determined by the octant rule of saturated cyclic ketone. Compounds 1, 2, 4, and 5 showed moderate neuroprotective effects against L-glutamic acid-induced cellular damage in human neuroblastoma SK-N-SH cells at 10 μM. PMID:27268442

  14. Encapsulation of curcumin in polyelectrolyte nanocapsules and their neuroprotective activity

    NASA Astrophysics Data System (ADS)

    Szczepanowicz, Krzysztof; Jantas, Danuta; Piotrowski, Marek; Staroń, Jakub; Leśkiewicz, Monika; Regulska, Magdalena; Lasoń, Władysław; Warszyński, Piotr

    2016-09-01

    Poor water solubility and low bioavailability of lipophilic drugs can be potentially improved with the use of delivery systems. In this study, encapsulation of nanoemulsion droplets was utilized to prepare curcumin nanocarriers. Nanosize droplets containing the drug were encapsulated in polyelectrolyte shells formed by the layer-by-layer (LbL) adsorption of biocompatible polyelectrolytes: poly-L-lysine (PLL) and poly-L-glutamic acid (PGA). The size of synthesized nanocapsules was around 100 nm. Their biocompatibility and neuroprotective effects were evaluated on the SH-SY5Y human neuroblastoma cell line using cell viability/toxicity assays (MTT reduction, LDH release). Statistically significant toxic effect was clearly observed for PLL coated nanocapsules (reduction in cell viability about 20%–60%), while nanocapsules with PLL/PGA coating did not evoke any detrimental effects on SH-SY5Y cells. Curcumin encapsulated in PLL/PGA showed similar neuroprotective activity against hydrogen peroxide (H2O2)-induced cell damage, as did 5 μM curcumin pre-dissolved in DMSO (about 16% of protection). Determination of concentration of curcumin in cell lysate confirmed that curcumin in nanocapsules has cell protective effect in lower concentrations (at least 20 times) than when given alone. Intracellular mechanisms of encapsulated curcumin-mediated protection engaged the prevention of the H2O2-induced decrease in mitochondrial membrane potential (MMP) but did not attenuate Reactive Oxygen Species (ROS) formation. The obtained results indicate the utility of PLL/PGA shell nanocapsules as a promising, alternative way of curcumin delivery for neuroprotective purposes with improved efficiency and reduced toxicity.

  15. Encapsulation of curcumin in polyelectrolyte nanocapsules and their neuroprotective activity.

    PubMed

    Szczepanowicz, Krzysztof; Jantas, Danuta; Piotrowski, Marek; Staroń, Jakub; Leśkiewicz, Monika; Regulska, Magdalena; Lasoń, Władysław; Warszyński, Piotr

    2016-09-01

    Poor water solubility and low bioavailability of lipophilic drugs can be potentially improved with the use of delivery systems. In this study, encapsulation of nanoemulsion droplets was utilized to prepare curcumin nanocarriers. Nanosize droplets containing the drug were encapsulated in polyelectrolyte shells formed by the layer-by-layer (LbL) adsorption of biocompatible polyelectrolytes: poly-L-lysine (PLL) and poly-L-glutamic acid (PGA). The size of synthesized nanocapsules was around 100 nm. Their biocompatibility and neuroprotective effects were evaluated on the SH-SY5Y human neuroblastoma cell line using cell viability/toxicity assays (MTT reduction, LDH release). Statistically significant toxic effect was clearly observed for PLL coated nanocapsules (reduction in cell viability about 20%-60%), while nanocapsules with PLL/PGA coating did not evoke any detrimental effects on SH-SY5Y cells. Curcumin encapsulated in PLL/PGA showed similar neuroprotective activity against hydrogen peroxide (H2O2)-induced cell damage, as did 5 μM curcumin pre-dissolved in DMSO (about 16% of protection). Determination of concentration of curcumin in cell lysate confirmed that curcumin in nanocapsules has cell protective effect in lower concentrations (at least 20 times) than when given alone. Intracellular mechanisms of encapsulated curcumin-mediated protection engaged the prevention of the H2O2-induced decrease in mitochondrial membrane potential (MMP) but did not attenuate Reactive Oxygen Species (ROS) formation. The obtained results indicate the utility of PLL/PGA shell nanocapsules as a promising, alternative way of curcumin delivery for neuroprotective purposes with improved efficiency and reduced toxicity. PMID:27454207

  16. Guanosine controls inflammatory pathways to afford neuroprotection of hippocampal slices under oxygen and glucose deprivation conditions.

    PubMed

    Dal-Cim, Tharine; Ludka, Fabiana K; Martins, Wagner C; Reginato, Charlise; Parada, Esther; Egea, Javier; López, Manuela G; Tasca, Carla I

    2013-08-01

    Guanosine (GUO) is an endogenous modulator of glutamatergic excitotoxicity and has been shown to promote neuroprotection in in vivo and in vitro models of neurotoxicity. This study was designed to understand the neuroprotective mechanism of GUO against oxidative damage promoted by oxygen/glucose deprivation and reoxygenation (OGD). GUO (100 μM) reduced reactive oxygen species production and prevented mitochondrial membrane depolarization induced by OGD. GUO also exhibited anti-inflammatory actions as inhibition of nuclear factor kappa B activation and reduction of inducible nitric oxide synthase induction induced by OGD. These GUO neuroprotective effects were mediated by adenosine A1 receptor, phosphatidylinositol-3 kinase and MAPK/ERK. Furthermore, GUO recovered the impairment of glutamate uptake caused by OGD, an effect that occurred via a Pertussis toxin-sensitive G-protein-coupled signaling, blockade of adenosine A2A receptors (A2A R), but not via A1 receptor. The modulation of glutamate uptake by GUO also involved MAPK/ERK activation. In conclusion, GUO, by modulating adenosine receptor function and activating MAPK/ERK, affords neuroprotection of hippocampal slices subjected to OGD by a mechanism that implicates the following: (i) prevention of mitochondrial membrane depolarization, (ii) reduction of oxidative stress, (iii) regulation of inflammation by inhibition of nuclear factor kappa B and inducible nitric oxide synthase, and (iv) promoting glutamate uptake. PMID:23713463

  17. Hospital-acquired pneumonia

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000146.htm Hospital-acquired pneumonia To use the sharing features on this page, please enable JavaScript. Hospital-acquired pneumonia is an infection of the lungs ...

  18. Helicobacter pylori-infected MSCs acquire a pro-inflammatory phenotype and induce human gastric cancer migration by promoting EMT in gastric cancer cells

    PubMed Central

    ZHANG, QIANG; DING, JUAN; LIU, JINJUN; WANG, WEI; ZHANG, FENG; WANG, JUNHE; LI, YUYUN

    2016-01-01

    Accumulating clinical and experimental evidence has suggested that Helicobacter pylori (H. pylori) infection-associated gastric cancer (GC) is associated with high rates of mortality and serious health effects. The majority of patients succumb to H. pylori infection-associated GC due to metastasis. Mesenchymal stem cells (MSCs), which have multipotent differentiation potential, may be recruited into the tumor-associated stroma. MSCs are crucial components of the H. pylori infection-associated GC microenvironment, and may be critical for GC cell migration. In this study, an MSCs/H. pylori co-culture model was designed, and the effect of H. pylori-infected MSCs on the migration of GC cells was evaluated using a Transwell migration assay. H. pylori-infected MSC cytokine expression was evaluated using Luminex/ELISA. The expression of epithelial-mesenchymal transition (EMT) markers in the GC cells treated with supernatants from H. pylori-infected MSCs were detected by western blot analysis. The results demonstrated that the interaction between MSCs and H. pylori may induce GC cell migration, through secretion of a combination of cytokines that promote EMT in GC cells. The expression of phosphorylated forms of nuclear factor-κB (NF-κB) was observed to be increased in MSCs by H. pylori. Inhibition of NF-κB activation by pyrrolidine dithiocarbamate blocked the effects of H. pylori-infected MSCs on SGC-7901 human stomach adenocarcinoma cell migration. Overall, the results of the present study suggest that H. pylori-infected MSCs acquire a pro-inflammatory phenotype through secretion of a combination of multiple cytokines, a number of which are NF-κB-dependent. These cytokines enhance H. pylori infection-associated GC cell migration by promoting EMT in GC cells. The results of the present study provide novel evidence for the modulatory effect of MSCs in the tumor microenvironment and provide insight into the significance of stromal cell involvement in GC progression

  19. Efficacy of clorsulon for treatment of mature naturally acquired and 8-week-old experimentally induced Fasciola hepatica infections in cattle.

    PubMed

    Malone, J B; Ramsey, R T; Loyacano, A F

    1984-05-01

    In a dose-titration study against experimentally induced 8-week-old Fasciola hepatica infection (study A), 20 calves were allotted to 5 groups, each of 4 calves, and treated with different doses of an injectable formulation of clorsulon or its vehicle: group 1--controls, no drug; group 2--2 mg of clorsulon /kg; group 3--4 mg of drug/kg; group 4--8 mg/kg; and group 5--16 mg/kg. Mean numbers of flukes recovered from 4 calves in each treatment group were as follows: group 1--112.2, group 2--42, group 3--4.8, group 4--3.0, and group 5--0.2. Percentages of fluke reductions for groups 2, 3, 4, and 5 ( clorsulon -treated) calves were 62.6%, 95.7%, 97.3%, and 99.8%, respectively. Against naturally acquired mature (greater than 14-week-old) F hepatica infections (study B), a total of 161 flukes were recovered from 7 vehicle-treated control calves (group 6; mean fluke recovery = 23) and no flukes were recovered from 9 calves (group 7) given orally a formulation containing 7 mg of clorsulon /kg of body weight. Eggs were not found in the feces of clorsulon -treated calves at 20 to 21 days after treatment as compared with a mean of 7.4 eggs per gram (epg) in group 6 (control) calves. Mean bile egg recoveries were 13,532 (456 to 66,861) from group 6 calves as compared to recovery of a total of 162 (0 to 160) eggs from 3 of the 9 treated calves.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6732013

  20. Activated protein C promotes neuroprotection: mechanisms and translation to the clinic.

    PubMed

    Griffin, John H; Fernández, José A; Lyden, Patrick D; Zlokovic, Berislav V

    2016-05-01

    Activated protein C (APC) is a plasma serine protease that is capable of antithrombotic, anti-inflammatory, anti-apoptotic, and cell-signaling activities. Animal injury studies show that recombinant APC and some of its mutants are remarkably therapeutic for a wide range of injuries. In particular, for neurologic injuries, APC reduces damage caused by ischemia/reperfusion in the brain, by acute brain trauma, and by chronic neurodegenerative conditions. For these neuroprotective effects, APC requires endothelial cell protein C receptor. APC activates cell signaling networks with alterations in gene expression profiles by activating protease activated receptors 1 and 3. To minimize APC-induced bleeding risk, APC variants were engineered to lack > 90% anticoagulant activity but retain normal cell signaling. The neuroprotective APC mutant, 3K3A-APC which has Lys191-193 mutated to Ala191-193, is very neuroprotective and it is currently in clinical trials for ischemic stroke. PMID:27207428

  1. Zonarol, a sesquiterpene from the brown algae Dictyopteris undulata, provides neuroprotection by activating the Nrf2/ARE pathway

    PubMed Central

    Shimizu, Hiroya; Koyama, Tomoyuki; Yamada, Sohsuke; Lipton, Stuart A.; Satoh, Takumi

    2015-01-01

    Seaweed-origin electrophilic compounds are proposed as a class of neuroprotective compounds that provide neuroprotection through activation of the Nrf2/ARE pathway. Electrophilic hydroquinones are of particular interest due to their ability to become electrophilic quinones upon auto-oxidation. Although many marine plants produce a variety of electrophilic compounds, the detailed mechanism of action of these compounds remain unknown. Here, we focused on the neuroprotective effects of zonarol (ZO), a para-hydroquinone-type pro-electrophilic compound from the brown algae Dictyopteris undulata. We show that ZO activates the Nrf2/ARE pathway, induces phase-2 enzymes, and protects neuronal cells from oxidative stress. ZO is the first example of a neuroprotective pro-electrophilic compound obtained from brown algae. PMID:25623531

  2. Neuroprotective Activity of (-)-Epigallocatechin Gallate against Lipopolysaccharide-Mediated Cytotoxicity.

    PubMed

    Liu, Jin-Biao; Zhou, Li; Wang, Yi-Zhong; Wang, Xu; Zhou, Yu; Ho, Wen-Zhe; Li, Jie-Liang

    2016-01-01

    Lipopolysaccharide- (LPS-) mediated systemic inflammation plays a critical role in neurodegenerative diseases. The present study was conducted to evaluate the protective effects of epigallocatechin gallate (EGCG), the major component in green tea, on LPS-mediated inflammation and neurotoxicity. LPS treatment of macrophages induced expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). However, EGCG pretreatment of macrophages significantly inhibited LPS-mediated induction of these cytokines. In addition, EGCG significantly diminished LPS-induced inflammatory cytokines in the peripheral mononuclear blood cells (PBMCs). Supernatant from EGCG-pretreated and LPS-activated macrophage cultures was found to be less cytotoxic to neurons than that from non-EGCG-pretreated and LPS-activated macrophage cultures. Furthermore, EGCG treatment of neurons could inhibit LPS-induced production of reactive oxygen species (ROS). Thus EGCG represents a potent and useful neuroprotective agent for inflammation-mediated neurological disorders. PMID:27191001

  3. Electrical stimulation and tinnitus: neuroplasticity, neuromodulation, neuroprotection.

    PubMed

    Abraham, Shulman; Barbara, Goldstein; Arnold, Strashun

    2013-01-01

    Neuroplasticity (NPL), neuromodulation (NM), and neuroprotection (NPT) are ongoing biophysiological processes that are linked together in sensory systems, the goal being the maintenance of a homeostasis of normal sensory function in the central nervous system. It is hypothesized that when the balance between excitatory - inhibitory action is broken in sensory systems, predominantly due to neuromodulatory activity with reduced induced inhibition and excitation predominates, sensory circuits become plastic with adaptation at synaptic levels to environmental inputs(1). Tinnitus an aberrant auditory sensation, for all clinical types, is clinically considered to reflect a failure of NPL, NM, and NPT to maintain normal auditory function at synaptic levels in sensory cortex and projected to downstream levels in the central auditory system in brain and sensorineural elements in ear. Clinically, the tinnitus sensation becomes behaviorally manifest with varying degrees of annoyance, reflecting a principle of sensory physiology that each sensation has components, i.e. sensory, affect/behavior, psychomotor and memory. Modalities of tinnitus therapies, eg instrumentation, pharmacology, surgery, target a particular component of tinnitus, with resultant activation of neuromodulators at multiple neuromodulatory centers in brain and ear. Effective neuromodulation at sensory neuronal synaptic levels results in NPL in sensory cortex, NPT and tinnitus relief. Functional brain imaging, metabolic (PET brain) and electrophysiology quantitative electroencephalography (QEEG) data in a cochlear implant soft failure patient demonstrates what is clinically considered to reflect NPL, NM, NPT. The reader is provided with a rationale for tinnitus diagnosis and treatment, with a focus on ES, reflecting the biology underlying NPL, NM, NPT. PMID:24995902

  4. Neuroprotective effects of Withania somnifera dunal.: A possible mechanism.

    PubMed

    Bhatnagar, Maheep; Sharma, Durgesh; Salvi, Mahendra

    2009-11-01

    Present study was carried out to understand the possible mechanism of neuroprotective action of the root extract of Withania somnifera Dunal (WS). The study is focused on WS mediated inhibition of nitric oxide production, which is known to mediate neurodegeneration during stress. Adult mice (28 +/- 5 g) were exposed to restraint stress for 30 days. Activity of NADPH diaphorase (NADPH-d) and factors (Acetylcholine, serotonin and corticosterone), which regulates NADPH-d activity were studied. Treatment with WS extract for 30 days during stress, significantly reversed the stress induced NADPH-d activation. Observations suggest that inhibition of NADPH-d by WS is not a direct effect of extract on NADPH-d, instead it inhibits via suppressing corticosterone release and activating cholineacetyltransferase, which in turn increase serotonin level in hippocampus to inhibit NADPH-d. Together, the main mechanism underlying the neuroprotective effects of WS can be attributed to its role in the down regulation of nNOS and neurochemical alterations of specific neurotransmitter systems. These observations thus suggest that WS root extract could be developed as a potential preventive or therapeutic drug for stress induced neurological disorders. PMID:19444606

  5. Pharmacological treatment of laser eye injuries by neuroprotection

    NASA Astrophysics Data System (ADS)

    Solberg, Yoram; Rosner, Mordechai; Belkin, Michael

    1996-04-01

    Many retinal injuries result in an irreversible neuronal loss, which can not yet be reduced by pharmacological methods. To determine whether glutamate-receptor blockers can serve as neuroprotective agents in the retina, as they do in the central nervous system, we examined the effects of MK-801, an NMDA-receptor antagonist, on laser-induced retinal injury in a rat model. Immediately and 8 h after argon laser retinal photocoagulation, rats were treated with intraperitoneal injections of MK-801 (3 mg/kg) or saline. After 3, 20 or 60 days the animals were sacrificed and their retinal lesions were evaluated histologically and morphometrically. Photoreceptor cell loss, both immediately and up to 2 months after laser irradiation, was significantly smaller in MK-801-treated rats than controls. MK-801 exhibits neuroprotective property in the retina. This points to the involvement of glutamate in the laser-induced retinal neuronal damage. Glutamate-receptor blockers should be further investigated for therapy of retinal diseases characterized by neuronal cell destruction.

  6. Neurotropic and neuroprotective activities of the earthworm peptide Lumbricusin.

    PubMed

    Kim, Dae Hong; Lee, Ik Hwan; Nam, Seung Taek; Hong, Ji; Zhang, Peng; Hwang, Jae Sam; Seok, Heon; Choi, Hyemin; Lee, Dong Gun; Kim, Jae Il; Kim, Ho

    2014-06-01

    We recently isolated a polypeptide from the earthworm Lumbricus terrestris that is structurally similar to defensin, a well-known antibacterial peptide. An 11-mer antibacterial peptide (NH2-RNRRWCIDQQA), designated Lumbricusin, was synthesized based on the amino acid sequence of the isolated polypeptide. Since we previously reported that CopA3, a dung beetle peptide, enhanced neuronal cell proliferation, we here examined whether Lumbricusin exerted neurotropic and/or neuroprotective effects. Lumbricusin treatment induced a time-dependent increase (∼51%) in the proliferation of human neuroblastoma SH-SY5Y cells. Lumbricusin also significantly inhibited the apoptosis and decreased viability induced by treatment with 6-hydroxy dopamine, a Parkinson's disease-mimicking agent. Immunoblot analyses revealed that Lumbricusin treatment increased ubiquitination of p27(Kip1) protein, a negative regulator of cell-cycle progression, in SH-SY5Y cells, and markedly promoted its degradation. Notably, adenoviral-mediated over-expression of p27(Kip1) significantly blocked the antiapoptotic effect of Lumbricusin in 6-hydroxy dopamine-treated SH-SY5Y cells. These results suggest that promotion of p27(Kip1) degradation may be the main mechanism underlying the neuroprotective and neurotropic effects of Lumbricusin. PMID:24796676

  7. Synthesis and biological evaluation of aryloxyacetamide derivatives as neuroprotective agents.

    PubMed

    Zhong, Yan; Xu, Yi; Zhang, Ai-Xia; Li, Xiao-Feng; Xu, Zhao-Ying; Li, Ping; Wu, Bin

    2016-05-15

    A series of new aryloxyacetamide derivatives 10a-s and 14a-m are designed and synthesized. Their protective activities against the glutamate-induced cell death were investigated in differentiated rat pheochromocytoma cells (PC12 cells). Most compounds exhibited neuroprotective effects, especially for 10m, 10r, 14b and 14c, which showed potential protection of PC12 cells at three doses (0.1, 1.0, 10μM). MTT assay, Hoechst 33342/PI double staining, and high content screening (HCS) revealed that pretreatment of the cells with 10m, 10r, 14b and 14c has significantly decreased the extent of cell apoptosis in a dose-dependent manner. The results of western blot analysis demonstrated these compounds suppressed apoptosis of glutamate-induced PC12 cells via caspase-3 pathway. These compounds can be lead compounds for further discovery of neuroprotective agents for treating cerebral ischemic stroke. Basic structure-activity relationships are also presented. PMID:27038495

  8. Neuroprotective Mechanisms of Taurine against Ischemic Stroke

    PubMed Central

    Menzie, Janet; Prentice, Howard; Wu, Jang-Yen

    2013-01-01

    Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions. It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect. Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology. In this review, we describe the neuroprotective mechanisms employed by taurine against ischemic stroke and its use in clinical trial for ischemic stroke. PMID:24961429

  9. Neuroprotection in Stroke: Past, Present, and Future

    PubMed Central

    Majid, Arshad

    2014-01-01

    Stroke is a devastating medical condition, killing millions of people each year and causing serious injury to many more. Despite advances in treatment, there is still little that can be done to prevent stroke-related brain damage. The concept of neuroprotection is a source of considerable interest in the search for novel therapies that have the potential to preserve brain tissue and improve overall outcome. Key points of intervention have been identified in many of the processes that are the source of damage to the brain after stroke, and numerous treatment strategies designed to exploit them have been developed. In this review, potential targets of neuroprotection in stroke are discussed, as well as the various treatments that have been targeted against them. In addition, a summary of recent progress in clinical trials of neuroprotective agents in stroke is provided. PMID:24579051

  10. Epigenetics and therapeutic targets mediating neuroprotection.

    PubMed

    Qureshi, Irfan A; Mehler, Mark F

    2015-12-01

    The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. This article is part of a Special Issue entitled SI: Neuroprotection. PMID:26236020

  11. Wine Polyphenols: Potential Agents in Neuroprotection

    PubMed Central

    Basli, Abdelkader; Soulet, Stéphanie; Chaher, Nassima; Mérillon, Jean-Michel; Chibane, Mohamed; Monti, Jean-Pierre; Richard, Tristan

    2012-01-01

    There are numerous studies indicating that a moderate consumption of red wine provides certain health benefits, such as the protection against neurodegenerative diseases. This protective effect is most likely due to the presence of phenolic compounds in wine. Wine polyphenolic compounds are well known for the antioxidant properties. Oxidative stress is involved in many forms of cellular and molecular deterioration. This damage can lead to cell death and various neurodegenerative disorders, such as Parkinson's or Alzheimer's diseases. Extensive investigations have been undertaken to determine the neuroprotective effects of wine-related polyphenols. In this review we present the neuroprotective abilities of the major classes of wine-related polyphenols. PMID:22829964

  12. SIRT1 Activation Confers Neuroprotection in Experimental Optic Neuritis

    PubMed Central

    Shindler, Kenneth S.; Ventura, Elvira; Rex, Tonia S.; Elliott, Peter; Rostami, Abdolmohamad

    2007-01-01

    Purpose Axonal damage and loss of neurons correlate with permanent vision loss and neurologic disability in patients with optic neuritis and multiple sclerosis (MS). Current therapies involve immunomodulation, with limited effects on neuronal damage. The authors examined potential neuroprotective effects in optic neuritis by SRT647 and SRT501, two structurally and mechanistically distinct activators of SIRT1, an enzyme involved in cellular stress resistance and survival. Methods Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, was induced by immunization with proteolipid protein peptide in SJL/J mice. Optic neuritis developed in two thirds of eyes with significant retinal ganglion cell (RGC) loss detected 14 days after immunization. RGCs were labeled in a retrograde fashion with fluorogold by injection into superior colliculi. Optic neuritis was detected by inflammatory cell infiltration of the optic nerve. Results Intravitreal injection of SIRT1 activators 0, 3, 7, and 11 days after immunization significantly attenuated RGC loss in a dose-dependent manner. This neuroprotective effect was blocked by sirtinol, a SIRT1 inhibitor. Treatment with either SIRT1 activator did not prevent EAE or optic nerve inflammation. A single dose of SRT501 on day 11 was sufficient to limit RGC loss and to preserve axon function. Conclusions SIRT1 activators provide an important potential therapy to prevent the neuronal damage that leads to permanent neurologic disability in optic neuritis and MS patients. Intravitreal administration of SIRT1 activators does not suppress inflammation in this model, suggesting that their neuroprotective effects will be additive or synergistic with current immunomodulatory therapies. PMID:17652729

  13. Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

    PubMed

    Sun, Bao-liang; He, Mei-qing; Han, Xiang-yu; Sun, Jing-yi; Yang, Ming-feng; Yuan, Hui; Fan, Cun-dong; Zhang, Shuai; Mao, Lei-lei; Li, Da-wei; Zhang, Zong-yong; Zheng, Cheng-bi; Yang, Xiao-yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic. PMID:25432887

  14. Effects of Vinpocetine on mitochondrial function and neuroprotection in primary cortical neurons.

    PubMed

    Tárnok, K; Kiss, E; Luiten, P G M; Nyakas, C; Tihanyi, K; Schlett, K; Eisel, U L M

    2008-12-01

    Vinpocetine (ethyl apovincaminate), a synthetic derivative of the Vinca minor alkaloid vincamine, is widely used for the treatment of cerebrovascular-related diseases. One of the proposed mechanisms underlying its action is to protect against the cytotoxic effects of glutamate overexposure. Glutamate excitotoxicity leads to the disregulation of mitochondrial function and neuronal metabolism. As Vinpocetine has a binding affinity to the peripheral-type benzodiazepine receptor (PBR) involved in the mitochondrial transition pore complex, we investigated whether neuroprotection can be at least partially due to Vinpocetine's effects on PBRs. Neuroprotective effects of PK11195 and Ro5-4864, two drugs with selective and high affinity to PBR, were compared to Vinpocetine in glutamate excitotoxicity assays on primary cortical neuronal cultures. Vinpocetine exerted a neuroprotective action in a 1-50microM concentration range while PK11195 and Ro5-4864 were only slightly neuroprotective, especially in high (>25microM) concentrations. Combined pretreatment of neuronal cultures with Vinpocetine and PK11195 or Ro5-4864 showed increased neuroprotection in a dose-dependent manner, indicating that the different drugs may have different targets. To test this hypothesis, mitochondrial membrane potential (MMP) of cultured neurons was measured by flow cytometry. 25microM Vinpocetine reduced the decrease of mitochondrial inner membrane potential induced by glutamate exposure, but Ro5-4864 in itself was found to be more potent to block glutamate-evoked changes in MMP. Combination of Ro5-4864 and Vinpocetine treatment was found to be even more effective. In summary, the present results indicate that the neuroprotective action of vinpocetine in culture can not be explained by its effect on neuronal PBRs alone and that additional drug targets are involved. PMID:18793690

  15. Mutant Erythropoietin without Erythropoietic Activity is Neuroprotective against Ischemic Brain Injury

    PubMed Central

    Gan, Yu; Xing, Juan; Jing, Zheng; Stetler, R. Anne; Zhang, Feng; Luo, Yumin; Ji, Xunmin; Gao, Yanqin; Cao, Guodong

    2012-01-01

    Background and Purpose Erythropoietin (EPO) confers potent neuroprotection against ischemic injury. However, treatment for stroke requires high doses and multiple administrations of EPO, which may cause deleterious side effects due to its erythropoietic activity. This study identifies a novel non-erythropoietic mutant EPO (MEPO) and investigates its potential neuroprotective effects and underlying mechanism in animal model of cerebral ischemia. Methods We constructed a series of MEPOs, each containing a single amino acid mutation within the erythropoietic motif, and tested their erythropoietic activity. Using cortical neuronal cultures exposed to NMDA neurotoxicity and a murine model of transient middle cerebral artery occlusion (MCAO), neuroprotection and neurofunctional outcomes were assessed as well as activation of intracellular signaling pathways. Results The serine to isoleucine mutation at position 104 (S104I-EPO) completely abolished the erythropoietic and platelet-stimulating activity of EPO. Administration of S104I-EPO significantly inhibited NMDA-induced neuronal death in primary cultures, and protected against cerebral infarction and neurological deficits with an efficacy similar to that of wild-type EPO. Both S104I-EPO and wild-type EPO activated similar pro-survival signaling pathways, such as PI3K/AKT, MAPK/ERK1/2 and STAT5. Inhibition of PI3K/AKT or MAPK/ERK1/2 signaling pathways significantly attenuated the neuroprotective effects of S104I-EPO, indicating that activation of these pathways underlies the neuroprotective mechanism of MEPO against cerebral ischemia. Conclusions S104I-EPO confers neuroprotective effects comparable to those of wild-type EPO against ischemic brain injury, with the added benefit of lacking erythropoietic and platelet-stimulating side effects. Our novel findings suggest that the non-erythropoietic mutant EPO is a legitimate candidate for ischemic stroke intervention. PMID:22984011

  16. Erythropoietin: still on the neuroprotection road

    PubMed Central

    del Barco, Diana García; Coro-Antich, Rosa M.

    2012-01-01

    Acute stroke is one of the major causes of death and disabilities. Since the 1980s many clinical studies have been conducted to evaluate neuroprotective approaches to treat this important brain vascular event. However, to date the only drug approved (recombinant tissue plasminogen activator [rtPA]) represents a thrombolytic, nonneuroprotective approach. An important neuroprotective strategy is based on erythropoietin (EPO). Exogenously administered EPO exhibits neuroprotective effects in numerous animal models, through the activation of anti-apoptotic, anti-oxidant and anti-inflammatory pathways as well as through the stimulation of angiogenic and neurogenic events. The capability of EPO to cross the blood–brain barrier after systemic administration and its effective therapeutic window are advantages for human acute stroke therapy. However, a multicenter stroke trial where recombinant human EPO (rhEPO) was combined with rtPA had negative outcomes. The present paper reviews the EPO neuroprotective strategy and its mechanisms in ischemic stroke and in other human nervous system diseases. PMID:22590480

  17. NAP (davunetide) provides functional and structural neuroprotection.

    PubMed

    Gozes, Illana

    2011-01-01

    NAP (davunetide) is an eight amino acid peptide (NAPVSIPQ) that has been shown to provide potent neuroprotection, in vitro and in vivo. In human clinical trials, NAP has been shown to increase memory scores in patients suffering from amnestic mild cognitive impairment, a precursor to Alzheimer's disease and to enhance functional daily behaviors in schizophrenia patients. NAP is derived from activity-dependent neuroprotective protein (ADNP) a molecule that is essential for brain formation, interacting with chromatin associated protein alpha and the chromatin remodeling complex SWI/SNF and regulating >400 genes during embryonic development. Partial loss in ADNP results in cognitive deficits and pathology of the microtubule associated protein tau (tauopathy) that is ameliorated in part by NAP replacement therapy. Recent studies increased the scope of NAP neuroprotection and provided further insights into the NAP mechanisms of action. Thus, it has been hypothesized that the presence of tau on axonal microtubules renders them notably less sensitive to the microtubule-severing protein katanin, and NAP was shown to protect microtubules from katanin disruption in the face of reduced tau expression. Parallel studies showed that NAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate or both PI-3K/Akt and MAPK/MEK1 kinases in the white matter. The interaction of these disparate yet complementary pathways is the subject of future studies toward human brain neuroprotection in the clinical scenario. PMID:21524250

  18. Neuroprotective Effect of Combination Therapy of Glatiramer Acetate and Epigallocatechin-3-Gallate in Neuroinflammation

    PubMed Central

    Hentschel, Nicole; Infante-Duarte, Carmen; Aktas, Orhan; Zipp, Frauke

    2011-01-01

    Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. However, studies of MS and the animal model, experimental autoimmune encephalomyelitis (EAE), indicate that neuronal pathology is the principle cause of clinical disability. Thus, there is need to develop new therapeutic strategies that not only address immunomodulation but also neuroprotection. Here we show that the combination therapy of Glatiramer acetate (GA), an immunomodulatory MS therapeutic, and the neuroprotectant epigallocatechin-3-gallate (EGCG), the main phenol in green tea, have synergistic protective effects in vitro and in the EAE model. EGCG and GA together led to increased protection from glutamate- and TRAIL-induced neuronal cell death in vitro. EGCG combined with GA induced regeneration of hippocampal axons in an outgrowth assay. The combined application of EGCG and GA did not result in unexpected adverse events in vivo. Neuroprotective and neuroregenerative effects could be translated in the in vivo model, where combination treatment with EGCG and GA significantly delayed disease onset, strongly reduced clinical severity, even after onset of symptoms and reduced inflammatory infiltrates. These results illustrate the promise of combining neuroprotective and anti-inflammatory treatments and strengthen the prospects of EGCG as an adjunct therapy for neuroinflammatory and neurodegenerative diseases. PMID:22022398

  19. Neuroprotective effects of rutaecarpine on cerebral ischemia reperfusion injury

    PubMed Central

    Yan, Chunlin; Zhang, Ji; Wang, Shu; Xue, Guiping; Hou, Yong

    2013-01-01

    Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia reperfusion injury. Because both cardiovascular and cerebrovascular diseases are forms of ischemic vascular disease, they are closely related. We hypothesized that rutaecarpine also has neuroprotective effects on cerebral ischemia reperfusion injury. A cerebral ischemia reperfusion model was established after 84, 252 and 504 μg/kg carpine were given to mice via intraperitoneal injection, daily for 7 days. Results of the step through test, 2,3,5-triphenyl tetrazolium chloride dyeing and oxidative stress indicators showed that rutaecarpine could improve learning and memory ability, neurological symptoms and reduce infarction volume and cerebral water content in mice with cerebral ischemia reperfusion injury. Rutaecarpine could significantly decrease the malondialdehyde content and increase the activities of superoxide dismutase and glutathione peroxidase in mouse brain. Therefore, rutaecarpine could improve neurological function following injury induced by cerebral ischemia reperfusion, and the mechanism of this improvement may be associated with oxidative stress. These results verify that rutaecarpine has neuroprotective effects on cerebral ischemia reperfusion in mice. PMID:25206511

  20. Neuroprotective effects of adenosine deaminase in the striatum.

    PubMed

    Tamura, Risa; Ohta, Hiroyuki; Satoh, Yasushi; Nonoyama, Shigeaki; Nishida, Yasuhiro; Nibuya, Masashi

    2016-04-01

    Adenosine deaminase (ADA) is a ubiquitous enzyme that catabolizes adenosine and deoxyadenosine. During cerebral ischemia, extracellular adenosine levels increase acutely and adenosine deaminase catabolizes the increased levels of adenosine. Since adenosine is a known neuroprotective agent, adenosine deaminase was thought to have a negative effect during ischemia. In this study, however, we demonstrate that adenosine deaminase has substantial neuroprotective effects in the striatum, which is especially vulnerable during cerebral ischemia. We used temporary oxygen/glucose deprivation (OGD) to simulate ischemia in rat corticostriatal brain slices. We used field potentials as the primary measure of neuronal damage. For stable and efficient electrophysiological assessment, we used transgenic rats expressing channelrhodopsin-2, which depolarizes neurons in response to blue light. Time courses of electrically evoked striatal field potential (eFP) and optogenetically evoked striatal field potential (optFP) were recorded during and after oxygen/glucose deprivation. The levels of both eFP and optFP decreased after 10 min of oxygen/glucose deprivation. Bath-application of 10 µg/ml adenosine deaminase during oxygen/glucose deprivation significantly attenuated the oxygen/glucose deprivation-induced reduction in levels of eFP and optFP. The number of injured cells decreased significantly, and western blot analysis indicated a significant decrease of autophagic signaling in the adenosine deaminase-treated oxygen/glucose deprivation slices. These results indicate that adenosine deaminase has protective effects in the striatum. PMID:26746865

  1. Neuroprotective and Cytotoxic Phthalides from Angelicae Sinensis Radix.

    PubMed

    Gong, Wenxia; Zhou, Yuzhi; Li, Xiao; Gao, Xiaoxia; Tian, Junsheng; Qin, Xuemei; Du, Guanhua

    2016-01-01

    Seven phthalides, including a new dimeric one named tokinolide C (7), were isolated from Angelicae Sinensis Radix and characterized. The structures of these compounds were elucidated on the basis of comprehensive analysis of spectroscopic data and comparison with literature data. All of the compounds were evaluated for their cytotoxic activities against the A549, HCT-8, and HepG2 cancer cell lines. Riligustilide (4) showed cytotoxicity against three cancer cell lines, with IC50 values of 13.82, 6.79, and 7.92 μM, respectively. Tokinolide A (6) and tokinolide C (6) exerted low cytotoxicity in these cancer cell lines, while the remaining compounds were inactive. Flow cytometry analysis was employed to evaluate the possible mechanism of cytotoxic action of riligustilide (4). We observed that compound 4 was able to arrest the cell cycle in the G1, S phases and induce apoptosis in a time-dependent manner in HCT-8 cell lines. In addition, these compounds were evaluated for neuroprotective effect against SH-SY5Y cells injured by glutamate. The result showed that ligustilide (1), Z-butylidenephthalide (3) and tokinolide A (6) exhibited significant neuroprotective effects. PMID:27128890

  2. Neuroprotective Effect of Radix Trichosanthis Saponins on Subarachnoid Hemorrhage

    PubMed Central

    Chen, Ying; Sun, Haiyan; Huang, Liyong; Li, Juxiang; Zhou, Wenke; Chang, Jingling

    2015-01-01

    Redox homeostasis has been implicated in subarachnoid hemorrhage (SAH). As a result, antioxidants and/or free radical scavengers have become an important therapeutic modality. Considering that radix trichosanthis (RT) saponins exhibited strong antioxidant ability both in vivo and in vitro, the present study aimed to reveal whether the neuroprotective activities of RT saponins were mediated by p38/p53 signal pathway after SAH. An established SAH model was used and superoxide dismutase (SOD), malondialdehyde (MDA), induced nitric oxide synthase (iNOS), nitric oxide (NO), lactate dehydrogenase (LDH), p-p38, and p53 activation were detected after 48 h of SAH. The results showed that RT saponins inhibited iNOS expression to restore NO to basal level. Moreover, compared with Cu/Zn-SOD, RT saponins (2 mg/kg/d dosage) significantly increased Mn-SOD activity after SAH. Accompanied with lowered NO and elevated SOD, decreased p38 phosphorylation and p53 activities were observed, especially for RT saponins at 2 mg/kg/d dosage. In this setting, the neurological outcome was also improved with less neuronal cells damage after RT saponins pretreatment. Our findings demonstrated the beneficial effects of RT saponins in enhancing neuroprotective effects by deducing iNOS activity, normalizing SOD level, and inhibiting p-p38 and p53 expression, hence offering significant therapeutic implications for SAH. PMID:26089937

  3. Prolactin mediates neuroprotection against excitotoxicity in primary cell cultures of hippocampal neurons via its receptor.

    PubMed

    Vergara-Castañeda, E; Grattan, D R; Pasantes-Morales, H; Pérez-Domínguez, M; Cabrera-Reyes, E A; Morales, T; Cerbón, M

    2016-04-01

    Recently it has been reported that prolactin (PRL) exerts a neuroprotective effect against excitotoxicity in hippocampus in the rat in vivo models. However, the exact mechanism by which PRL mediates this effect is not completely understood. The aim of our study was to assess whether prolactin exerts neuroprotection against excitotoxicity in an in vitro model using primary cell cultures of hippocampal neurons, and to determine whether this effect is mediated via the prolactin receptor (PRLR). Primary cell cultures of rat hippocampal neurons were used in all experiments, gene expression was evaluated by RT-qPCR, and protein expression was assessed by Western blot analysis and immunocytochemistry. Cell viability was assessed by using the MTT method. The results demonstrated that PRL treatment of neurons from primary cultures did not modify cell viability, but that it exerted a neuroprotective effect, with cells treated with PRL showing a significant increase of viability after glutamate (Glu)--induced excitotoxicity as compared with neurons treated with Glu alone. Cultured neurons expressed mRNA for both PRL and its receptor (PRLR), and both PRL and PRLR expression levels changed after the excitotoxic insult. Interestingly, the PRLR protein was detected as two main isoforms of 100 and 40 kDa as compared with that expressed in hypothalamic cells, which was present only as a 30 kDa variant. On the other hand, PRL was not detected in neuron cultures, either by western blot or by immunohistochemistry. Neuroprotection induced by PRL was significantly blocked by specific oligonucleotides against PRLR, thus suggesting that the PRL role is mediated by its receptor expressed in these neurons. The overall results indicated that PRL induces neuroprotection in neurons from primary cell cultures. PMID:26874070

  4. Progress in Neuroprotective Strategies for Preventing Epilepsy

    PubMed Central

    Acharya, Munjal M.; Hattiangady, Bharathi; Shetty, Ashok K.

    2008-01-01

    Neuroprotection is increasingly considered as a promising therapy for preventing and treating temporal lobe epilepsy (TLE). The development of chronic TLE, also termed as epileptogenesis, is a dynamic process. An initial precipitating injury (IPI) such as the status epilepticus (SE) leads to neurodegeneration, abnormal reorganization of the brain circuitry and a significant loss of functional inhibition. All of these changes likely contribute to the development of chronic epilepsy, characterized by spontaneous recurrent motor seizures (SRMS) and learning and memory deficits. The purpose of this review is to discuss the current state of knowledge pertaining to neuroprotection in epileptic conditions, and to highlight the efficacy of distinct neuroprotective strategies for preventing or treating chronic TLE. Although the administration of certain conventional and new generation antiepileptic drugs is effective for primary neuroprotection such as reduced neurodegeneration after acute seizures or the SE, their competence for preventing the development of chronic epilepsy after an IPI is either unknown or not promising. On the other hand, alternative strategies such as the ketogenic diet therapy, administration of distinct neurotrophic factors, hormones or antioxidants seem useful for preventing and treating chronic TLE. However, long term studies on the efficacy of these approaches introduced at different time-points after the SE or an IPI are lacking. Additionally, grafting of fetal hippocampal cells at early time-points after an IPI holds considerable promise for preventing TLE, though issues regarding availability of donor cells, ethical concerns, timing of grafting after SE, and durability of graft-mediated seizure suppression need to be resolved for further advances with this approach. Overall, from the studies performed so far, there is consensus that neuroprotective strategies need to be employed as quickly as possible after the onset of the SE or an IPI for

  5. Acquired reactive perforating collagenosis.

    PubMed

    Basak, P Y; Turkmen, C

    2001-01-01

    Acquired perforating disorder has been recognized as an uncommon distinct dermatosis in which altered collagen is eliminated through the epidermis. Several disorders accompanied by itching and scratching were reported to be associated with reactive perforating collagenosis. A 67-year-old white woman diagnosed as acquired reactive perforating collagenosis with poorly controlled diabetes mellitus and congestive cardiac failure is presented. PMID:11525959

  6. The vitamin D receptor and inducible nitric oxide synthase associated pathways in the development of acquired resistance to Cooperia oncophora infection in cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cooperia oncophora is an economically important gastrointestinal nematode in ruminants. Acquired resistance to Cooperia oncophora infection in cattle develops rapidly resulting from prior infections. Naïve cattle, when given a primary infection of high-dose infective L3 larvae, develop a strong immu...

  7. Adenosine A3 receptor activation is neuroprotective against retinal neurodegeneration.

    PubMed

    Galvao, Joana; Elvas, Filipe; Martins, Tiago; Cordeiro, M Francesca; Ambrósio, António Francisco; Santiago, Ana Raquel

    2015-11-01

    Death of retinal neural cells, namely retinal ganglion cells (RGCs), is a characteristic of several retinal neurodegenerative diseases. Although the role of adenosine A3 receptor (A3R) in neuroprotection is controversial, A3R activation has been reported to afford protection against several brain insults, with few studies in the retina. In vitro models (retinal neural and organotypic cultures) and animal models [ischemia-reperfusion (I-R) and partial optic nerve transection (pONT)] were used to study the neuroprotective properties of A3R activation against retinal neurodegeneration. The A3R selective agonist (2-Cl-IB-MECA, 1 μM) prevented apoptosis (TUNEL(+)-cells) induced by kainate and cyclothiazide (KA + CTZ) in retinal neural cultures (86.5 ± 7.4 and 37.2 ± 6.1 TUNEL(+)-cells/field, in KA + CTZ and KA + CTZ + 2-Cl-IB-MECA, respectively). In retinal organotypic cultures, 2-Cl-IB-MECA attenuated NMDA-induced cell death, assessed by TUNEL (17.3 ± 2.3 and 8.3 ± 1.2 TUNEL(+)-cells/mm(2) in NMDA and NMDA+2-Cl-IB-MECA, respectively) and PI incorporation (ratio DIV4/DIV2 3.3 ± 0.3 and 1.3 ± 0.1 in NMDA and NMDA+2-Cl-IB-MECA, respectively) assays. Intravitreal 2-Cl-IB-MECA administration afforded protection against I-R injury decreasing the number of TUNEL(+) cells by 72%, and increased RGC survival by 57%. Also, intravitreal administration of 2-Cl-IB-MECA inhibited apoptosis (from 449.4 ± 37.8 to 207.6 ± 48.9 annexin-V(+)-cells) and RGC loss (from 1.2 ± 0.6 to 8.1 ± 1.7 cells/mm) induced by pONT. This study demonstrates that 2-Cl-IB-MECA is neuroprotective to the retina, both in vitro and in vivo. Activation of A3R may have great potential in the management of retinal neurodegenerative diseases characterized by RGC death, as glaucoma and diabetic retinopathy, and ischemic diseases. PMID:26297614

  8. Neuroprotective effect of the endogenous neural peptide apelin in cultured mouse cortical neurons

    SciTech Connect

    Zeng, Xiang Jun; Yu, Shan Ping; Zhang, Like; Wei, Ling

    2010-07-01

    The adipocytokine apelin and its G protein-coupled APJ receptor were initially isolated from a bovine stomach and have been detected in the brain and cardiovascular system. Recent studies suggest that apelin can protect cardiomyocytes from ischemic injury. Here, we investigated the effect of apelin on apoptosis in mouse primary cultures of cortical neurons. Exposure of the cortical cultures to a serum-free medium for 24 h induced nuclear fragmentation and apoptotic death; apelin-13 (1.0-5.0 nM) markedly prevented the neuronal apoptosis. Apelin neuroprotective effects were mediated by multiple mechanisms. Apelin-13 reduced serum deprivation (SD)-induced ROS generation, mitochondria depolarization, cytochrome c release and activation of caspase-3. Apelin-13 prevented SD-induced changes in phosphorylation status of Akt and ERK1/2. In addition, apelin-13 attenuated NMDA-induced intracellular Ca{sup 2+} accumulation. These results indicate that apelin is an endogenous neuroprotective adipocytokine that may block apoptosis and excitotoxic death via cellular and molecular mechanisms. It is suggested that apelins may be further explored as a potential neuroprotective reagent for ischemia-induced brain damage.

  9. 4'-Chlorodiazepam is neuroprotective against amyloid-beta through the modulation of survivin and bax protein expression in vitro.

    PubMed

    Arbo, B D; Marques, C V; Ruiz-Palmero, I; Ortiz-Rodriguez, A; Ghorbanpoor, S; Arevalo, M A; Garcia-Segura, L M; Ribeiro, M F

    2016-02-01

    The translocator protein of 18kDa (TSPO) is located in the outer mitochondrial membrane and is involved in the cholesterol transport into the mitochondria and in the regulation of steroidogenesis, mitochondrial permeability transition pore opening and apoptosis. TSPO ligands have been investigated as therapeutic agents that promote neuroprotective effects in experimental models of brain injury and neurodegenerative diseases. The aim of this study was to identify the neuroprotective effects of 4'-chlorodiazepam (4'-CD), a ligand of TSPO, against amyloid-beta (Aβ) in SHSY-5Y neuroblastoma cells and its mechanisms of action. Aβ decreased the viability of SHSY-5Y neuroblastoma cells, while 4'-CD had a neuroprotective effect at the doses of 1nM and 10nM. The neuroprotective effects of 4'-CD against Aβ were associated with the inhibition of Aβ-induced upregulation of Bax and downregulation of survivin. In summary, our findings indicate that 4'-CD is neuroprotective against Aβ-induced neurotoxicity by a mechanism that may involve the regulation of Bax and survivin expression. PMID:26707976

  10. Increased BDNF protein expression after ischemic or PKC epsilon preconditioning promotes electrophysiologic changes that lead to neuroprotection

    PubMed Central

    Neumann, Jake T; Thompson, John W; Raval, Ami P; Cohan, Charles H; Koronowski, Kevin B; Perez-Pinzon, Miguel A

    2015-01-01

    Ischemic preconditioning (IPC) via protein kinase C epsilon (PKCɛ) activation induces neuroprotection against lethal ischemia. Brain-derived neurotrophic factor (BDNF) is a pro-survival signaling molecule that modulates synaptic plasticity and neurogenesis. Interestingly, BDNF mRNA expression increases after IPC. In this study, we investigated whether IPC or pharmacological preconditioning (PKCɛ activation) promoted BDNF-induced neuroprotection, if neuroprotection by IPC or PKCɛ activation altered neuronal excitability, and whether these changes were BDNF-mediated. We used both in vitro (hippocampal organotypic cultures and cortical neuronal-glial cocultures) and in vivo (acute hippocampal slices 48 hours after preconditioning) models of IPC or PKCɛ activation. BDNF protein expression increased 24 to 48 hours after preconditioning, where inhibition of the BDNF Trk receptors abolished neuroprotection against oxygen and glucose deprivation (OGD) in vitro. In addition, there was a significant decrease in neuronal firing frequency and increase in threshold potential 48 hours after preconditioning in vivo, where this threshold modulation was dependent on BDNF activation of Trk receptors in excitatory cortical neurons. In addition, 48 hours after PKCɛ activation in vivo, the onset of anoxic depolarization during OGD was significantly delayed in hippocampal slices. Overall, these results suggest that after IPC or PKCɛ activation, there are BDNF-dependent electrophysiologic modifications that lead to neuroprotection. PMID:25370861

  11. The alteration of components in the fermented Hwangryunhaedok-tang and its neuroprotective activity

    PubMed Central

    Yang, Hye Jin; Weon, Jin Bae; Lee, Bohyoung; Ma, Choong Je

    2011-01-01

    Background: Hwangryunhaedok-tang is a traditional herbal prescription that has sedative activity, hypotensive and anti-bacterial effects. Objective: In this study, we investigated the alteration of contents of components in Hwangryunhaedok-tang, antioxidant activity and neuroprotective activity by fermentation with Lactobacillus acidophilus KFRI 128. Materials and Methods: Contents of three marker compounds (geniposide, berberine and palmatine) and unknown compounds in the Hwangryunhaedok-tang (HR) and the fermented Hwangryunhaedok-tang (FHR) were measured and compared using the established high-performance liqued chromatograph coupled with a photodiode (HPLC-DAD) method. The antioxidant activity of HR and FHR were determined by DPPH free radical and hydrogen peroxide (H2O2) scavenging assay. Also, the neuroprotective activities of HR and FHR against glutamate-induced oxidative stress in a mouse hippocampal cell line (HT22) were evaluated by MTT assay. Results: The contents of geniposide and palmatine were decreased but the content of berberine was increased in the FHR. And the contents of unknown compounds (1), (2), (3), (4) and (5) in the HR were altered by fermentation. Electron donating activity (EDA, %) value of FHR was higher than HR for DPPH radical scavenging activity and H2O2 scavenging activity, respectively. In the MTT assay, FHR showed more potent neuroprotective activity than HR by 513.90%. Conclusion: The FHR using microorganism could convert compounds in HR and enhance the antioxidant and neuroprotective activity. PMID:21969791

  12. Striatal Pleiotrophin Overexpression Provides Functional and Morphological Neuroprotection in the 6-Hydroxydopamine Model

    PubMed Central

    Gombash, Sara E; Lipton, Jack W; Collier, Timothy J; Madhavan, Lalitha; Steece-Collier, Kathy; Cole-Strauss, Allyson; Terpstra, Brian T; Spieles-Engemann, Anne L; Daley, Brian F; Wohlgenant, Susan L; Thompson, Valerie B; Manfredsson, Fredric P; Mandel, Ronald J; Sortwell, Caryl E

    2012-01-01

    Neurotrophic factors are integrally involved in the development of the nigrostriatal system and in combination with gene therapy, possess great therapeutic potential for Parkinson's disease (PD). Pleiotrophin (PTN) is involved in the development, maintenance, and repair of the nigrostriatal dopamine (DA) system. The present study examined the ability of striatal PTN overexpression, delivered via psueudotyped recombinant adeno-associated virus type 2/1 (rAAV2/1), to provide neuroprotection and functional restoration from 6-hydroxydopamine (6-OHDA). Striatal PTN overexpression led to significant neuroprotection of tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) and THir neurite density in the striatum, with long-term PTN overexpression producing recovery from 6-OHDA-induced deficits in contralateral forelimb use. Transduced striatal PTN levels were increased threefold compared to adult striatal PTN expression and approximated peak endogenous developmental levels (P1). rAAV2/1 vector exclusively transduced neurons within the striatum and SNpc with approximately half the total striatal volume routinely transduced using our injection parameters. Our results indicate that striatal PTN overexpression can provide neuroprotection for the 6-OHDA lesioned nigrostriatal system based upon morphological and functional measures and that striatal PTN levels similar in magnitude to those expressed in the striatum during development are sufficient to provide neuroprotection from Parkinsonian insult. PMID:22008908

  13. Neuroprotective effects of citicoline in in vitro models of retinal neurodegeneration.

    PubMed

    Matteucci, Andrea; Varano, Monica; Gaddini, Lucia; Mallozzi, Cinzia; Villa, Marika; Pricci, Flavia; Malchiodi-Albedi, Fiorella

    2014-01-01

    In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 µM) and analyzed in terms of apoptosis and caspase activation and characterized by immunocytochemistry to identify neuronal and glial cells. Subsequently, excitotoxic concentration of glutamate or High Glucose-containing cell culture medium (HG) was administered as well-known conditions modeling neurodegeneration. Glutamate or HG treatments were performed in the presence or not of citicoline. Neuronal degeneration was evaluated in terms of apoptosis and loss of synapses. The results showed that citicoline did not cause any damage to the retinal neuroglial population up to 1000 µM. At the concentration of 100 µM, it was able to counteract neuronal cell damage both in glutamate- and HG-treated retinal cultures by decreasing proapoptotic effects and contrasting synapse loss. These data confirm that citicoline can efficiently exert a neuroprotective activity. In addition, the results suggest that primary retinal cultures, under conditions inducing neurodegeneration, may represent a useful system to investigate citicoline neuroprotective mechanisms. PMID:24736780

  14. Modulation of morphological changes of microglia and neuroprotection by monocyte chemoattractant protein-1 in experimental glaucoma

    PubMed Central

    Chiu, Kin; Yeung, Sze-Chun; So, Kwok-Fai; Chang, Raymond Chuen-Chung

    2010-01-01

    Monocyte chemoattractant protein-1 (MCP-1)/CCL2 is a C–C chemokine involved in the activation and recruitment of monocytic cells to injury sites. MCP-1/CCL2 can induce either neuroprotection or neurodestruction in vitro, depending on the experimental model. We aim to use MCP-1/CCL2 as an experimental tool to investigate the morphological changes of microglia when loss of healthy retinal ganglion cells (RGCs) is exacerbated or attenuated in an experimental glaucoma model. While a high concentration (1000 ng) of MCP-1/CCL2 and lipopolysaccharide (LPS)-exacerbated RGC loss, 100 ng MCP-1/CCL2 provided neuroprotection towards RGC. Neuroprotective MCP-1/CCL2 (100 ng) also upregulated insulin-like growth factor-1 (IGF-1) immunoreactivity in the RGCs. The neuroprotective effect of MCP-1/CCL2 was not due to the massive infiltration of microglia/macrophages. Taken together, this is the first report showing that an appropriate amount of MCP-1/CCL2 can protect RGCs in experimental glaucoma. PMID:20081877

  15. Neuroactive gonadal drugs for neuroprotection in male and female models of Parkinson's disease.

    PubMed

    Litim, Nadhir; Morissette, Marc; Di Paolo, Thérèse

    2016-08-01

    The existence of sex differences in Parkinson's disease (PD) incidence is well documented with greater prevalence and earlier age at onset in men than in women. These reported sex differences could be related to estrogen exposure. In PD animal models, estrogen is well documented to be neuroprotective against dopaminergic neuron loss induced by neurotoxins. Using the 1-methyl 4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) mouse model, we showed that several compounds are neuroprotective on dopaminergic neurons including estrogen, the selective estrogen receptor modulator raloxifene, progesterone, dehydroepiandrosterone, the estrogen receptor alpha (ERα) agonist PPT as well as the G protein-coupled membrane estrogen receptor (GPER1) specific agonist G1. Accumulating evidence suggests that GPER1 could be implicated in the neuroprotective effects of estrogen, raloxifene and G1 in collaboration with ERα. We recently reported that the 5α-reductase inhibitor Dutasteride is also neuroprotective and could bring an alternative to estrogens for therapy in male. Additional studies are needed to optimize therapies with these gonadal drugs into safe personalized treatments according to sex for treatment of PD. PMID:26708712

  16. The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia

    PubMed Central

    Choy, Fong Chan; Klarić, Thomas S.; Koblar, Simon A.; Lewis, Martin D.

    2015-01-01

    Stroke is one of the leading causes of death and adult disability in the world. Although many molecules have been documented to have a neuroprotective effect, the majority of these molecules failed to improve the neurological outcomes for patients with brain ischemia. It has been proposed that neuroprotection alone may, in fact, not be adequate for improving the prognosis of ischemic stroke. Neuroprotectants that can regulate other processes which occur in the brain during ischemia could potentially be targets for the development of effective therapeutic interventions in stroke. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischemia. It has been shown that Npas4 plays an important role in protecting neurons against many types of neurodegenerative insult. Recently, it was demonstrated that Npas4 indeed has a neuroprotective role in ischemic stroke and that Npas4 might be involved in modulating the cell death pathway and inflammatory response. In this review, we summarize the current knowledge of the roles that Npas4 may play in neuroinflammation and ischemia. Understanding how ischemic lesion size in stroke may be reduced through modulation of Npas4-dependent apoptotic and inflammatory pathways could lead to the development of new stroke therapies. PMID:26690124

  17. Acquired Cystic Kidney Disease

    MedlinePlus

    ... a kidney transplant or blood-filtering treatments called dialysis. The cysts are more likely to develop in people who are on kidney dialysis. The chance of developing acquired cystic kidney disease ...

  18. Hospital-acquired pneumonia

    MedlinePlus

    ... tends to be more serious than other lung infections because: People in the hospital are often very sick and cannot fight off ... prevent pneumonia. Most hospitals have programs to prevent hospital-acquired infections.

  19. Current perspective of neuroprotection and glaucoma

    PubMed Central

    Tian, Kailin; Shibata-Germanos, Shannon; Pahlitzsch, Milena; Cordeiro, M Francesca

    2015-01-01

    Glaucoma is the second leading cause of blindness worldwide and is most notably characterized by progressive optic nerve atrophy and advancing loss of retinal ganglion cells (RGCs). The main concomitant factor is the elevated intraocular pressure (IOP). Existing treatments are focused generally on lowering IOP. However, both RGC loss and optic nerve atrophy can independently occur with IOP at normal levels. In recent years, there has been substantial progress in the development of neuroprotective therapies for glaucoma in order to restore vital visual function. The present review intends to offer a brief insight into conventional glaucoma treatments and discuss exciting current developments of mostly preclinical data in novel neuroprotective strategies for glaucoma that include recent advances in noninvasive diagnostics going beyond IOP maintenance for an enhanced global view. Such strategies now target RGC loss and optic nerve damage, opening a critical therapeutic window for preventative monitoring and treatment. PMID:26635467

  20. Exosomes: Mediators of Neurodegeneration, Neuroprotection and Therapeutics

    PubMed Central

    Kalani, Anuradha; Tyagi, Alka

    2014-01-01

    Exosomes have emerged as prominent mediators of neurodegenerative diseases where they have been shown to carry disease particles such as beta amyloid and prions from their cells of origin to other cells. Their simple structure and ability to cross the blood-brain barrier allow great opportunity to design a “makeup” with drugs and genetic elements, such as siRNA or miRNA, and use them as delivery vehicles for neurotherapeutics. Their role in neuroprotection is evident by the fact that they are involved in the regeneration of peripheral nerves and repair of neuronal injuries. This review is focused on the role of exosomes in mediating neurodegeneration and neuroprotection. PMID:23999871

  1. Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy

    PubMed Central

    Dixon, Brandon J.; Reis, Cesar; Ho, Wing Mann; Tang, Jiping; Zhang, John H.

    2015-01-01

    Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating disease that primarily causes neuronal and white matter injury and is among the leading cause of death among infants. Currently there are no well-established treatments; thus, it is important to understand the pathophysiology of the disease and elucidate complications that are creating a gap between basic science and clinical translation. In the development of neuroprotective strategies and translation of experimental results in HIE, there are many limitations and challenges to master based on an appropriate study design, drug delivery properties, dosage, and use in neonates. We will identify understudied targets after HIE, as well as neuroprotective molecules that bring hope to future treatments such as melatonin, topiramate, xenon, interferon-beta, stem cell transplantation. This review will also discuss some of the most recent trials being conducted in the clinical setting and evaluate what directions are needed in the future. PMID:26389893

  2. Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy.

    PubMed

    Dixon, Brandon J; Reis, Cesar; Ho, Wing Mann; Tang, Jiping; Zhang, John H

    2015-01-01

    Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating disease that primarily causes neuronal and white matter injury and is among the leading cause of death among infants. Currently there are no well-established treatments; thus, it is important to understand the pathophysiology of the disease and elucidate complications that are creating a gap between basic science and clinical translation. In the development of neuroprotective strategies and translation of experimental results in HIE, there are many limitations and challenges to master based on an appropriate study design, drug delivery properties, dosage, and use in neonates. We will identify understudied targets after HIE, as well as neuroprotective molecules that bring hope to future treatments such as melatonin, topiramate, xenon, interferon-beta, stem cell transplantation. This review will also discuss some of the most recent trials being conducted in the clinical setting and evaluate what directions are needed in the future. PMID:26389893

  3. Perspectives of drug-based neuroprotection targeting mitochondria.

    PubMed

    Procaccio, V; Bris, C; Chao de la Barca, J M; Oca, F; Chevrollier, A; Amati-Bonneau, P; Bonneau, D; Reynier, P

    2014-05-01

    Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet. PMID:24792485

  4. Neuritogenic and neuroprotective activities of fruit residues.

    PubMed

    Tadtong, Sarin; Kanlayavattanakul, Mayuree; Lourith, Nattaya

    2013-11-01

    Neuritogenic and neuroprotective activities of litchi (Litchi chinensis Sonn., Sapindaceae) and salacca (Salacca edulis Reinw., Arecaceae) pericarp, and sapodilla (Achras sapota L., Sapotaceae) and tamarind Srichompu cultivar (Tamarindus indica L., Caesalpiniaceae) seed coat extracts were evaluated on cultured cholinergic P19-derived neurons. All the extracts, at a very low concentration (1 ng/mL of litchi and salacca pericarp extracts, 10 ng/mL of sapodilla and 100 ng/mL of tamarind seed coat extracts), enhanced the survival of cultured neurons (% viability more than 100%) by XTT reduction assay. The extracts were further evaluated for their neuritogenicity by observing cell morphology by phase-contrast microscopy and neuroprotective activity in serum deprivation and pre- and co-administration of hydrogen peroxide models. The phase-contrast micrographs displayed that all of the extracts possessed neurogenic activity by promoting the neurite outgrowth of the cultured neurons. Moreover, these extracts can protect neurons from oxidative stress-caused cell death in a serum deprivation model, and prevent and protect neuron cells from the toxicity of hydrogen peroxide. In this study we assured that the neuritogenic and neuroprotective activities of these extracts derived from the phenolic components and flavonoids contained in the extracts by acting as signaling molecules to enhance neuron survival and promote neurite outgrowth. These results suggest that all of the extracts are potentially sources of neuritogenic and neuroprotective components which might be used either as pharmaceutical products or dietary supplements for neurodegenerative disorder patients, for example, those suffering from Alzheimer's disease. PMID:24427947

  5. Polyphenols and neuroprotection against ischemia and neurodegeneration.

    PubMed

    Lin, B

    2011-12-01

    Neuroprotection of polyphenols in medical plants is getting attention in the world. Scutellaria baicalensis, paeonia veitchii and paeonia suffruticosa have been extensively studied in the last 10 years and show multi-function. They are neuroprotectants, antioxidants, anti-inflammatory and antithrombic agents as well as vasoconstriction inhibitors and amyloid-peptide (Aβ) cleaners by means of their polyphenols: baicalin, baicalein, wogonin (in scutellaria), and paeonol, paeonoside, paeoniflorin (PF) and 1, 2, 3, 4, 6-Penta-O-galloyl-beta-D-glucose (PGG) (in paeonia veitchii and paeonia suffruticosa). Other 4 medical plants: astragali, ligusticum wallichii, angelica sinensis and carthamus tinctorius (saffron) have been the major medicines to treat ischemia for hundreds of years in China, Korea and Japan. Our recent experimental studies demonstrated the neuroprotective efficacy of the combination of these phyotmedicines on mitigating brain infarction and global ischemia as well as preventing the neurodegeneration following ischemia. Owing to their multi-function, including improving cerebral blood circulation, they therefore have the potential to alleviate the symptoms of degenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD). Pharmacology of the 7 herbs and their major relative polyphenols is depicted in the article. PMID:22070681

  6. Ginseng: a promising neuroprotective strategy in stroke

    PubMed Central

    Rastogi, Vaibhav; Santiago-Moreno, Juan; Doré, Sylvain

    2015-01-01

    Ginseng is one of the most widely used herbal medicines in the world. It has been used in the treatment of various ailments and to boost immunity for centuries; especially in Asian countries. The most common ginseng variant in traditional herbal medicine is ginseng, which is made from the peeled and dried root of Panax Ginseng. Ginseng has been suggested as an effective treatment for a vast array of neurological disorders, including stroke and other acute and chronic neurodegenerative disorders. Ginseng’s neuroprotective effects are focused on the maintenance of homeostasis. This review involves a comprehensive literature search that highlights aspects of ginseng’s putative neuroprotective effectiveness, focusing on stroke. Attenuation of inflammation through inhibition of various proinflammatory mediators, along with suppression of oxidative stress by various mechanisms, including activation of the cytoprotective transcriptional factor Nrf2, which results in decrease in reactive oxygen species, could account for its neuroprotective efficacy. It can also prevent neuronal death as a result of stroke, thus decreasing anatomical and functional stroke damage. Although there are diverse studies that have investigated the mechanisms involved in the efficacy of ginseng in treating disorders, there is still much that needs to be clarified. Both in vitro and in vivo studies including randomized controlled clinical trials are necessary to develop in-depth knowledge of ginseng and its practical applications. PMID:25653588

  7. Long non-coding RNA UCA1 induces non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway in EGFR-mutant non-small cell lung cancer

    PubMed Central

    Ren, Shengxiang; Li, Xuefei; Wang, Qi; Pan, Hui; Zhao, Mingchuan; Li, Jiayu; Zhang, Yishi; Zhao, Chao; Chen, Xiaoxia; Fei, Ke; Zhou, Caicun; Hirsch, Fred R.

    2015-01-01

    The aim of this study was to explore the role of long non-coding RNA UCA1 (urothelial cancer-associated 1) in acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). In our study, UCA1 expression was significantly increased in lung cancer cells and patients with acquired resistance to EGFR-TKIs. Over-expression of UCA1 was significantly associated with a shorter progression-free survival (PFS) [13.0 vs. 8.5 months, P < 0.01] in tumors with respond to EGFR-TKIs. The significant relationship was not observed in patients with T790M mutation (10.5 vs. 12.0 months, P = 0.778), but in patients with non-T790M (19.0 vs. 9.0 months, P = 0.023). UCA1 knockdown restored gefitinib sensitivity in acquired resistant cells with non-T790M and inhibited the activation of the AKT/mTOR pathway and epithelial-mesenchymal transition (EMT). The mTOR inhibitor was effective in UCA1-expressing cell PC9/R. Inhibiting mTOR could change the expression of UCA1, although there was no significant difference. In conclusion, the influence of over-expression of UCA1 on PFS for patients with acquired resistance to EGFR-TKIs was from the subgroup with non-T790M mutation. UCA1 may induce non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway and EMT. PMID:26160838

  8. JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation.

    PubMed

    Harada, Daijiro; Takigawa, Nagio; Ochi, Nobuaki; Ninomiya, Takashi; Yasugi, Masayuki; Kubo, Toshio; Takeda, Hiromasa; Ichihara, Eiki; Ohashi, Kadoaki; Takata, Saburo; Tanimoto, Mitsune; Kiura, Katsuyuki

    2012-10-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 6-12 months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 3-12 h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance. PMID:22712764

  9. Neuroprotection For Huntington’s Disease: Ready, Set, Slow

    PubMed Central

    Hersch, Steven M.; Rosas, H. Diana

    2008-01-01

    Summary The ultimate goal for Huntington’s disease (HD) is to develop disease-modifying neuroprotective therapies able to delay or prevent illness in those who are at genetic risk and able to slow progression in those who are affected clinically. Neuroprotection is the preservation of neuronal structure, function, and viability and neuroprotective therapy is thus targeted at the underlying pathology of HD, rather than at its specific symptoms. Preclinical target discovery research in HD is identifying numerous distinct targets and options for modulating them with some proceeding into large-scale efficacy studies in early symptomatic HD subjects. The first pilot studies of neuroprotective compounds in premanifest HD are also soon to begin. This review discusses the opportunities for neuroprotection in HD, clinical methodology in premanifest and manifest HD, the clinical assessment of neuroprotection, molecular targets and therapeutic leads, and the current state of clinical development. PMID:18394565

  10. EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines.

    PubMed

    Kim, Sung-Moo; Kim, Hwan; Jang, Kang Won; Kim, Min Hwan; Sohn, Jinyoung; Yun, Mi Ran; Kang, Han Na; Kang, Chan Woo; Kim, Hye Ryun; Lim, Sun Min; Moon, Yong Wha; Kim, Joo Hang; Paik, Soonmyung; Cho, Byoung Chul

    2016-07-01

    Although treatment of BRAF V600E-mutant non-small cell lung cancer (NSCLC(V600E)) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLC(V600E), we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLC(V600E) to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR-RAS-CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436. Treatment of GSR cells with GSK2118436 enhanced EGFR-mediated RAS activity, leading to the formation of BRAF-CRAF dimers and transactivation of CRAF. Interestingly, sustained activation of ERK1/2 was partly dependent on receptor-interacting protein kinase-2 (RIP2) activity, but not on MEK1/2 activity. Combined BRAF and EGFR inhibition blocked reactivation of ERK signaling and improved efficacy in vitro and in vivo Our findings support the evaluation of combined BRAF and EGFR inhibition in NSCLC(V600E) with acquired resistance to BRAF inhibitors. Mol Cancer Ther; 15(7); 1627-36. ©2016 AACR. PMID:27196768

  11. Carbamylated Erythropoietin: A Prospective Drug Candidate for Neuroprotection

    PubMed Central

    Chen, Jianmin; Yang, Zheng; Zhang, Xiao

    2015-01-01

    Carbamylated erythropoietin (cEpo), which is neuroprotective but lacks hematopoietic activity, has been attracting rising concerns. However, the cellular and molecular mechanisms involved in the process of neuroprotection of cEpo are not well known. Based on several recent reports, the neuroprotective effects of cEpo are illustrated, and signaling pathways involved in the different effects of erythropoietin and cEpo are discussed. These newly reported researches may shed new light on the development and application of cEpo, a prospective drug candidate for neuroprotection. PMID:26862298

  12. Community-acquired pneumonia.

    PubMed

    Falguera, M; Ramírez, M F

    2015-11-01

    This article not only reviews the essential aspects of community-acquired pneumonia for daily clinical practice, but also highlights the controversial issues and provides the newest available information. Community-acquired pneumonia is considered in a broad sense, without excluding certain variants that, in recent years, a number of authors have managed to delineate, such as healthcare-associated pneumonia. The latter form is nothing more than the same disease that affects more frail patients, with a greater number of risk factors, both sharing an overall common approach. PMID:26186969

  13. Anticonvulsant and neuroprotective effects of Pimpinella anisum in rat brain

    PubMed Central

    2012-01-01

    Background Essential oil of Pimpinella anisum L. Apiaceae (anise oil) has been widely used in traditional Persian medicine to treat a variety of diseases, including some neurological disorders. This study was aimed to test the possible anti-seizure and anti-hypoxia effects of anise oil. Methods The effects of different concentrations of anise oil were tested on seizure attacks induced by pentylenetetrazol (PTZ) injection and neuronal hypoxia induced by oxygen withdrawal as well as on production of dark neurons and induction of long-term potentiation (LTP) in in vivo and in vitro experimental models of rat brain. Results Anise oil significantly prolonged the latency of seizure attacks and reduced the amplitude and duration of epileptiform burst discharges induced by injection of intraperitoneal PTZ. In addition, anise oil significantly inhibited production of dark neurons in different regions of the brain in epileptic rats. Anise oil also significantly enhanced the duration of the appearance of anoxic terminal negativity induced by oxygen withdrawal and inhibited induction of LTP in hippocampal slices. Conclusions Our data indicate the anticonvulsant and neuroprotective effects of anise oil, likely via inhibition of synaptic plasticity. Further evaluation of anise oil to use in the treatment of neurological disorders is suggested. PMID:22709243

  14. Neuroprotective and anti-inflammatory effects of morin in a murine model of Parkinson's disease.

    PubMed

    Lee, Kyung Moon; Lee, Yujeong; Chun, Hye Jeong; Kim, Ah Hyun; Kim, Ju Yeon; Lee, Joo Yeon; Ishigami, Akihito; Lee, Jaewon

    2016-10-01

    Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that oxidative stress, mitochondrial dysfunction, and inflammation are associated with its pathogenesis. Morin (3,5,7,2',4'-pentahydroxyflavone) is a flavonol found in wine and many herbs and fruits. Previous studies have suggested that morin prevents oxidative damage and inflammation and ameliorates mitochondrial dysfunction. The present study describes the neuroprotective effects of morin in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, and we report the results of our investigation into its neuroprotective mechanism in primary neurons and astrocytes. In the mouse model, morin pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in SN and striatum, and alleviated MPTP-induced astrocyte activation. In vitro studies revealed that morin protected primary cultured neurons against 1-methyl-4-phenylpyridine (MPP(+) )-mediated reactive oxygen species production and mitochondrial membrane potential (MMP) disruption. In addition, morin effectively reduced MPP(+) -induced astroglial activation and nuclear translocation of nuclear factor-κB in primary cultured astrocytes. These results indicate that morin acts via multiple neuroprotective mechanisms in our mouse model and suggest that morin be viewed as a potential treatment and preventative for PD. © 2016 Wiley Periodicals, Inc. PMID:27265894

  15. Preclinical anticonvulsant and neuroprotective profile of 8319, a non-competitive NMDA antagonist

    SciTech Connect

    Fielding, S.; Wilker, J.C.; Chernack, J.; Ramirez, V.; Wilmot, C.A.; Martin, L.L.; Payack, J.F.; Cornfeldt, M.L.; Rudolphi, K.A.; Rush, D.K. )

    1990-01-01

    8319, ((+-)-2-Amino-N-ethyl-alpha- (3-methyl-2-thienyl) benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced (3H) TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia.

  16. Distinct roles of N-acetyl and 5-methoxy groups in the antiproliferative and neuroprotective effects of melatonin.

    PubMed

    Letra-Vilela, Ricardo; Sánchez-Sánchez, Ana María; Rocha, Ana Maia; Martin, Vanesa; Branco-Santos, Joana; Puente-Moncada, Noelia; Santa-Marta, Mariana; Outeiro, Tiago Fleming; Antolín, Isaac; Rodriguez, Carmen; Herrera, Federico

    2016-10-15

    Melatonin (N-acetyl-5-methoxytryptamine) is a highly pleiotropic hormone with antioxidant, antiproliferative, oncolytic and neuroprotective properties. Here, we present evidence that the N-acetyl side chain plays a key role in melatonin's antiproliferative effect in HT22 and sw-1353 cells, but it does so at the expense of antioxidant and neuroprotective properties. Removal of the N-acetyl group enhances the antioxidant and neuroprotective properties of the indole, but it can lead to toxic methamphetamine-like effects in several cell lines. Inhibition of NFkB mimicked melatonin's antiproliferative and antioxidant effects, but not neuroprotection. Our results strongly suggest that neuroprotective and antiproliferative effects of melatonin rely on different parts of the molecule and are likely mediated by different mechanisms. We also predict that melatonin metabolism by target cells could determine whether melatonin inhibits cell proliferation, prevents toxicity or induces cell death (e.g. apoptosis or autophagy). These observations could have important implications for the rational use of melatonin in personalized medicine. PMID:27402602

  17. Neuroprotective effects of (E)-3,4-diacetoxystyryl sulfone and sulfoxide derivatives in vitro models of Parkinson's disease.

    PubMed

    Ning, Xianling; Yuan, Mengmeng; Guo, Ying; Tian, Chao; Wang, Xiaowei; Zhang, Zhili; Liu, Junyi

    2016-06-01

    (E)-3,4-dihydroxystyryl aralkyl sulfones and sulfoxides have been reported as novel multifunctional neuroprotective agents in previous studies, which as phenolic compounds display antioxidative and antineuroinflammatory properties. To further enhance the neuroprotective effects and study structure-activity relationship of the derivatives, we synthesized their acetylated derivatives, (E)-3,4-diacetoxystyryl sulfones and sulfoxides, and examined their neuroprotective effects in vitro models of Parkinson's disease. The results indicate that (E)-3,4-diacetoxystyryl sulfones and sulfoxides can significantly inhibit kinds of neuron cell injury induced by toxicities, including 6-OHDA, NO, and H2O2. More important, they show higher antineuroinflammatory properties and similar antioxidative properties to corresponding un-acetylated compounds. Thus, we suggest that (E)-3,4-diacetoxystyryl sulfones and sulfoxides may have potential for the treatment of neurodegenerative disorders, especially Parkinson's disease. PMID:26176683

  18. Neuroprotective effect of alkyl hydroxytyrosyl ethers in rat brain slices subjected to a hypoxia-reoxygenation model.

    PubMed

    Guerrero, A; De la Cruz, J P; Muñoz-Marín, J; López-Villodres, J A; Madrona, A; Espartero, J L; González-Correa, J A

    2012-10-15

    The aim of the present study was to investigate the antioxidant and possible neuroprotective and antioxidant effects of five alkyl hydroxytyrosyl (HT) ethers (ethyl, butyl, hexyl, octyl and dodecyl) in rat brain slices. None of the compounds modified lipid peroxidation or glutathione concentrations (GSH) in oxygenated samples. The effects of oxidative stress were investigated with ferrous salts to induce lipid peroxidation and diethylmaleate (DEM) to reduce GSH. All compounds inhibited lipid peroxidation with an inhibitory concentration 50% (IC(50)) one tenth that of HT. These compounds, especially the butyl derivative, prevented GSH depletion after incubation with DEM. We also explored the neuroprotective effect of these compounds in an experimental model of hypoxia-reoxygenation in rat brain slices. All compounds showed neuroprotective and antioxidant effects. Our results established a relationship between these effects and the length of the carbon chain (maximum effect in the range of C4-C8). PMID:23442672

  19. Acquired Brain Injury Program.

    ERIC Educational Resources Information Center

    Schwartz, Stacey Hunter

    This paper reviews the Acquired Brain Injury (ABI) Program at Coastline Community College (California). The ABI Program is a two-year, for-credit educational curriculum designed to provide structured cognitive retraining for adults who have sustained an ABI due to traumatic (such as motor vehicle accident or fall) or non-traumatic(such as…

  20. Acquired von Willebrand disease.

    PubMed

    Petrini, P

    1999-05-01

    Acquired von Willebrand disease (AvWD) is a syndrome that has clinical and laboratory features similar to hereditary vWD. In contrast to the latter it occurs in patients without a family history of previous bleeding tendency. PMID:23401904

  1. Pleiotropic neuroprotective and metabolic effects of Actovegin's mode of action.

    PubMed

    Machicao, Fausto; Muresanu, Dafin Fior; Hundsberger, Harald; Pflüger, Maren; Guekht, Alla

    2012-11-15

    This article reviews the mechanisms of action of Actovegin in the context of its preclinical effects and new concepts in the pharmacological treatment of neurological disorders. Actovegin is an ultrafiltrate of calf blood, composed of more than 200 biological substances. The drug is used for a broad spectrum of diseases, including disturbances of peripheral and cerebral blood circulation, burns, impaired wound healing, radiation-induced damage and diabetic polyneuropathy. Actovegin is composed of small molecules present under normal physiological conditions, therefore pharmacokinetic and pharmacodynamic studies to determine its active substance are not feasible. Preclinical data have revealed that it improves metabolic balance by increasing glucose uptake and improving oxygen uptake under conditions of ischemia. Actovegin also resists the effects of gamma-irradiation and stimulates wound healing. More recent preclinical studies have suggested that anti-oxidative and anti-apoptotic mechanisms of action specifically underlie the neuroprotective properties of Actovegin. The drug has been found to exert these beneficial effects experimentally, in primary rat hippocampal neurons and in an STZ-rat model of diabetic polyneuropathy, while also providing evidence that it positively affects the functional recovery of neurons. Latest data suggest that Actovegin also has a positive influence on the NF-κB pathway, but many molecular and cellular pathways remain unexplored. In particular, Actovegin's influence on neuroplasticity, neurogenesis and neurotrophicity are questions that ideally should be answered by future research. Nevertheless, it is clear that the multifactorial and complex nature of Actovegin underlies its pleiotropic neuroprotective mechanisms of action and positive effect on clinical outcomes. PMID:22910148

  2. In Vivo Therapeutic Gas Delivery for Neuroprotection with Echogenic Liposomes

    PubMed Central

    Britton, George L.; Kim, Hyunggun; Kee, Patrick H.; Aronowski, Jaroslaw; Holland, Christy K.; McPherson, David D.; Huang, Shao-Ling

    2010-01-01

    Background Ischemia-related neurologic injury is a primary cause of stroke disability. Studies have demonstrated that xenon (Xe) may have potential as an effective and nontoxic neuroprotectant. Xe delivery is, however, hampered by lack of suitable administration methods. We have developed a pressurization-freeze method to encapsulate Xe into echogenic liposomes (Xe-ELIP) and have modulated local gas release with transvascular ultrasound exposure. Methods and Results Fifteen microliters of Xe were encapsulated into each 1 mg of liposomes (70% Xe and 30% argon). Xe delivery from Xe-ELIP into cells and consequent neuroprotective effects were evaluated with oxygen-glucose deprived and control neuronal cells in vitro. Xe-ELIP were administered into Sprague-Dawley rats intravenously or intraarterially following right middle cerebral artery occlusion. 1-MHz low-amplitude (0.18 MPa) continuous wave ultrasound directed onto the internal carotid artery triggered Xe release from circulating Xe-ELIP. Effects of Xe delivery on ischemia-induced neurologic injury and disability were evaluated. Xe-ELIP delivery to oxygen-glucose deprived neuronal cells improved cell viability in vitro and 48% infarct volume decrease in vivo. Intravenous Xe-ELIP administration in combination with the ultrasound directed onto the carotid artery enhanced local Xe release from circulating Xe-ELIP and demonstrated 75% infarct volume reduction. This was comparable to the effect following intraarterial administration. Behavioral tests on limb placement and grid and beam walking correlated with infarct reduction. Conclusions This novel methodology may provide a noninvasive strategy for ultrasound-enhanced local therapeutic gas delivery for cerebral ischemia-related injury while minimizing systemic side effects. PMID:20921443

  3. Neuroprotective copper bis(thiosemicarbazonato) complexes promote neurite elongation.

    PubMed

    Bica, Laura; Liddell, Jeffrey R; Donnelly, Paul S; Duncan, Clare; Caragounis, Aphrodite; Volitakis, Irene; Paterson, Brett M; Cappai, Roberto; Grubman, Alexandra; Camakaris, James; Crouch, Peter J; White, Anthony R

    2014-01-01

    Abnormal biometal homeostasis is a central feature of many neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and motor neuron disease. Recent studies have shown that metal complexing compounds behaving as ionophores such as clioquinol and PBT2 have robust therapeutic activity in animal models of neurodegenerative disease; however, the mechanism of neuroprotective action remains unclear. These neuroprotective or neurogenerative processes may be related to the delivery or redistribution of biometals, such as copper and zinc, by metal ionophores. To investigate this further, we examined the effect of the bis(thiosemicarbazonato)-copper complex, Cu(II)(gtsm) on neuritogenesis and neurite elongation (neurogenerative outcomes) in PC12 neuronal-related cultures. We found that Cu(II)(gtsm) induced robust neurite elongation in PC12 cells when delivered at concentrations of 25 or 50 nM overnight. Analogous effects were observed with an alternative copper bis(thiosemicarbazonato) complex, Cu(II)(atsm), but at a higher concentration. Induction of neurite elongation by Cu(II)(gtsm) was restricted to neurites within the length range of 75-99 µm with a 2.3-fold increase in numbers of neurites in this length range with 50 nM Cu(II)(gtsm) treatment. The mechanism of neurogenerative action was investigated and revealed that Cu(II)(gtsm) inhibited cellular phosphatase activity. Treatment of cultures with 5 nM FK506 (calcineurin phosphatase inhibitor) resulted in analogous elongation of neurites compared to 50 nM Cu(II)(gtsm), suggesting a potential link between Cu(II)(gtsm)-mediated phosphatase inhibition and neurogenerative outcomes. PMID:24587210

  4. Prucalopride exerts neuroprotection in human enteric neurons.

    PubMed

    Bianco, Francesca; Bonora, Elena; Natarajan, Dipa; Vargiolu, Manuela; Thapar, Nikhil; Torresan, Francesco; Giancola, Fiorella; Boschetti, Elisa; Volta, Umberto; Bazzoli, Franco; Mazzoni, Maurizio; Seri, Marco; Clavenzani, Paolo; Stanghellini, Vincenzo; Sternini, Catia; De Giorgio, Roberto

    2016-05-15

    Serotonin (5-hydroxytryptamine, 5-HT) and its transporters and receptors are involved in a wide array of digestive functions. In particular, 5-HT4 receptors are known to mediate intestinal peristalsis and recent data in experimental animals have shown their role in neuronal maintenance and neurogenesis. This study has been designed to test whether prucalopride, a well-known full 5-HT4 agonist, exerts protective effects on neurons, including enteric neurons, exposed to oxidative stress challenge. Sulforhodamine B assay was used to determine the survival of SH-SY5Y cells, human enteric neurospheres, and ex vivo submucosal neurons following H2O2 exposure in the presence or absence of prucalopride (1 nM). Specificity of 5-HT4-mediated neuroprotection was established by experiments performed in the presence of GR113808, a 5-HT4 antagonist. Prucalopride exhibited a significant neuroprotective effect. SH-SY5Y cells pretreated with prucalopride were protected from the injury elicited by H2O2 as shown by increased survival (73.5 ± 0.1% of neuronal survival vs. 33.3 ± 0.1%, respectively; P < 0.0001) and a significant reduction of proapoptotic caspase-3 and caspase-9 activation in all neurons tested. The protective effect of prucalopride was reversed by the specific 5-HT4 antagonist GR113808. Prucalopride promotes a significant neuroprotection against oxidative-mediated proapoptotic mechanisms. Our data pave the way for novel therapeutic implications of full 5-HT4 agonists in gut dysmotility characterized by neuronal degeneration, which go beyond the well-known enterokinetic effect. PMID:26893157

  5. Synthesis and Evaluation of Neuroprotective Selenoflavanones

    PubMed Central

    Choi, Yong-Sung; Kim, Dong-Myung; Kim, Yoon-Jung; Yang, Sai; Lee, Kyung-Tae; Ryu, Jong Hoon; Jeong, Jin-Hyun

    2015-01-01

    The physicochemical properties and antioxidant activity of a molecule could be improved by the substitution of an oxygen atom in a molecule with selenium. We synthesized selenoflavanones and flavanones to evaluate their neuroprotective effects. The selenoflavanones showed improved physicochemical properties, suggestive of the ability to pass through the blood-brain barrier (BBB). They showed in vitro antioxidant effects against hydrogen peroxide, and did not result in severe cytotoxicity. Moreover, infarction volumes in a transient ischemia mouse model were significantly reduced by the selenoflavanone treatments. PMID:26690420

  6. Cerium and yttrium oxide nanoparticles are neuroprotective

    SciTech Connect

    Schubert, David . E-mail: schubert@salk.edu; Dargusch, Richard; Raitano, Joan; Chan, S.-W.

    2006-03-31

    The responses of cells exposed to nanoparticles have been studied with regard to toxicity, but very little attention has been paid to the possibility that some types of particles can protect cells from various forms of lethal stress. It is shown here that nanoparticles composed of cerium oxide or yttrium oxide protect nerve cells from oxidative stress and that the neuroprotection is independent of particle size. The ceria and yttria nanoparticles act as direct antioxidants to limit the amount of reactive oxygen species required to kill the cells. It follows that this group of nanoparticles could be used to modulate oxidative stress in biological systems.

  7. Acquired Resistance in Barley (The Resistance Mechanism Induced by 2,6-Dichloroisonicotinic Acid Is a Phenocopy of a Genetically Based Mechanism Governing Race-Specific Powdery Mildew Resistance).

    PubMed Central

    Kogel, K. H.; Beckhove, U.; Dreschers, J.; Munch, S.; Romme, Y.

    1994-01-01

    Treatment of susceptible barley (Hordeum vulgare) seedlings with 2,6-dichloroisonicotinic acid (DCINA) induces disease resistance against the powdery mildew fungus (Erysiphe graminis f. sp. hordei). A cytological analysis of the interaction reveals the hypersensitive cell collapse in attacked, short epidermal cells, along with the accumulation of fluorescent material in papillae, that appear at the time of fungal arrest. The cell-type-specific hypersensitive reaction occurs prior to formation of haustoria, reminiscent of the mechanism identified in genetically resistant barley plants containing the functionally active Mlg gene (R. Gorg, K. Hollricher, P. Schulze-Lefert [1993] Plant J 3: 857-866). This observation indicates that the mechanism of DCINA-induced resistance is a phenocopy of the mechanism governed by the Mlg locus. The onset of acquired resistance correlates with high-level transcript accumulation of barley defense-related genes encoding pathogenesis-related protein-1, peroxidase, and chitinase but not [beta]-1,3-glucanase. Subcellular localization of peroxidase activity shows an increase in enzyme activity in the epidermal cell layer and in the intercellular fluids of barley leaves. Four out of more than 10 identified extracellular isozymes are induced by DCINA. The epidermal cell layer contains a major constitutively formed isozyme, together with two isozymes specifically induced by DCINA. The data support the hypothesis that host cell death and high-level accumulation of defense-related gene transcripts are not only commonly controlled in certain types of race-specific resistance (A. Freialdenhoven, B. Scherag, K. Hollricher, D.B. Collinge, H. Thordal-Christensen, P. Schulze-Lefert [1994] Plant Cell 6: 983-994) but also in acquired resistance, which confers protection to a broad spectrum of different pathogens. PMID:12232407

  8. [Neuroprotective effects of peptides bioregulators in people of various age].

    PubMed

    Umnov, R S; Lin'kova, N S; Khavinson, V Kh

    2013-01-01

    The review presents comparative characteristics of 2 peptide neuroprotective groups: polypeptide complexes (cortexin, cerebrolizin) and short peptides (semax, kortagen, pinealon). The data of clinical applying of peptides in elderly and old age people and cellular and molecular mechanisms of their neuroprotective activity is described. PMID:24738258

  9. Intranasal pyrrolidine dithiocarbamate decreases brain inflammatory mediators and provides neuroprotection after brain hypoxia-ischemia in neonatal rats

    PubMed Central

    Wang, Zhi; Zhao, Huijuan; Peng, Shuling; Zuo, Zhiyi

    2013-01-01

    Brain injury due to birth asphyxia is the major cause of death and long-term disabilities in newborns. We determined whether intranasal pyrrolidine dithiocarbamate (PDTC) could provide neuroprotection in neonatal rats after brain hypoxia-ischemia (HI). Seven-day old male and female Sprague-Dawley rats were subjected to brain HI. They were then treated by intranasal PDTC. Neurological outcome were evaluated 7 or 30 days after the brain HI. Brain tissues were harvested 6 or 24 h after the brain HI for biochemical analysis. Here, PDTC dose-dependently reduced brain HI-induced brain tissue loss with an effective dose (ED)50 at 27 mg/kg. PDTC needed to be applied within 45 min after the brain HI for this neuroprotection. This treatment reduced brain tissue loss and improved neurological and cognitive functions assessed 30 days after the HI. PDTC attenuated brain HI-induced lipid oxidative stress, nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells, and various inflammatory mediators in the brain tissues. Inhibition of inducible nitric oxide synthase after brain HI reduced brain tissue loss. Our results suggest that intranasal PDTC provides neuroprotection possibly via re