Identification of proteins regulated by ferulic acid in a middle cerebral artery occlusion animal model-a proteomics approach.

PubMed

Sung, Jin-Hee; Cho, Eun-Hae; Cho, Jae-Hyeon; Won, Chung-Kil; Kim, Myeong-Ok; Koh, Phil-Ok

2012-11-01

Ferulic acid plays a neuroprotective role in cerebral ischemia. The aim of this study was to identify the proteins that are differentially expressed following ferulic acid treatment during ischemic brain injury using a proteomics technique. Middle cerebral artery occlusion (MCAO) was performed to induce a focal cerebral ischemic injury in adult male rats, and ferulic acid (100 mg/kg) or vehicle was administered immediately after MCAO. Brain tissues were collected 24 hr after MCAO. The proteins in the cerebral cortex were separated using two-dimensional gel electrophoresis and were identified by mass spectrometry. We detected differentially expressed proteins between vehicle- and ferulic acid-treated animals. Adenosylhomocysteinase, isocitrate dehydrogenase [NAD(+)], mitogen-activated protein kinase kinase 1 and glyceraldehyde-3-phosphate dehydrogenase were decreased in the vehicle-treated group, and ferulic acid prevented the injury-induced decreases in these proteins. However, pyridoxal phosphate phosphatase and heat shock protein 60 were increased in the vehicle-treated group, while ferulic acid prevented the injury-induced increase in these proteins. It is accepted that these enzymes are involved in cellular metabolism and differentiation. Thus, these findings suggest evidence that ferulic acid plays a neuroprotective role against focal cerebral ischemia through the up- and down-modulation of specific enzymes.

Magnolol Reduces Glutamate-Induced Neuronal Excitotoxicity and Protects against Permanent Focal Cerebral Ischemia Up to 4 Hours

PubMed Central

Lee, E-Jian; Hung, Yu-Chang; Tai, Shih-Huang; Chen, Hung-Yi; Chen, Tsung-Ying; Wu, Tian-Shung

2012-01-01

Neuroprotective efficacy of magnolol, 5,5′-dially-2,2′-dihydroxydiphenyl, was investigated in a model of stroke and cultured neurons exposed to glutamate-induced excitotoxicity. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO). Magnolol or vehicle was administered intraperitoneally, at 1 hr pre-insult or 1–6 hrs post-insult. Brain infarction was measured upon sacrifice. Relative to controls, animals pre-treated with magnolol (50–200 mg/kg) had significant infarct volume reductions by 30.9–37.8% and improved neurobehavioral outcomes (P<0.05, respectively). Delayed treatment with magnolol (100 mg/kg) also protected against ischemic brain damage and improved neurobehavioral scores, even when administered up to 4 hrs post-insult (P<0.05, respectively). Additionally, magnolol (0.1 µM) effectively attenuated the rises of intracellular Ca2+ levels, [Ca2+](i), in cultured neurons exposed to glutamate. Consequently, magnolol (0.1–1 µM) significantly attenuated glutamate-induced cytotoxicity and cell swelling (P<0.05). Thus, magnolol offers neuroprotection against permanent focal cerebral ischemia with a therapeutic window of 4 hrs. This neuroprotection may be, partly, mediated by its ability to limit the glutamate-induced excitotoxicity. PMID:22808077

Ferulic acid regulates the AKT/GSK-3β/CRMP-2 signaling pathway in a middle cerebral artery occlusion animal model

PubMed Central

Gim, Sang-A; Sung, Jin-Hee; Shah, Fawad-Ali; Kim, Myeong-Ok

2013-01-01

Ferulic acid, a component of the plants Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort, exerts a neuroprotective effect by regulating various signaling pathways. This study showed that ferulic acid treatment prevents the injury-induced increase of collapsin response mediator protein 2 (CRMP-2) in focal cerebral ischemia. Glycogen synthase kinase-3β (GSK-3β) regulates CRMP-2 function through phosphorylation of CRMP-2. Moreover, the pro-apoptotic activity of GSK-3β is inactivated by phosphorylation by Akt. This study investigated whether ferulic acid modulates the expression of CRMP-2 and its upstream targets, Akt and GSK-3β, in focal cerebral ischemia. Male rats were treated immediately with ferulic acid (100 mg/kg, i.v.) or vehicle after middle cerebral artery occlusion (MCAO), and then cerebral cortices were collected 24 hr after MCAO. MCAO resulted in decreased levels of phospho-Akt and phospho-GSK-3β, while ferulic acid treatment prevented the decrease in the levels of these proteins. Moreover, phospho-CRMP-2 and CRMP-2 levels increased during MCAO, whereas ferulic acid attenuated these injury-induced increases. These results demonstrate that ferulic acid regulates the Akt/GSK-3β/CRMP-2 signaling pathway in focal cerebral ischemic injury, thereby protecting against brain injury. PMID:23825478

BID Mediates Oxygen-Glucose Deprivation-Induced Neuronal Injury in Organotypic Hippocampal Slice Cultures and Modulates Tissue Inflammation in a Transient Focal Cerebral Ischemia Model without Changing Lesion Volume

PubMed Central

Martin, Nellie Anne; Bonner, Helena; Elkjær, Maria Louise; D’Orsi, Beatrice; Chen, Gang; König, Hans Georg; Svensson, Martina; Deierborg, Tomas; Pfeiffer, Shona; Prehn, Jochen H.; Lambertsen, Kate Lykke

2016-01-01

The BH3 interacting-domain death agonist (BID) is a pro-apoptotic protein involved in death receptor-induced and mitochondria-mediated apoptosis. Recently, it has also been suggested that BID is involved in the regulation of inflammatory responses in the central nervous system. We found that BID deficiency protected organotypic hippocampal slice cultures in vitro from neuronal injury induced by oxygen-glucose deprivation. In vivo, BID-knockout (KO) mice and wild type (WT) mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO) to induce focal cerebral ischemia, and allowed to recover for 24 h. Infarct volumes and functional outcome were assessed and the inflammatory response was evaluated using immunofluorescence, Western blotting, quantitative PCR (qPCR) and Mesoscale multiplex analysis. We observed no difference in the infarct volume or neurological outcome between BID-KO and WT mice. The inflammatory response was reduced by BID deficiency as indicated by a change in microglial/leukocyte response. In conclusion, our data suggest that BID deficiency is neuroprotective in an in vitro model and modulates the inflammatory response to focal cerebral ischemia in vivo. However, this is not translated into a robust neuroprotection in vivo. PMID:26869884

IMM-H004, A New Coumarin Derivative, Improved Focal Cerebral Ischemia via Blood-Brain Barrier Protection in Rats.

PubMed

Niu, Fei; Song, Xiu-Yun; Hu, Jin-Feng; Zuo, Wei; Kong, Ling-Lei; Wang, Xiao-Feng; Han, Ning; Chen, Nai-Hong

2017-10-01

IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-[4-methylpiperazin-1-yl]-2H-chromen-2-one) is a novel coumarin derivative that showed better effect in improving global cerebral ischemia in rats. However, the effects and mechanisms in focal cerebral ischemia were not clear. Blood-brain barrier (BBB) protection is a vital strategy for the treatment of cerebral ischemia. This study is to investigate whether IMM-H004 improves brain ischemia injury via BBB protection. Focal brain ischemia model was induced by middle cerebral artery occlusion for 1 hour and reperfusion (MCAO/R) for 24 hours in rats. IMM-H004 (1.5, 3, 6 mg/kg) and edaravone (positive drug, 6 mg/kg) were administered after 5 minutes of occlusion. Neurological score and TTC staining were used to evaluate the effect of IMM-H004. Evans Blue (EB) staining and electron microscopy were used to assess BBB permeability. Western blot, reverse transcription-polymerase chain reaction, and immunohistochemistry were used to detect the expression of BBB structure-related proteins. Compared with the model group, IMM-H004 in the focal brain ischemia model improved neurological function and reduced cerebral infarction size and edema content. IMM-H004 sharply reduced the EB content and alleviated BBB structure. In addition, IMM-H004 increased the level of zonula occludens (ZO-1) and occluding, decreased the level of aquaporin 4 and matrix metalloproteinase 9, either in cortex or in hippocampus. And all of these changed were related to BBB protection. IMM-H004 improved cerebral ischemia injury via BBB protection. For a potential therapy drug of cerebral ischemia, IMM-H004 merits further study. Copyright © 2017. Published by Elsevier Inc.

Carvacrol Exerts Neuroprotective Effects Via Suppression of the Inflammatory Response in Middle Cerebral Artery Occlusion Rats.

PubMed

Li, Zhenlan; Hua, Cong; Pan, Xiaoqiang; Fu, Xijia; Wu, Wei

2016-08-01

Increasing evidence demonstrates that inflammation plays an important role in cerebral ischemia. Carvacrol, a monoterpenic phenol, is naturally occurring in various plants belonging to the family Lamiaceae and exerts protective effects in a mice model of focal cerebral ischemia/reperfusion injury by reducing infarct volume and decreasing the expression of cleaved caspase-3. However, the anti-inflammatory mechanisms by which carvacrol protect the brain have yet to be fully elucidated. We investigated the effects of carvacrol on inflammatory reaction and inflammatory mediators in middle cerebral artery occlusion rats. The results of the present study showed that carvacrol inhibited the levels of inflammatory cytokines and myeloperoxidase (MPO) activity, as well as the expression of iNOS and COX-2. It also increased SOD activity and decreased MDA level in ischemic cortical tissues. In addition, carvacrol treatment suppressed the ischemia/reperfusion-induced increase in the protein expression of nuclear NF-kB p65. In conclusion, we have shown that carvacrol inhibits the inflammatory response via inhibition of the NF-kB signaling pathway in a rat model of focal cerebral ischemia. Therefore, carvacrol may be a potential therapeutic agent for the treatment of cerebral ischemia injury.

Downregulation of potassium chloride cotransporter KCC2 after transient focal cerebral ischemia.

PubMed

Jaenisch, Nadine; Witte, Otto W; Frahm, Christiane

2010-03-01

The potassium chloride cotransporter 2 (KCC2) is the main neuronal chloride extruder in the adult nervous system. Therefore, KCC2 is responsible for an inwardly directed electrochemical gradient of chloride that leads to hyperpolarizing GABA-mediated responses. Under some pathophysiological conditions, GABA has been reported to be depolarizing because of a downregulation of KCC2. This is the first study to our knowledge analyzing the expression of KCC2 after a focal cerebral ischemia. Mild and severe ischemia were induced in rats by a transient occlusion of the middle cerebral artery for 30 and 120 minutes, respectively. KCC2 mRNA and protein expression were studied in the ischemic hemisphere after different reperfusion times (2 hour, 1 day, 7 days, 30 days, 168 days) by using quantitative polymerase chain reaction, Western blotting, and immunohistological staining. We found a substantial decrease of KCC2 mRNA and protein levels in the ischemic hemisphere, with a stronger downregulation of KCC2 after severe vs mild ischemia. Long-term surviving cells expressing KCC2 could be detected in the infarct core. These cells were identified as GABAergic interneurons mainly expressing parvalbumin. Our study revealed a substantial neuron-specific downregulation of KCC2 after focal cerebral ischemia.

Zingiber officinale Mitigates Brain Damage and Improves Memory Impairment in Focal Cerebral Ischemic Rat

PubMed Central

Wattanathorn, Jintanaporn; Jittiwat, Jinatta; Tongun, Terdthai; Muchimapura, Supaporn; Ingkaninan, Kornkanok

2011-01-01

Cerebral ischemia is known to produce brain damage and related behavioral deficits including memory. Recently, accumulating lines of evidence showed that dietary enrichment with nutritional antioxidants could reduce brain damage and improve cognitive function. In this study, possible protective effect of Zingiber officinale, a medicinal plant reputed for neuroprotective effect against oxidative stress-related brain damage, on brain damage and memory deficit induced by focal cerebral ischemia was elucidated. Male adult Wistar rats were administrated an alcoholic extract of ginger rhizome orally 14 days before and 21 days after the permanent occlusion of right middle cerebral artery (MCAO). Cognitive function assessment was performed at 7, 14, and 21 days after MCAO using the Morris water maze test. The brain infarct volume and density of neurons in hippocampus were also determined. Furthermore, the level of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in cerebral cortex, striatum, and hippocampus was also quantified at the end of experiment. The results showed that cognitive function and neurons density in hippocampus of rats receiving ginger rhizome extract were improved while the brain infarct volume was decreased. The cognitive enhancing effect and neuroprotective effect occurred partly via the antioxidant activity of the extract. In conclusion, our study demonstrated the beneficial effect of ginger rhizome to protect against focal cerebral ischemia. PMID:21197427

Neuroprotection by the Traditional Chinese Medicine, Tao-Hong-Si-Wu-Tang, against Middle Cerebral Artery Occlusion-Induced Cerebral Ischemia in Rats

PubMed Central

Wu, Chih-Jen; Chen, Jui-Tai; Yen, Ting-Lin; Jayakumar, Thanasekaran; Chou, Duen-Suey; Hsiao, George; Sheu, Joen-Rong

2011-01-01

Tao-Hong-Si-Wu-Tang (THSWT) is a famous traditional Chinese medicine (TMC). In the present study, oral administration of THSWT (0.7 and 1.4 g kg−1day−1) for 14 days before MCAO dose-dependently attenuated focal cerebral ischemia in rats. MCAO-induced focal cerebral ischemia was associated with increases in hypoxia-inducible factor (HIF)-1α, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and active caspase-3 expressions in ischemic regions. These expressions were obviously inhibited by 0.7 g kg−1day−1 THSWT treatment. In addition, THSWT inhibited platelet aggregation stimulated by collagen in washed platelets. In an in vivo study, THSWT (16 g kg−1) significantly prolonged platelet plug formation in mice. However, THSWT (20 and 40 μg mL−1) did not significantly reduce the electron spin resonance (ESR) signal intensity of hydroxyl radical (OH•) formation. In conclusion, the most important findings of this study demonstrate for the first time that THSWT possesses potent neuroprotective activity against MCAO-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by the inhibition of both HIF-1α and TNF-α activation, followed by the inhibition of inflammatory responses (i.e., iNOS expression), apoptosis formation (active caspase-3), and platelet activation, resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. PMID:21076527

[Focal cerebral ischemia in rats with estrogen deficiency and endothelial dysfunction].

PubMed

Litvinov, A A; Volotova, E V; Kurkin, D V; Logvinova, E O; Darmanyan, A P; Tyurenkov, I N

2017-01-01

To assess an effect of ovariectomy (OE) on the cerebral blood flow, endothelium-dependent vasodilation, neurological, cognitive and locomotor deficit as markers of brain damage after focal ischemia in rats. The study was conducted in 48 female Wistar rats. Ovariectomy was performed with ovaries and uterine body extirpation, cerebral ischemia was performed by middle cerebral artery occlusion (MCAO) in rats. To assess brain damage, Combs and Garcia scores, 'open field' test (OFT), 'extrapolatory escape test' (EET), 'passive avoidance test' (PAT), 'beam-walking test' were used. Cerebral blood flow was measured using ultrasonic flowmetry. After 7 days of MCAO, the cerebral blood flow in ovarioectomized animals was reduced by 20% compared to sham-ovariectomized animals. Ovariectomized animals with MCAO showed a three-fold endothelium-dependent vasodilation reduction (the reaction of cerebral vessels to the introduction of acetylcholine and N-L-arginine), indicating the presence of severe endothelial dysfunction. In ovarioectomized animals, the cerebral blood flow was reduced by 34% compared to sham-operated animals. MCAO and OE taken together resulted in more than 2-fold increase in neurological, motor disturbances, 3-fold decrease in motor activity of the animals in the OP test. Focal ischemia in ovarioectomized animals with endothelial dysfunction led to memory decrease by 1/5 fold in PAT and by 2-fold in EET.

CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia.

PubMed

Choe, Chi-un; Lardong, Kerstin; Gelderblom, Mathias; Ludewig, Peter; Leypoldt, Frank; Koch-Nolte, Friedrich; Gerloff, Christian; Magnus, Tim

2011-01-01

Converging evidence suggests that inflammatory processes significantly influence brain injury and clinical impairment in ischemic stroke. Although early studies suggested a key role of lymphocytes, recent data has emphasized the orchestrating function of innate immunity, i.e., macrophages and microglia. The bifunctional receptor and ectoenzyme CD38 synthesizes calcium-mobilizing second messengers (e.g., cyclic ADP-ribose), which have been shown to be necessary for activation and migration of myeloid immune cells. Therefore, we investigated the dynamics of CD38 in stroke and the impact of CD38-deficiency on cytokine production, inflammation and cerebral damage in a mouse model of cerebral ischemia-reperfusion. We show that the local expression of the chemokine MCP-1 was attenuated in CD38-deficient mice compared with wildtype mice after focal cerebral ischemia and reperfusion. In contrast, no significant induction of MCP-1 expression was observed in peripheral blood after 6 hours. Flow cytometry analysis revealed less infiltrating macrophages and lymphocytes in the ischemic hemisphere of CD38-deficient mice, whereas the amount of resident microglia was unaltered. An up-regulation of CD38 expression was observed in macrophages and CD8(+) cells after focal cerebral ischemia in wildtype mice, whereas CD38 expression was unchanged in microglia. Finally, we demonstrate that CD38-deficiency decreases the cerebral ischemic injury and the persistent neurological deficit after three days of reperfusion in this murine temporary middle cerebral artery occlusion (tMCAO) model. CD38 is differentially regulated following stroke and its deficiency attenuates the postischemic chemokine production, the immune cell infiltration and the cerebral injury after temporary ischemia and reperfusion. Therefore CD38 might prove a therapeutic target in ischemic stroke.

Evaluation of cerebral blood flow changes in focal cerebral ischemia rats by using transcranial Doppler ultrasonography.

PubMed

Li, Le; Ke, Zheng; Tong, Kai Yu; Ying, Michael

2010-04-01

Ischemic stroke is typically characterized by the disruption of cerebral blood flow. This study aimed to consecutively evaluate the cerebral blood flow changes in a focal ischemia rat model during the occlusion-reperfusion procedure and along the recovery stage after stroke. In 12 Sprague Dawley (SD) rats, a middle cerebral artery occlusion/reperfusion (MCAo/r) surgery was conducted, which combines a permanent occlusion of the right common carotid artery (CCA), external carotid artery (ECA) and a transient occlusion of the right internal carotid artery (ICA) and middle cerebral artery (MCA) with a monofilament introduced from the proximal ICA towards the distal right ICA then removed after 90 min. Blood flow velocity (BFV) from the concerned arteries were measured using ultrasonography (13-4 MHz) at the basal stage before the surgery, after the reperfusion stage and during the post-stroke status. At reperfusion stage and after, BFV increased significantly in the left ICA and in the basilar artery (BA) (starting from post-24 h, p < 0.05 vs. basal). Moreover, BFV were reversed in the distal right ICA and reflow was recorded in the right MCA. Time-average maximum BFV in the right MCA at reperfusion and post-stroke 24-96 h was decreased significantly (p < 0.05 vs. basal). The reversed flow in the right ICA was enabled by the settlement of the collateral supply through the circle of Willis which consisted in higher BFV in the opposite ICA and in the BA still 24 h, although the proximal right ICA remain occluded. Ultrasound measurement of BFV helps to provide information on the redistribution of the blood flow supply after the onset of stroke. Copyright 2010 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Identification of Proteins Differentially Expressed by Quercetin Treatment in a Middle Cerebral Artery Occlusion Model: A Proteomics Approach.

PubMed

Shah, Fawad-Ali; Park, Dong-Ju; Koh, Phil-Ok

2018-06-20

Cerebral ischemia is a major cause of death and neurological disability. It also leads to severe brain tissue damage by excessive generation of oxidative stress. Quercetin is a bioflavonoid substance that acts an antioxidant agent and exerts a neuroprotective effect against cerebral ischemia. The aim of this study was to detect specific proteins that are differentially expressed in response to quercetin treatment in focal cerebral ischemia. Adult male rats were intraperitoneally injected with vehicle or quercetin (10 mg/kg) 30 min prior to right middle cerebral artery occlusion (MCAO). Brain tissues were collected 24 h after MCAO surgery and right cerebral cortices proteins were identified by two-dimensional gel electrophoresis and mass spectrometry. MCAO leads to neurological behavior disorders, infarction, and histopathological change. However, quercetin treatment alleviated MCAO-induced neuronal deficits and damages. We identified specific proteins differentially expressed between vehicle- and quercetin-treated animals. Among these detected proteins, isocitrate dehydrogenase [NAD + ], adenosylhomocysteinase, pyruvate kinase, and ubiquitin carboxy terminal hydrolase L1 were decreased in vehicle-treated animals, while quercetin administration alleviated the MCAO-induced decreases in these proteins. However, 60 kDa heat shock protein and collapsin response mediator protein 2 were increased in the vehicle-treated animals, and quercetin treatment attenuated increases in these proteins. The expression changes in these proteins were confirmed by Western blot and reverse transcription-PCR analyses. These proteins are associated with cellular differentiation, metabolism, and oxidative stress related proteins. These results suggest that quercetin reduces ischemic injury by modulating the expression of various proteins in focal cerebral ischemia.

The Akt/GSK-3β pathway mediates flurbiprofen-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rats.

PubMed

Sun, Baozhu; Chen, Lin; Wei, Xinbing; Xiang, Yanxiao; Liu, Xiaoqian; Zhang, Xiumei

2011-06-17

Apoptosis is one of the major mechanisms of cell death during cerebral ischemia and reperfusion injury. Flurbiprofen has been shown to reduce cerebral ischemia/reperfusion injury in both focal and global cerebral ischemia models, but the mechanism remains unclear. This study aimed to investigate the potential association between the neuroprotective effect of flurbiprofen and the apoptosis inhibiting signaling pathways, in particularly the Akt/GSK-3β pathway. A focal cerebral ischemia rat model was subjected to middle cerebral artery occlusion (MCAO) for 120 min and then treated with flurbiprofen at the onset of reperfusion. The infarct volume and the neurological deficit scores were evaluated at 24h after reperfusion. Cell apoptosis, apoptosis-related proteins and the levels of p-Akt and p-GSK-3β in ischemic penumbra were measured using TUNEL and western blot. The results showed that administration of flurbiprofen at the doses of 5 and 10mg/kg significantly attenuated brain ischemia/reperfusion injury, as shown by a reduction in the infarct volume, neurological deficit scores and cell apoptosis. Moreover, flurbiprofen not only inhibited the expression of Bax protein and p-GSK-3β, but also increased the expression of Bcl-2 protein, the ratio of Bcl-2/Bax as well as the P-Akt level. Taken together, these results suggest that flurbiprofen protects the brain from ischemia/reperfusion injury by reducing apoptosis and this neuroprotective effect may be partly due to the activation of Akt/GSK-3β signaling pathway. Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

Multi-unit activity suppression and sensorimotor deficits after endothelin-1-induced middle cerebral artery occlusion in conscious rats.

PubMed

Moyanova, Slavianka; Kirov, Roumen; Kortenska, Lidia

2003-08-15

Conscious Wistar rats with stereotaxically and unilaterally implanted cannula just above the middle cerebral artery (MCA) were injected with the powerful vasoconstrictor peptide endothelin-1 (ET1, 60 pmol in 3 microl). The purpose was to examine the long-term (from the 1st to the 14th day) changes in neuronal bioelectrical activity together with sensorimotor deficits after ET1-induced MCA occlusion (MCAO). Extracellular multi-unit activity (MUA) recorded from the ipsilateral fronto-parietal cortical area (supplied by MCA) and sensorimotor behavior (one postural reflex test and six limb placing tests) were examined. A significant suppression of the multi-unit activity was observed until the 14th day post-ET1. The rats exhibited significant unilateral sensorimotor deficits with a maximum at the 3-7 days after ET1 and a spontaneous partial recovery by days 11-14. A significant correlation was found between the suppression of the multi-unit activity and the sensorimotor deficits between the 3rd and the 10th day post-ET1. The results suggest that studying the bioelectrical activity in combination with the behavioral sensorimotor functions may be of use to assess the functional disturbances associated with focal cerebral ischemia and would help to examine the therapeutic benefits of various cerebroprotective treatments before initiating human clinical trials.

The protective effect of dexanabinol (HU-211) on nitric oxide and cysteine protease-mediated neuronal death in focal cerebral ischemia.

PubMed

Durmaz, Ramazan; Ozden, Hilmi; Kanbak, Güngör; Aral, Erinç; Arslan, Okan Can; Kartkaya, Kazim; Uzuner, Kubilay

2008-09-01

We hypothesized that dexanabinol can prevent neuronal death by protecting neuronal lysosomes from nitric oxide (NO)-mediated toxicity, and in turn, by suppressing the release of cathepsins during cerebral ischemia. Focal cerebral ischemia was induced in two sets of animals by permanent middle cerebral artery occlusion. The first set was used to monitor NO concentration and cathepsin activity, while the second was used for histological examination with hematoxylin and eosin, and TUNEL staining. In post-ischemic brain tissue, NO content and cathepsin B and L activity increased (p < 0.05). Dexanabinol treatment reduced NO concentration and cathepsin activity to the control level (p > 0.05). The number of eosinophilic and apoptotic neurons increased in the post-ischemic cerebral cortex (p < 0.05). However, dexanabinol treatment lowered both of these (p < 0.05). We conclude that dexanabinol might be a useful agent for the treatment of stroke patients.

Extracerebral Tissue Damage in the Intraluminal Filament Mouse Model of Middle Cerebral Artery Occlusion

PubMed Central

Vaas, Markus; Ni, Ruiqing; Rudin, Markus; Kipar, Anja; Klohs, Jan

2017-01-01

Middle cerebral artery occlusion is the most common model of focal cerebral ischemia in the mouse. In the surgical procedure, the external carotid artery (ECA) is ligated; however, its effect on the tissue supplied by the vessel has not been described so far. C57BL/6 mice underwent 1 h of transient MCAO (tMCAO) or sham surgery. Multi-spectral optoacoustic tomography was employed at 30 min after surgery to assess oxygenation in the temporal muscles. Microstructural changes were assessed with magnetic resonance imaging and histological examination at 24 h and 48 h after surgery. Ligation of the ECA resulted in decreased oxygenation of the left temporal muscle in most sham-operated and tMCAO animals. Susceptible mice of both groups exhibited increased T2 relaxation times in the affected muscle with histological evidence of myofibre degeneration, interstitial edema, and neutrophil influx. Ligatures had induced an extensive neutrophil-dominated inflammatory response. ECA ligation leads to distinct hypoxic degenerative changes in the tissue of the ECA territory and to ligature-induced inflammatory processes. An impact on outcome needs to be considered in this stroke model. PMID:28348545

Effects of propofol, midazolam and thiopental sodium on outcome and amino acids accumulation in focal cerebral ischemia-reperfusion in rats.

PubMed

Chen, Lianhua; Gong, Qinyan; Xiao, Changsi

2003-02-01

To investigate the effects of propofol, midazolam and thiopental sodium on outcomes and amino acid accumulation in focal cerebral ischemia-reperfusion in rats. Male Sprague Dawley (SD) rats were scheduled to undergo 3-hour middle cerebral artery occlusion by intraluminal suture and 24-hour reperfusion. Neurologic outcomes were scored on a 0-5 grading scale. Infarct volume was shown with triphenyltetrazolium chloride staining and measured by an image analysis system. Concentrations of various amino acids (aspartate, glutamate, glycine, taurine, and gama-aminobutyric acid) were measured after 3 hours of reperfusion using high performance liquid chromatography. Propofol, midazolam and thiopental sodium were given intraperitoneally at the beginning of reperfusion. Both propofol and midazolam attenuated neurological deficits and reduced infarct and edema volumes. Propofol showed better neurological protection than midazolam while thiopental sodium did not exhibit any protective effect. Both propofol and midazolam decreased excitatory amino acids accumulation, while propofol increased gama-aminobutyric acid accumulation in ischemic areas in reperfusion. Propofol and midazolam, but not thiopental sodium, may provide protective effects against reperfusion induced injury in rats subjected to focal cerebral ischemia. This neurological protection may be due to the acceleration of excitatory amino acids elimination in reperfusion.

Effect of oral administration of Pheretima aspergillum (earthworm) in rats with cerebral infarction induced by middle-cerebral artery occlusion.

PubMed

Liu, Chung-Hsiang; Lin, Yi-Wen; Tang, Nou-Ying; Liu, Hsu-Jan; Huang, Chih-Yang; Hsieh, Ching-Liang

2012-01-01

We investigated the curative effect of Pheretima aspergillum (earthworm, PA) on rats with middle cerebral artery occlusion (MCAo). The MCAo-induced cerebral infarction was established and its underlying mechanisms by counting the infarction areas and evaluating the rats' neurological status. Immunostaining was used to test the expression of NeuN, and glial fibrillary acidic (GFAP), S100B, and brain-derived neurotrophic factor (BDNF) proteins. Our results showed that oral administration of PA for two weeks to rats with MCAo successfully reduced cerebral infarction areas in the cortex and striatum, and also reduced scores of neurological deficit. The PA-treated MCAo rats showed greatly decreased neuronal death, glial proliferation, and S100B proteins in the penumbra area of the cortex and in the ischemic core area of the cortex, but BDNF did not changed. These results demonstrated novel and detailed cellular mechanisms underlying the neuroprotective effects of PA in MCAo rats.

Opposite effects of the gap junction blocker octanol on focal cerebral ischemia occluded for different durations.

PubMed

Ding, Wenting; Zhou, Lequan; Liu, Wei; Guan, Li; Li, Xiaoying; Liu, Haimei; Yan, Fuman; Xu, Jinwen; Zeng, Weiyong; Qiu, Min

2014-06-01

Protectants and executioners have been demonstrated to be used by gap junctions in focal cerebral ischemia. Certain researchers hypothesized that the opposite role of gap junctions may be associated with the injury extent, which has been demonstrated to be highly correlated with occlusion duration. In order to examine this hypothesis directly, the effects of octanol, a frequently used drug, were examined to investigate the role of gap junctions, in rats following middle cerebral artery occlusion (MCAO) for 30 min/2 h and 24 h reperfusion, respectively. Octanol significantly reduced the infarct volume following 2 h of occlusion concomitant with lower neurological deficits, whereas it enlarged the infarct volume following 30 min of occlusion. Consistently, octanol attenuated the number of transferase dUTP nick-end labeling (TUNEL) positive neurons in the hippocampal CA1 region following 2 h of occlusion, while opposite effects were observed for 30 min of occlusion. Further immunohistochemical studies demonstrated that the expression of B-cell leukemia-2 (Bcl-2, anti-apoptotic protein) was upregulated and that Bcl-2-associated X (Bax, proapoptotic protein) was downregulated following 2 h of occlusion in the octanol group compared with the ischemic group. Conversely, octanol downregulated the expression of the Bcl-2 protein concomitant with increased Bax protein following 30 min of occlusion. These results indicated that the gap junction blocker octanol can protect against ischemic injury following long-term occlusion, however, can aggravate ischemic injury following short-term occlusion.

Neuroprotective effect of 4-methylcyclopentadecanone on focal cerebral ischemia/reperfusion injury in rats.

PubMed

Ma, Yukui; Li, Yue; Zhang, Chunxia; Zhou, Xiaomian; Wu, Yingliang

2014-01-01

The present study aimed to investigate the effect of 4-methylcyclopentadecanone (4-MCPC) on local cerebral ischemia-reperfusion and the possible mechanisms involved. For this purpose, the focal cerebral ischemia rat model was induced by middle cerebral artery occlusion (MCAO) for 2 h, and the rats were treated with 4-MCPC (4 or 8 mg·kg(-1), p.o.) just 0.5 h before reperfusion. The neurological deficit scores and the ischemic infarct volume were recorded 24 h after the MCAO. In addition, the number of apoptotic cells was measured by TUNEL assay, and the expression of apoptosis-regulatory proteins and the PI3K/Akt neuroprotective signaling pathway were investigated by western blotting. Our results indicated that 4-MCPC (4 or 8 mg·kg(-1)) remarkably alleviated cerebral I/R injury by decreasing infarct volume and neurological deficit scores. 4-MCPC also decreased the number of apoptotic cells, regulated the expression of Bcl-2 and Bax, and increased the ratio of Bcl-2/Bax. Further study revealed that 4-MCPC treatment also increased the level of p-Akt and p-GSK-3β. Wortmannin (PI3K inhibitor) markedly abolished the effects of 4-MCPC. Taken together, our results suggest that 4-MCPC protects against cerebral I/R injury through the inhibition of apoptosis, and this neuroprotective effect may be partly related to the activation of the PI3K/Akt signal pathway.

Mapping the dynamics of brain perfusion using functional ultrasound in a rat model of transient middle cerebral artery occlusion

PubMed Central

Brunner, Clément; Isabel, Clothilde; Martin, Abraham; Dussaux, Clara; Savoye, Anne; Emmrich, Julius; Montaldo, Gabriel; Mas, Jean-Louis; Urban, Alan

2015-01-01

Following middle cerebral artery occlusion, tissue outcome ranges from normal to infarcted depending on depth and duration of hypoperfusion as well as occurrence and efficiency of reperfusion. However, the precise time course of these changes in relation to tissue and behavioral outcome remains unsettled. To address these issues, a three-dimensional wide field-of-view and real-time quantitative functional imaging technique able to map perfusion in the rodent brain would be desirable. Here, we applied functional ultrasound imaging, a novel approach to map relative cerebral blood volume without contrast agent, in a rat model of brief proximal transient middle cerebral artery occlusion to assess perfusion in penetrating arterioles and venules acutely and over six days thanks to a thinned-skull preparation. Functional ultrasound imaging efficiently mapped the acute changes in relative cerebral blood volume during occlusion and following reperfusion with high spatial resolution (100 µm), notably documenting marked focal decreases during occlusion, and was able to chart the fine dynamics of tissue reperfusion (rate: one frame/5 s) in the individual rat. No behavioral and only mild post-mortem immunofluorescence changes were observed. Our study suggests functional ultrasound is a particularly well-adapted imaging technique to study cerebral perfusion in acute experimental stroke longitudinally from the hyper-acute up to the chronic stage in the same subject. PMID:26721392

Combination of Zizyphus jujuba and silymarin showed better neuroprotective effect as compared to single agent in MCAo-induced focal cerebral ischemia in rats.

PubMed

Gupta, Sangeetha; Gupta, Yogendra Kumar

2017-02-02

Traditionally, Zizyphus jujuba is used for anticonvulsant, hypnotic-sedative, anxiolytic, tranquilizer, antioxidant and anti-inflammatory properties. Likewise silymarin is popularly used for its potent antioxidant and hepatoprotective effects. Stroke being a multifactorial disease with unsatisfactory treatment outcomes, necessitates development of multimodal therapeutic interventions. Thus, we evaluated the therapeutic benefits of herbal combination of Z. jujuba and silymarin in a focal cerebral ischemia model. To evaluate the neuroprotective potential of hydroalcoholic extract of Z. jujuba (HEZJ) fruit and silymarin alone and in combination in middle cerebral artery occlusion (MCAo) model of focal cerebral ischemia in rats. Male Wistar rats were pretreated with HEZJ (100, 250 and 500mg/kg, p.o.) or silymarin (250mg/kg, p.o.) for 3 days prior to induction of MCAo. Neurological deficit score, motor impairment and cerebral infarction were assessed 24h following MCAo. HEZJ (250mg/kg) co-administered with silymarin (250mg/kg) for 3 days prior to induction of MCAo was also evaluated for above parameters and oxidative stress. Malondialdehyde (MDA), nitric oxide (NO) and superoxide dismutase (SOD) levels in the cortex, striatum and hippocampal brain regions were estimated 24h post MCAo. Pretreatment with HEZJ and silymarin reduced the neurological deficit score, motor impairment and cerebral infarction volume. HEZJ and silymarin pretreatment also ameliorated the oxidative stress in different brain regions, which was evident from increased SOD levels, decreased MDA and NO levels as compared to MCAo control rats. Interestingly neuroprotective efficacy was potentiated by pretreatment with HEZJ and silymarin combination. Pretreatment with HEZJ and silymarin combination was observed to have better neuroprotection mediated via amelioration of oxidative stress in the focal cerebral ischemia model. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Stroke onset time estimation from multispectral quantitative magnetic resonance imaging in a rat model of focal permanent cerebral ischemia.

PubMed

McGarry, Bryony L; Rogers, Harriet J; Knight, Michael J; Jokivarsi, Kimmo T; Sierra, Alejandra; Gröhn, Olli Hj; Kauppinen, Risto A

2016-08-01

Quantitative T2 relaxation magnetic resonance imaging allows estimation of stroke onset time. We aimed to examine the accuracy of quantitative T1 and quantitative T2 relaxation times alone and in combination to provide estimates of stroke onset time in a rat model of permanent focal cerebral ischemia and map the spatial distribution of elevated quantitative T1 and quantitative T2 to assess tissue status. Permanent middle cerebral artery occlusion was induced in Wistar rats. Animals were scanned at 9.4T for quantitative T1, quantitative T2, and Trace of Diffusion Tensor (Dav) up to 4 h post-middle cerebral artery occlusion. Time courses of differentials of quantitative T1 and quantitative T2 in ischemic and non-ischemic contralateral brain tissue (ΔT1, ΔT2) and volumes of tissue with elevated T1 and T2 relaxation times (f1, f2) were determined. TTC staining was used to highlight permanent ischemic damage. ΔT1, ΔT2, f1, f2, and the volume of tissue with both elevated quantitative T1 and quantitative T2 (V(Overlap)) increased with time post-middle cerebral artery occlusion allowing stroke onset time to be estimated. V(Overlap) provided the most accurate estimate with an uncertainty of ±25 min. At all times-points regions with elevated relaxation times were smaller than areas with Dav defined ischemia. Stroke onset time can be determined by quantitative T1 and quantitative T2 relaxation times and tissue volumes. Combining quantitative T1 and quantitative T2 provides the most accurate estimate and potentially identifies irreversibly damaged brain tissue. © 2016 World Stroke Organization.

Identification of proteins regulated by curcumin in cerebral ischemia.

PubMed

Shah, Fawad-Ali; Gim, Sang-Ah; Sung, Jin-Hee; Jeon, Seong-Jun; Kim, Myeong-Ok; Koh, Phil-Ok

2016-03-01

Curcumin is known to have a neuroprotective effect against cerebral ischemia. The objective of this study was to identify various proteins that are differentially expressed by curcumin treatment in focal cerebral ischemia using a proteomic approach. Adult male rats were treated with vehicle or curcumin 1 h after middle cerebral artery occlusion. Brain tissues were collected 24 h after the onset of middle cerebral artery occlusion, and cerebral cortices proteins were identified by two-dimensional gel electrophoresis and mass spectrometry. We detected several proteins with altered expression levels between vehicle- and curcumin-treated animals. Among these proteins, ubiquitin carboxy-terminal hydrolase L1, isocitrate dehydrogenase, adenosylhomocysteinase, and eukaryotic initiation factor 4A were decreased in the vehicle-treated animal, and curcumin treatment attenuated the injury-induced decreases of these proteins. Conversely, pyridoxal phosphate phosphatase was increased in the vehicle-treated animal, and curcumin treatment prevented decreases in this protein. The identified altered proteins are associated with cellular metabolism and differentiation. The results of this study suggest that curcumin exerts a neuroprotective effect by regulating the expression of various proteins in focal cerebral ischemia. Copyright © 2016 Elsevier Inc. All rights reserved.

Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia.

PubMed

Chen, Zheng-Zhen; Yang, Dan-Dan; Zhao, Zhan; Yan, Hui; Ji, Juan; Sun, Xiu-Lan

2016-04-01

Memantine is a low-moderate affinity and uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist, which is also a potential neuroprotectant in acute ischemic stroke for its particular action profiles. The present study was to reveal the mechanisms involved in the neuroprotection of memantine. We used a mouse model of permanent focal cerebral ischemia via middle cerebral artery occlusion to verify our hypothesis. 2,3,5-Triphenyltetrazolium chloride staining was used to compare infarct size. The amount of astrocytes and the somal volume of the microglia cell body were analyzed by immunohistochemistry and stereological estimates. Western blotting was used to determine the protein expressions. Memantine prevented cerebral ischemia-induced brain infarct and neuronal injury, and reduced oxygen-glucose deprivation-induced cortical neuronal apoptosis. Moreover, memantine reduced the amount of the damaged astrocytes and over activated microglia after 24h of ischemia. In the early phase of ischemia, higher production of MMP-9 was observed, and thereby collagen IV was dramatically disrupted. Meanwhile, the post-synaptic density protein 95(PSD-95) was also severely cleavaged. Memantine decreased MMP-9 secretion, prevented the degradation of collagen IV in mouse brain. PSD-95 cleavage was also inhibited by memantine. These results suggested that memantine exerted neuroprotection effects in acute ischemic brain damage, partially via improving the functions of neurovascular unit. Taking all these findings together, we consider that memantine might be a promising protective agent against ischemic stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

Endothelin-1-induced focal cerebral ischemia in the growth hormone/IGF-1 deficient Lewis Dwarf rat.

PubMed

Yan, Han; Mitschelen, Matthew; Toth, Peter; Ashpole, Nicole M; Farley, Julie A; Hodges, Erik L; Warrington, Junie P; Han, Song; Fung, Kar-Ming; Csiszar, Anna; Ungvari, Zoltan; Sonntag, William E

2014-11-01

Aging is a major risk factor for cerebrovascular disease. Growth hormone (GH) and its anabolic mediator, insulin-like growth factor (IGF)-1, decrease with advancing age and this decline has been shown to promote vascular dysfunction. In addition, lower GH/IGF-1 levels are associated with higher stroke mortality in humans. These results suggest that decreased GH/IGF-1 level is an important factor in increased risk of cerebrovascular diseases. This study was designed to assess whether GH/IGF-1-deficiency influences the outcome of cerebral ischemia. We found that endothelin-1-induced middle cerebral artery occlusion resulted in a modest but nonsignificant decrease in cerebral infarct size in GH/IGF-1 deficient dw/dw rats compared with control heterozygous littermates and dw/dw rats with early-life GH treatment. Expression of endothelin receptors and endothelin-1-induced constriction of the middle cerebral arteries were similar in the three experimental groups. Interestingly, dw/dw rats exhibited reduced brain edema and less astrocytic infiltration compared with their heterozygous littermates and this effect was reversed by GH-treatment. Because reactive astrocytes are critical for the regulation of poststroke inflammatory processes, maintenance of the blood-brain barrier and neural repair, further studies are warranted to determine the long-term functional consequences of decreased astrocytic activation in GH/IGF-1 deficient animals after cerebral ischemia. Published by Oxford University Press on behalf of the Gerontological Society of America 2014.

Focal epidural cooling reduces the infarction volume of permanent middle cerebral artery occlusion in swine.

PubMed

Zhang, Lihua; Cheng, Huilin; Shi, Jixin; Chen, Jun

2007-02-01

The protective effect against ischemic stroke by systemic hypothermia is limited by the cooling rate and it has severe complications. This study was designed to evaluate the effect of SBH induced by epidural cooling on infarction volume in a swine model of PMCAO. Permanent middle cerebral artery occlusion was performed in 12 domestic swine assigned to groups A and B. In group A, the cranial and rectal temperatures were maintained at normal range (37 degrees C-39 degrees C) for 6 hours after PMCAO. In group B, cranial temperature was reduced to moderate (deep brain, <30 degrees C) and deep (brain surface, <20 degrees C) temperature and maintained at that level for 5 hours after 1 hour after PMCAO, by the epidural cooling method. All animals were euthanized 6 hours after MCAO; their brains were sectioned and stained with 2,3,5-triphenyltetrazolium chloride and their infarct volumes were calculated. The moderate and deep brain temperature (at deep brain and brain surface) can be induced by rapid epidural cooling, whereas the rectal temperature was maintained within normal range. The infarction volume after PMCAO was significantly reduced by epidural cooling compared with controls (13.73% +/- 1.82% vs 5.62% +/- 2.57%, P < .05). The present study has demonstrated, with histologic confirmation, that epidural cooling may be a useful strategy for reducing infarct volume after the onset of ischemia.

Mannitol infusion immediately after reperfusion suppresses the development of focal cortical infarction after temporary cerebral ischemia in gerbils

PubMed Central

Ito, Umeo; Hakamata, Yoji; Watabe, Kazuhiko; Oyanagi, Kiyomitsu

2014-01-01

Previously we found that, after temporary cerebral ischemia, microvasculogenic secondary focal cerebral cortical ischemia occurred, caused by microvascular obstruction due to compression by swollen astrocytic end-feet, resulting in focal infarction. Herein, we examined whether mannitol infusion immediately after restoration of blood flow could protect the cerebral cortex against the development of such an infarction. If so, the infusion of mannitol might improve the results of vascular reperfusion therapy. We selected stroke-positive animals during the first 10 min after left carotid occlusion performed twice with a 5-h interval, and allocated them into four groups: sham-operated control, no-treatment, mannitol-infusion, and saline-infusion groups. Light- and electron-microscopic studies were performed on cerebral cortices of coronal sections prepared at the chiasmatic level, where the focal infarction develops abruptly in the area where disseminated selective neuronal necrosis is maturing. Measurements were performed to determine the following: (A) infarct size in HE-stained specimens from all groups at 72 and 120 h after return of blood flow; (B) number of carbon-black-suspension-perfused microvessels in the control and at 0.5, 3, 5, 8, 12 and 24 h in the no-treatment and mannitol-infusion groups; (C) area of astrocytic end-feet; and (D) number of mitochondria in the astrocytic end-feet in electron microscopic pictures taken at 5 h. The average decimal fraction area ratio of infarct size in the mannitol group was significantly reduced at 72 and 120 h, associated with an increased decimal fraction number ratio of carbon-black-suspension-perfused microvessels at 3, 5 and 8 h, and a marked reduction in the size of the end-feet at 5 h. Mannitol infusion performed immediately after restitution of blood flow following temporary cerebral ischemia remarkably reduced the size of the cerebral cortical focal infarction by decreasing the swelling of the end

Histopathology of motor cortex in an experimental focal ischemic stroke in mouse model.

PubMed

de Oliveira, Juçara Loli; Crispin, Pedro di Tárique Barreto; Duarte, Elisa Cristiana Winkelmann; Marloch, Gilberto Domingos; Gargioni, Rogério; Trentin, Andréa Gonçalves; Alvarez-Silva, Marcio

2014-05-01

Experimental ischemia results in cortical brain lesion followed by ischemic stroke. In this study, focal cerebral ischemia was induced in mice by occlusion of the middle cerebral artery. We studied cortical layers I, II/III, V and VI in the caudal forelimb area (CFA) and medial agranular cortex (AGm) from control and C57BL/6 mice induced with ischemic stroke. Based on our analysis of CFA and AGm motor cortex, significant differences were observed in the numbers of neurons, astrocytes and microglia in the superficial II/III and deep V cortical layers. Cellular changes were more prominent in layer V of the CFA with nuclear pyknosis, chromatin fragmentation, necrosis and degeneration, as well as, morphological evidence of apoptosis, mainly in neurons. As result, the CFA was more severely impaired than the AGm in this focal cerebral ischemic model, as evidenced by the proliferation of astrocytes, potentially resulting in neuroinflammation by microglia-like cells. Copyright © 2014 Elsevier B.V. All rights reserved.

The antioxidant and antiapoptotic effects of crocin pretreatment on global cerebral ischemia reperfusion injury induced by four vessels occlusion in rats.

PubMed

Oruc, Serdar; Gönül, Yücel; Tunay, Kamil; Oruc, Oya Akpinar; Bozkurt, Mehmet Fatih; Karavelioğlu, Ergün; Bağcıoğlu, Erman; Coşkun, Kerem Senol; Celik, Sefa

2016-06-01

Cerebral ischemia reperfusion (IR) injury is a process in which oxidative and apoptotic mechanisms play a part. Neuroprotective agents to be found could work out well for the efficient and safe minimization of cerebral IR injury. Crocin is a strong antioxidant agent; however the influence of this agent on the experimental cerebral ischemia model has not been studied extensively and thus it is not well-known. The objective of our study was to investigate the antioxidant, antiapoptotic and protective effects of crocin on the global cerebral IR induced by four-vessel occlusion. A total of 30 adult female Sprague-Dawley rats were equally and randomly separated into three groups as follows: sham, IR and IR+crocin (40mg/kg/day orally for 10days). 24h after electrocauterization of bilateral vertebral arteries, bilateral common carotid arteries were occluded for 30min and reperfused for 30min. Oxidative stress parameters (TAS, TOS, OSI), haematoxylin and eosin staining, caspase-3 and hypoxia-inducible factor-1 alpha (HIF-1α) expressions and TUNEL methods were investigated. There was a significant difference between the IR and sham groups by means of OSI level, histopathological scoring, caspase-3, HIF-1α and TUNEL-positive cell parameters. We have also observed that pre-treatment with crocin reduced these parameter levels back to the baseline. The data obtained from the present study suggest that crocin may exert antiapoptotic, antioxidant and protective effects in IR-mediated brain injury induced by four-vessel occlusion. To the best of our knowledge, this would be the first study to be conducted in this field. Copyright © 2016 Elsevier Inc. All rights reserved.

The inhibitor of 20-HETE synthesis, TS-011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice.

PubMed

Marumo, Toshiyuki; Eto, Kei; Wake, Hiroaki; Omura, Tomohiro; Nabekura, Junichi

2010-11-01

20-Hydroxyeicosatetraenoic acid is a potent vasoconstrictor that contributes to cerebral ischaemia. An inhibitor of 20-Hydroxyeicosatetraenoic acid synthesis, TS-011, reduces infarct volume and improves neurological deficits in animal stroke models. However, little is known about how TS-011 affects the microvessels in ischaemic brain. Here, we investigated the effect of TS-011 on microvessels after cerebral ischaemia. TS-011 (0.3 mg·kg(-1) ) or a vehicle was infused intravenously for 1 h every 6 h in a mouse model of stroke, induced by transient occlusion of the middle cerebral artery occlusion following photothrombosis. The cerebral blood flow velocity and the vascular perfusion area of the peri-infarct microvessels were measured using in vivo two-photon imaging. The cerebral blood flow velocities in the peri-infarct microvessels decreased at 1 and 7 h after reperfusion, followed by an increase at 24 h after reperfusion in the vehicle-treated mice. We found that TS-011 significantly inhibited both the decrease and the increase in the blood flow velocities in the peri-infarct microvessels seen in the vehicle-treated mice after reperfusion. In addition, TS-011 significantly inhibited the reduction in the microvascular perfusion area after reperfusion, compared with the vehicle-treated group. Moreover, TS-011 significantly reduced the infarct volume by 40% at 72 h after middle cerebral artery occlusion. These findings demonstrated that infusion of TS-011 improved defects in the autoregulation of peri-infarct microcirculation and reduced the infarct volume. Our results could be relevant to the treatment of cerebral ischaemia. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

6-Mercaptopurine exerts an immunomodulatory and neuroprotective effect on permanent focal cerebral occlusion in rats.

PubMed

Chang, Chih-Zen; Kwan, Aij-Lie; Howng, Shen-Long

2010-08-01

A bursting cascade of inflammation imposes progressive neurological deterioration after experimental stroke has been demonstrated. In our study, 6-mercaptopurine (6-mp) has been successful in alleviating cerebral infarct in a rodent permanent middle cerebral artery occlusion (pMCAO) model. The present study was aimed to examine the effect of 6-mp on cytokine levels in experimental stroke. The rodent pMCAO model was employed. A dose of 2 mg/kg 6-mp or vehicle (0.1 mol/L PBS) was administered intraperitoneally 30 min after the induction of pMCAO. Neurological score, serum, and cerebrospinal fluid (CSF) cytokines such as IL-1beta, IL-6, and TNF-alpha and infarct volume were determined 48 h after pMCAO. Cerebral infarction volume was significantly decreased in animals treated with 6-mp (74.3%, p < 0.01), and the ratio of tissue edema was also decreased in 6-mp-treated groups (71%). Animals receiving 6-mp thus showed a significant decrease in IL-1 and TNF-alpha (18/43% and 48/64% in CSF/serum, respectively) when compared with the pMCAO groups (p < 0.01). This study demonstrates that 6-mp interposes the production of IL-1 and TNF-alpha in CSF and serum, attenuates ischemic brain injury, and thus alleviates neurological deficits in the pMCAO animals. These findings also offer first evidence that 6-mp may attenuate TNF-alpha-related neuron apoptosis and also support the notion that 6-mp and other anti-inflammatory agents could potentially have therapeutic uses in cases of cerebral infarct.

Cerebral misery perfusion due to carotid occlusive disease

PubMed Central

Maddula, Mohana; Sprigg, Nikola; Bath, Philip M; Munshi, Sunil

2017-01-01

Purpose Cerebral misery perfusion (CMP) is a condition where cerebral autoregulatory capacity is exhausted, and cerebral blood supply in insufficient to meet metabolic demand. We present an educational review of this important condition, which has a range of clinical manifestations. Method A non-systematic review of published literature was undertaken on CMP and major cerebral artery occlusive disease, using Pubmed and Sciencedirect. Findings Patients with CMP may present with strokes in watershed territories, collapses and transient ischaemic attacks or episodic movements associated with an orthostatic component. While positron emission tomography is the gold standard investigation for misery perfusion, advanced MRI is being increasingly used as an alternative investigation modality. The presence of CMP increases the risk of strokes. In addition to the devastating effect of stroke, there is accumulating evidence of impaired cognition and quality of life with carotid occlusive disease (COD) and misery perfusion. The evidence for revascularisation in the setting of complete carotid occlusion is weak. Medical management constitutes careful blood pressure management while addressing other vascular risk factors. Discussion The evidence for the management of patients with COD and CMP is discussed, together with recommendations based on our local experience. In this review, we focus on misery perfusion due to COD. Conclusion Patients with CMP and COD may present with a wide-ranging clinical phenotype and therefore to many specialties. Early identification of patients with misery perfusion may allow appropriate management and focus on strategies to maintain or improve cerebral blood flow, while avoiding potentially harmful treatment. PMID:28959496

Hemodynamic changes in a rat parietal cortex after endothelin-1-induced middle cerebral artery occlusion monitored by optical coherence tomography

NASA Astrophysics Data System (ADS)

Liu, Jian; Ma, Yushu; Dou, Shidan; Wang, Yi; La, Dongsheng; Liu, Jianghong; Ma, Zhenhe

2016-07-01

A blockage of the middle cerebral artery (MCA) on the cortical branch will seriously affect the blood supply of the cerebral cortex. Real-time monitoring of MCA hemodynamic parameters is critical for therapy and rehabilitation. Optical coherence tomography (OCT) is a powerful imaging modality that can produce not only structural images but also functional information on the tissue. We use OCT to detect hemodynamic changes after MCA branch occlusion. We injected a selected dose of endothelin-1 (ET-1) at a depth of 1 mm near the MCA and let the blood vessels follow a process first of occlusion and then of slow reperfusion as realistically as possible to simulate local cerebral ischemia. During this period, we used optical microangiography and Doppler OCT to obtain multiple hemodynamic MCA parameters. The change trend of these parameters from before to after ET-1 injection clearly reflects the dynamic regularity of the MCA. These results show the mechanism of the cerebral ischemia-reperfusion process after a transient middle cerebral artery occlusion and confirm that OCT can be used to monitor hemodynamic parameters.

Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats.

PubMed

Horiguchi, Takashi; Kis, Bela; Rajapakse, Nishadi; Shimizu, Katsuyoshi; Busija, David W

2003-04-01

The role of mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) in ischemic tolerance has been well documented in heart, but little work has been done in brain. To investigate the involvement of mitoK(ATP) activation in chemical preconditioning in brain, we examined the effect of 5-hydroxydecanoate (5-HD), a selective mitoK(ATP) blocker, on neurotoxin 3-nitropropionic acid (3-NPA)-induced ischemic tolerance to transient focal cerebral ischemia in rats. Male Wistar rats were administrated 3-NPA (20 mg/kg IP; n=16) or vehicle (saline; n=16) 3 days before temporary occlusion (120 minutes) of the middle cerebral artery; 5-HD (40 mg/kg IP; n=16) was injected 20 minutes before 3-NPA administration. Infarct volumes were measured 4 days after reperfusion. To directly investigate whether chemical preconditioning activates mitoK(ATP), we tested the effect of prior incubation with 1 mmol/L 5-HD on 300 micromol/L 3-NPA-induced alterations of mitochondrial membrane potential (Delta(Psi)m) in cultured neurons and astrocytes using the fluorescent dye tetramethylrhodamine ethyl ester. Treatment with 3-NPA exhibited a 16% reduction (P<0.05) and 23% reduction in infarct volume (P<0.01) for total brain and cortex, respectively. Pretreatment with 5-HD completely abolished the neuroprotective effect of chemical preconditioning. In cultured cells, 3-NPA resulted in mitochondrial depolarization. This change of Delta(Psi)m was completely blocked by 5-HD pretreatment. These results strongly suggest that opening of mitoK(ATP) plays a key role as the trigger in the development of 3-NPA-induced ischemic tolerance in brain.

Down-regulated Na+/K+-ATPase activity in ischemic penumbra after focal cerebral ischemia/reperfusion in rats

PubMed Central

Huang, Hao; Chen, Yang-Mei; Zhu, Fei; Tang, Shi-Ting; Xiao, Ji-Dong; Li, Lv-Li; Lin, Xin-Jing

2015-01-01

This study was aimed to examine whether the Na+/K+ adenosine triphosphatase (Na+/K+-ATPase) activity in ischemic penumbra is associated with the pathogenesis of ischemia/reperfusion-induced brain injury. An experimental model of cerebral ischemia/reperfusion was made by transient middle cerebral artery occlusion (tMCAO) in rats and the changes of Na+/K+-ATPase activity in the ischemic penumbra was examined by Enzyme Assay Kit. Extensive infarction was observed in the frontal and parietal cortical and subcortical areas at 6 h, 24 h, 48 h, 3 d and 7 d after tMCAO. Enzyme Assay analyses revealed the activity of Na+/K+-ATPase was decreased in the ischemic penumbra of model rats after focal cerebral ischemia/reperfusion compared with sham-operated rats, and reduced to its minimum at 48 h, while the infarct volume was enlarged gradually. In addition, accompanied by increased brain water content, apoptosis-related bcl-2 and Bax proteins, apoptotic index and neurologic deficits Longa scores, but fluctuated the ratio of bcl-2/Bax. Correlation analysis showed that the infarct volume, apoptotic index, neurologic deficits Longa scores and brain water content were negatively related with Na+/K+-ATPase activity, while the ratio of bcl-2/Bax was positively related with Na+/K+-ATPase activity. Our results suggest that down-regulated Na+/K+-ATPase activity in ischemic penumbra might be involved in the pathogenesis of cerebral ischemia/reperfusion injury presumably through the imbalance ratio of bcl-2/Bax and neuronal apoptosis, and identify novel target for neuroprotective therapeutic intervention in cerebral ischemic disease. PMID:26722460

Blood-Spinal Cord Barrier Alterations in Subacute and Chronic Stages of a Rat Model of Focal Cerebral Ischemia

PubMed Central

Haller, Edward; Tajiri, Naoki; Thomson, Avery; Barretta, Jennifer; Williams, Stephanie N.; Haim, Eithan D.; Qin, Hua; Frisina-Deyo, Aric; Abraham, Jerry V.; Sanberg, Paul R.; Van Loveren, Harry; Borlongan, Cesario V.

2016-01-01

We previously demonstrated blood-brain barrier impairment in remote contralateral brain areas in rats at 7 and 30 days after transient middle cerebral artery occlusion (tMCAO), indicating ischemic diaschisis. Here, we focused on effects of subacute and chronic focal cerebral ischemia on the blood-spinal cord barrier (BSCB). We observed BSCB damage on both sides of the cervical spinal cord in rats at 7 and 30 days post-tMCAO. Major BSCB ultrastructural changes in spinal cord gray and white matter included vacuolated endothelial cells containing autophagosomes, pericyte degeneration with enlarged mitochondria, astrocyte end-feet degeneration and perivascular edema; damaged motor neurons, swollen axons with unraveled myelin in ascending and descending tracts and astrogliosis were also observed. Evans Blue dye extravasation was maximal at 7 days. There was immunofluorescence evidence of reduction of microvascular expression of tight junction occludin, upregulation of Beclin-1 and LC3B immunoreactivities at 7 days and a reduction of the latter at 30 days post-ischemia. These novel pathological alterations on the cervical spinal cord microvasculature in rats after tMCAO suggest pervasive and long-lasting BSCB damage after focal cerebral ischemia, and that spinal cord ischemic diaschisis should be considered in the pathophysiology and therapeutic approaches in patients with ischemic cerebral infarction. PMID:27283328

Role of Hydrogen Sulfide in Early Blood-Brain Barrier Disruption following Transient Focal Cerebral Ischemia

PubMed Central

Jiang, Zheng; Li, Chun; Manuel, Morganne L.; Yuan, Shuai; Kevil, Christopher G.; McCarter, Kimberly D.; Lu, Wei; Sun, Hong

2015-01-01

We determined the role of endogenous hydrogen sulfide (H₂S) in cerebral vasodilation/hyperemia and early BBB disruption following ischemic stroke. A cranial window was prepared over the left frontal, parietal and temporal cortex in mice. Transient focal cerebral Ischemia was induced by directly ligating the middle cerebral artery (MCA) for two hours. Regional vascular response and cerebral blood flow (CBF) during ischemia and reperfusion were measured in real time. Early BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. Topical treatment with DL-propargylglycine (PAG, an inhibitor for cystathionine γ-lyase (CSE)) and aspartate (ASP, inhibitor for cysteine aminotransferase/3-mercaptopyruvate sulfurtransferase (CAT/3-MST)), but not O-(Carboxymethyl)hydroxylamine hemihydrochloride (CHH, an inhibitor for cystathionine β-synthase (CBS)), abolished postischemic cerebral vasodilation/hyperemia and prevented EB and Na-F extravasation. CSE knockout (CSE-/-) reduced postischemic cerebral vasodilation/hyperemia but only inhibited Na-F extravasation. An upregulated CBS was found in cerebral cortex of CSE-/- mice. Topical treatment with CHH didn’t further alter postischemic cerebral vasodilation/hyperemia, but prevented EB extravasation in CSE-/- mice. In addition, L-cysteine-induced hydrogen sulfide (H2S) production similarly increased in ischemic side cerebral cortex of control and CSE-/- mice. Our findings suggest that endogenous production of H2S by CSE and CAT/3-MST during reperfusion may be involved in postischemic cerebral vasodilation/hyperemia and play an important role in early BBB disruption following transient focal cerebral ischemia. PMID:25695633

Role of nitric oxide synthases in early blood-brain barrier disruption following transient focal cerebral ischemia.

PubMed

Jiang, Zheng; Li, Chun; Arrick, Denise M; Yang, Shu; Baluna, Alexandra E; Sun, Hong

2014-01-01

The role of nitric oxide synthases (NOSs) in early blood-brain barrier (BBB) disruption was determined using a new mouse model of transient focal cerebral ischemia. Ischemia was induced by ligating the middle cerebral artery (MCA) at its M2 segment and reperfusion was induced by releasing the ligation. The diameter alteration of the MCA, arterial anastomoses and collateral arteries were imaged and measured in real time. BBB disruption was assessed by Evans Blue (EB) and sodium fluorescein (Na-F) extravasation at 3 hours of reperfusion. The reperfusion produced an extensive vasodilation and a sustained hyperemia. Although expression of NOSs was not altered at 3 hours of reperfusion, L-NAME (a non-specific NOS inhibitor) abolished reperfusion-induced vasodilation/hyperemia and significantly reduced EB and Na-F extravasation. L-NIO (an endothelial NOS (eNOS) inhibitor) significantly attenuated cerebral vasodilation but not BBB disruption, whereas L-NPA and 7-NI (neuronal NOS (nNOS) inhibitors) significantly reduced BBB disruption but not cerebral vasodilation. In contrast, aminoguanidine (AG) (an inducible NOS (iNOS) inhibitor) had less effect on either cerebral vasodilation or BBB disruption. On the other hand, papaverine (PV) not only increased the vasodilation/hyperemia but also significantly reduced BBB disruption. Combined treatment with L-NAME and PV preserved the vasodilation/hyperemia and significantly reduced BBB disruption. Our findings suggest that nNOS may play a major role in early BBB disruption following transient focal cerebral ischemia via a hyperemia-independent mechanism.

Sodium transport through the cerebral sodium-glucose transporter exacerbates neuron damage during cerebral ischaemia.

PubMed

Yamazaki, Yui; Harada, Shinichi; Wada, Tetsuyuki; Yoshida, Shigeru; Tokuyama, Shogo

2016-07-01

We recently demonstrated that the cerebral sodium-glucose transporter (SGLT) is involved in postischaemic hyperglycaemia-induced exacerbation of cerebral ischaemia. However, the associated SGLT-mediated mechanisms remain unclear. Thus, we examined the involvement of cerebral SGLT-induced excessive sodium ion influx in the development of cerebral ischaemic neuronal damage. [Na+]i was estimated according to sodium-binding benzofuran isophthalate fluorescence. In the in vitro study, primary cortical neurons were prepared from fetuses of ddY mice. Primary cortical neurons were cultured for 5 days before each treatment with reagents, and these survival rates were assessed using biochemical assays. In in vivo study, a mouse model of focal ischaemia was generated using middle cerebral artery occlusion (MCAO). In these experiments, treatment with high concentrations of glucose induced increment in [Na+]i, and this phenomenon was suppressed by the SGLT-specific inhibitor phlorizin. SGLT-specific sodium ion influx was induced using a-methyl-D-glucopyranoside (a-MG) treatments, which led to significant concentration-dependent declines in neuronal survival rates and exacerbated hydrogen peroxide-induced neuronal cell death. Moreover, phlorizin ameliorated these effects. Finally, intracerebroventricular administration of a-MG exacerbated the development of neuronal damage induced by MCAO, and these effects were ameliorated by the administration of phlorizin. Hence, excessive influx of sodium ions into neuronal cells through cerebral SGLT may exacerbate the development of cerebral ischaemic neuronal damage. © 2016 Royal Pharmaceutical Society.

Neuroprotective effect of humic Acid on focal cerebral ischemia injury: an experimental study in rats.

PubMed

Ozkan, Adile; Sen, Halil Murat; Sehitoglu, Ibrahim; Alacam, Hasan; Guven, Mustafa; Aras, Adem Bozkurt; Akman, Tarik; Silan, Coşkun; Cosar, Murat; Karaman, Handan Isin Ozisik

2015-02-01

Stroke is still a major cause of death and permanent neurological disability. As humic acids are well-known antioxidant molecules, the purpose of this study was to investigate the potential neuroprotective effects of humic acid in a focal cerebral ischemia model. Twenty-four rats were divided equally into three groups. A middle cerebral artery occlusion model was performed in this study where control (group II) and humic acid (group III) were administered intraperitoneally following an ischemic experimental procedure. Group I was evaluated as sham. Malondialdehyde (MDA), superoxide dismutase (SOD), and nuclear respiratory factor-1 (NRF-1) levels were analyzed biochemically on the right side of the ischemic cerebral hemisphere, while ischemic histopathological studies were completed on the left side to investigate the antioxidant status. Biochemical results showed that SOD and NRF-1 levels were significantly increased in the humic acid group (III) compared with the control group (II) while MDA levels were significantly decreased. On histopathological examination, cerebral edema, vacuolization, degeneration, and destruction of neural elements were decreased in the humic acid group (III) compared with the control group (II). Cerebral ischemia was attenuated by humic acid administration. These observations indicate that humic acid may have potential as a therapeutic agent in cerebral ischemia by preventing oxidative stress.

Breviscapine confers a neuroprotective efficacy against transient focal cerebral ischemia by attenuating neuronal and astrocytic autophagy in the penumbra.

PubMed

Pengyue, Zhang; Tao, Guo; Hongyun, He; Liqiang, Yang; Yihao, Deng

2017-06-01

Breviscapine is a flavonoid derived from a traditional Chinese herb Erigerin breviscapus (Vant.) Hand-Mazz, and has been extensively used in clinical treatment for cerebral stroke in China, but the underlying pharmacological mechanisms are still unclear. In present study, we investigated whether breviscapine could confer a neuroprotection against cerebral ischemia injury by targeting autophagy mechanisms. A cerebral stroke model in Sprague-Dawley rats was prepared by middle cerebral artery occlusion (MCAO), rats were then randomly divided into 5 groups: MCAO+Bre group, rats were treated with breviscapine; MCAO+Tat-Beclin-1 group, animals were administrated with specific autophagy inducer Tat-Beclin-1; MCAO+Bre+Tat-Beclin-1 group, rats were treated with both breviscapine and Tat-Beclin-1, MCAO+saline group, rats received the same volume of physiological saline, and Sham surgery group. The autophagy levels in infarct penumbra were evaluated by western blotting, real-time PCR and immunofluorescence 7days after the insult. Meanwhile, infarct volume, brain water content and neurological deficit score were assessed. The results illustrated that the infarct volume, brain water content and neurofunctional deficiency were significantly reduced by 7days of breviscapine treatment in MCAO+Bre group, compared with those in MCAO+saline group. Meanwhile, the western blotting, quantitative PCR and immunofluorescence showed that the autophagy in both neurons and astrocytes at the penumbra were markedly attenuated by breviscapine admininstration. Moreover, these pharmacological effects of breviscapine could be counteracted by autophagy inducer Tat-Beclin-1. Our study suggests that breviscapine can provide a neuroprotection against transient focal cerebral ischemia, and this biological function is associated with attenuating autophagy in both neurons and astrocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Sulforaphane exerts neuroprotective effects via suppression of the inflammatory response in a rat model of focal cerebral ischemia.

PubMed

Ma, Li-Li; Xing, Guo-Ping; Yu, Yin; Liang, Hui; Yu, Tian-Xia; Zheng, Wei-Hong; Lai, Tian-Bao

2015-01-01

Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a promising target for treatment. Sulforaphane exerts protective effects in a rat model of focal cerebral ischemia/reperfusion injury by alleviating brain edema. However, the possible mechanisms of sulforaphane after cerebral ischemia/reperfusion injury have not been fully elucidated. Therefore, in the present study, we investigated the effect of sulforaphane on inflammatory reaction and the potential molecular mechanisms in cerebral ischemia rats. We found that sulforaphane significantly attenuated the blood-brain barrier (BBB) disruption; decreased the levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β; reduced the nitric oxide (NO) levels and inducible nitric oxide synthase (iNOS) activity; inhibited the expression of iNOS and cyclooxygenase-2 (COX-2). In addition, sulforaphane inhibits the expression of p-NF-κB p65 after focal cerebral ischemia-reperfusion injury. Taken together, our results suggest that sulforaphane suppresses the inflammatory response via inhibiting the NF-κB signaling pathway in a rat model of focal cerebral ischemia, and sulforaphane may be a potential therapeutic agent for the treatment of cerebral ischemia injury.

Cerebral hematocrit decreases with hemodynamic compromise in carotid artery occlusion: a PET study.

PubMed

Yamauchi, H; Fukuyama, H; Nagahama, Y; Katsumi, Y; Okazawa, H

1998-01-01

This study investigated whether in patients with internal carotid artery occlusion the regional cerebral hematocrit correlates with cerebral hemodynamics or metabolic state and, if so, how the regional cerebral hematocrit changes in the hemodynamically compromised region. We used positron emission tomography to study seven patients with unilateral internal carotid artery occlusion and no cortical infarction in the chronic stage. The distributions of red blood cell and plasma volumes were assessed using oxygen-15-labeled carbon monoxide and copper-62-labeled human serum albumin-dithiosemicarbazone tracers, respectively. The calculated hematocrit value was compared with the hemodynamic and metabolic parameters measured with the oxygen-15 steady-state technique. In the cerebral cortex, the value of the cerebral hematocrit varied but was correlated with the hemodynamic and metabolic status. Stepwise regression analysis revealed that the large vessel hematocrit, the cerebral metabolic rate of oxygen, and the cerebral blood flow or the oxygen extraction fraction accounted for a significant proportion of variance of the cerebral hematocrit. The oxygen extraction fraction and the cerebral metabolic rate of oxygen negatively correlated with the cerebral hematocrit, whereas the cerebral blood flow correlated positively: patients with reduced blood supply relative to metabolic demand (decreased blood flow with increased oxygen extraction fraction) showed low hematocrit values. In carotid artery occlusion in the chronic stage, regional cerebral hematocrit may vary according to cerebral hemodynamics and metabolic status. Regional cerebral hematocrit may decrease with hemodynamic compromise unless oxygen metabolism concomitantly decreases.

Alpha-Tocopherol Reduces Brain Edema and Protects Blood-Brain Barrier Integrity following Focal Cerebral Ischemia in Rats.

PubMed

Haghnejad Azar, Adel; Oryan, Shahrbanoo; Bohlooli, Shahab; Panahpour, Hamdollah

2017-01-01

This study was conducted to examine the neuroprotective effects of α-tocopherol against edema formation and disruption of the blood-brain barrier (BBB) following transient focal cerebral ischemia in rats. Ninety-six male Sprague-Dawley rats were divided into 3 major groups (n = 32 in each), namely the sham, and control and α-tocopherol-treated (30 mg/kg) ischemic groups. Transient focal cerebral ischemia (90 min) was induced by occlusion of the left middle cerebral artery. At the end of the 24-hour reperfusion period, the animals were randomly selected and used for 4 investigations (n = 8) in each of the 3 main groups: (a) assessment of neurological score and measurement of infarct size, (b) detection of brain edema formation by the wet/dry method, (c) evaluation of BBB permeability using the Evans blue (EB) extravasation technique, and (d) assessment of the malondialdehyde (MDA) and reduced glutathione (GSH) concentrations using high-performance liquid chromatography methods. Induction of cerebral ischemia in the control group produced extensive brain edema (brain water content 83.8 ± 0.11%) and EB leakage into brain parenchyma (14.58 ± 1.29 µg/g) in conjunction with reduced GSH and elevated MDA levels (5.86 ± 0.31 mmol/mg and 63.57 ± 5.42 nmol/mg, respectively). Treatment with α-tocopherol significantly lowered brain edema formation and reduced EB leakage compared with the control group (p < 0.001, 80.1 ± 0.32% and 6.66 ± 0.87 µg/g, respectively). Meanwhile, treatment with α-tocopherol retained tissue GSH levels and led to a lower MDA level (p < 0.01, 10.17 ± 0.83 mmol/mg, and p < 0.001, 26.84 ± 4.79 nmol/mg, respectively). Treatment with α-tocopherol reduced ischemic edema formation and produced protective effects on BBB function following ischemic stroke occurrence. This effect could be through increasing antioxidant activity. © 2016 S. Karger AG, Basel.

Licorice Pretreatment Protects Against Brain Damage Induced by Middle Cerebral Artery Occlusion in Mice.

PubMed

Lim, Chiyeon; Lim, Sehyun; Lee, Byoungho; Kim, Buyeo; Cho, Suin

2018-05-01

Licorice is extracted from the roots of plants in the Glycyrrhiza genus, especially Glycyrrhiza uralensis in China and Korea. It has several pharmacological activities, including neuro-protective, anti-fungal, and anti-cariogenic effects. Ischemia/reperfusion-induced brain injury is a leading cause of adult disability and death; thus, the identification of anti-apoptotic, neuro-protective therapeutic agents is viewed as an attractive drug development strategy. Infarct volumes and the expression of several apoptosis-related proteins, including Bcl-xL, Bcl-2, caspase-8, and caspase-9, were evaluated by western blotting in the brains of mice subjected to middle cerebral artery occlusion (MCAO). Three consecutive days of oral pretreatment with the methanol extract of licorice (GRex) significantly reduced infarct volumes 24 h after MCAO. In addition, GRex effectively inhibited the activation of caspase-9 by upregulating protein expression of Bcl-xL and Bcl-2. The neuro-protective effect of licorice was due to its regulation of apoptosis-related proteins. These data suggest that licorice could be a potential candidate for the treatment of ischemia-induced brain damage.

Microarray expression profiles of genes in lung tissues of rats subjected to focal cerebral ischemia-induced lung injury following bone marrow-derived mesenchymal stem cell transplantation.

PubMed

Hu, Yue; Xiong, Liu-Lin; Zhang, Piao; Wang, Ting-Hua

2017-01-01

Ischemia-induced stroke is the most common disease of the nervous system and is associated with a high mortality rate worldwide. Cerebral ischemia may lead to remote organ dysfunction, particular in the lungs, resulting in lung injury. Nowadays, bone marrow-derived mesenchymal stem cells (BMSCs) are widely studied in clinical trials as they may provide an effective solution to the treatment of neurological and cardiac diseases; however, the underlying molecular mechanisms remain unknown. In this study, a model of permanent focal cerebral ischemia-induced lung injury was successfully established and confirmed by neurological evaluation and lung injury scores. We demonstrated that the transplantation of BMSCs (passage 3) via the tail vein into the lung tissues attenuated lung injury. In order to elucidate the underlying molecular mechanisms, we analyzed the gene expression profiles in lung tissues from the rats with focal cerebral ischemia and transplanted with BMSCs using a Gene microarray. Moreover, the Gene Ontology database was employed to determine gene function. We found that the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) were downregulated in the BMSC transplantation groups, compared with the control group. These results suggested that BMSC transplantation may attenuate lung injury following focal cerebral ischemia and that this effect is associated with the downregulation of TGF-β, PDGF and the PI3K-AKT pathway.

[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.

Neuroprotective Mechanisms of Calycosin Against Focal Cerebral Ischemia and Reperfusion Injury in Rats.

PubMed

Wang, Yong; Ren, Qianyao; Zhang, Xing; Lu, Huiling; Chen, Jian

2018-01-01

Emerging evidence suggests that autophagy plays important roles in the pathophysiological processes of cerebral ischemia and reperfusion injury. Calycosin, an isoflavone phytoestrogen, possesses neuroprotective effects in cerebral ischemia and reperfusion in rats. Here, we investigated the neuroprotective effects of calycosin against ischemia and reperfusion injury, as well as related probable mechanisms behind autophagy pathways. A cerebral ischemic and reperfusion injury model was established by middle cerebral artery occlusion in male Sprague-Dawley rats. Neurological scores, infarct volumes, and brain water content were assessed after 24 h reperfusion following 2 h ischemia. Additionally, the expression of the autophagy-related protein p62 and NBR1 (neighbor of BRCA1 gene 1), as well as Bcl-2, and TNF-α in rat brain tissues was measured by RT-PCR, western blotting and immunohistochemical analyses. The results showed that calycosin pretreatment for 14 days markedly decreased infarct volume and brain edema, and ameliorated neurological scores in rats with focal cerebral ischemia and reperfusion. It was observed that levels of p62, NBR1 and Bcl-2 were greatly decreased, and levels of TNF-α significantly increased after ischemia and reperfusion injury. However, calycosin administration dramatically upregulated the expression of p62, NBR1 and Bcl-2, and downregulated the level of TNF-α. All data reveal that calycosin exerts a neuroprotective effect on cerebral ischemia and reperfusion injury, and the mechanisms maybe associated with its anti-autophagic, anti-apoptotic and anti-inflammatory action. © 2018 The Author(s). Published by S. Karger AG, Basel.

Intracerebral Hemorrhage Caused by Cerebral Hyperperfusion after Superficial Temporal Artery to Middle Cerebral Artery Bypass for Atherosclerotic Occlusive Cerebrovascular Disease

PubMed Central

Matano, Fumihiro; Murai, Yasuo; Mizunari, Takayuki; Adachi, Koji; Kobayashi, Shiro; Morita, Akio

Few papers have reported detailed accounts of intracerebral hemorrhage caused by cerebral hyperperfusion after superficial temporal artery to middle cerebral artery bypass (STA-MCA) bypass for atherosclerotic occlusive cerebrovascular disease. We report a case of vasogenic edema and subsequent intracerebral hemorrhage caused by the cerebral hyperperfusion syndrome (CHS) after STA-MCA bypass for atherosclerotic occlusive cerebrovascular disease disease without intense postoperative blood pressure control. A 63-year-old man with repeating left hemiparesis underwent magnetic resonance angiography (MRA), which revealed right internal carotid artery (ICA) occlusion. We performed a double bypass superficial temporal artery (STA)–middle cerebral artery (MCA) bypass surgery for the M2 and M3 branches. While the patient’s postoperative course was relatively uneventful, he suffered generalized convulsions, and computed tomography revealed a low area in the right frontal lobe on Day 4 after surgery. We considered this lesion to be pure vasogenic edema caused by cerebral hyperperfusion after revascularization. Intravenous drip infusion of a free radical scavenger (edaravone) and efforts to reduce systolic blood pressure to <120 mmHg were continued. The patient experienced severe left hemiparesis and disturbance of consciousness on Day 8 after surgery, due to intracerebral hemorrhage in the right frontal lobe at the site of the earlier vasogenic edema. Brain edema associated with cerebral hyperperfusion after STA-MCA bypass for atherosclerotic occlusive cerebrovascular disease should be recognized as a risk factor for intracerebral hemorrhage. The development of brain edema associated with CHS after STA-MCA bypass for atherosclerotic occlusive cerebrovascular disease requires not only intensive control of blood pressure, but also consideration of sedation therapy with propofol. PMID:28664022

Longitudinal imaging of the availability of dopamine transporter and D2 receptor in rat striatum following mild ischemia.

PubMed

Momosaki, Sotaro; Ito, Miwa; Yamato, Hiroko; Iimori, Hitoshi; Sumiyoshi, Hirokazu; Morimoto, Kenji; Imamoto, Natsumi; Watabe, Tadashi; Shimosegawa, Eku; Hatazawa, Jun; Abe, Kohji

2017-02-01

The changes in the availability of striatal dopamine transporter and dopamine D2 receptor after mild focal ischemia in rats were measured using a small animal positron emission tomography system. Mild focal ischemia was induced by 20-minute middle cerebral artery occlusion. [ 11 C]PE2I binding to dopamine transporter was transiently increased on the ipsilateral side of the striatum at 2 days after middle cerebral artery occlusion. On day 7 and 14 after middle cerebral artery occlusion, [ 11 C]PE2I binding levels were decreased. In contrast, [ 11 C]raclopride binding to dopamine D2 receptor in the ipsilateral striatum had not changed at 2 days after middle cerebral artery occlusion. [ 11 C]Raclopride binding was significantly decreased on the ischemic side of the striatum at 7 and 14 days after middle cerebral artery occlusion. Moreover, on day 1 and 2 after middle cerebral artery occlusion, significant circling behavior to the contralateral direction was induced by amphetamine challenge. This behavior disappeared at 7 days after middle cerebral artery occlusion. At 14 days, circling behavior to the ipsilateral direction (middle cerebral artery occlusion side) was significantly increased, and that to the contralateral direction also appeared again. The present study suggested that amphetamine-induced circling behavior indicated striatal dopaminergic alterations and that dopamine transporter and dopamine D2 receptor binding could be key markers for predicting motor dysfunction after mild focal ischemia.

Gene inactivation of Na+/H+ exchanger isoform 1 attenuates apoptosis and mitochondrial damage following transient focal cerebral ischemia

PubMed Central

Wang, Yanping; Luo, Jing; Chen, Xinzhi; Chen, Hai; Cramer, Sam W.; Sun, Dandan

2010-01-01

We investigated mechanisms underlying the Na+/H+ exchanger isoform 1 (NHE1)-mediated neuronal damage in transient focal ischemia. Physiological parameters, body and tympanic temperatures, and regional cerebral blood flow during 30 min middle cerebral artery occlusion (MCAO) were similar in wild-type NHE1 (NHE1+/+) and NHE1 heterozygous (NHE1+/−) mice. NHE1+/+ mice developed infarct volume of 57.3 ± 8.8 mm3 at 24 h reperfusion (Rp), which progressed to 86.1 ± 10.0 mm3 at 72 h Rp. This delayed cell death was preceded by release of mitochondrial cytochrome c (Cyt. C), nuclear translocation of apoptosis-inducing factor (AIF), activation of caspase-3, and TUNEL-positive staining and chromatin condensation in the ipsilateral hemispheres of NHE1+/+ brains. In contrast, NHE1+/− mice had a significantly smaller infarct volume and improved neurological function. A similar neuroprotection was obtained with NHE1 inhibitor HOE 642. The number of apoptotic cells, release of AIF and Cyt. C or levels of active caspase-3 was significantly reduced in NHE1+/− brains. These data imply that NHE1 activity may contribute to ischemic apoptosis. Ischemic brains did not exhibit changes of NHE1 protein expression. In contrast, up-regulation of NHE1 expression was found in NHE1+/+ neurons after in vitro ischemia. These data suggest that NHE1 activation following cerebral ischemia contributes to mitochondrial damage and ischemic apoptosis. PMID:18662334

Life-threatening Cerebral Edema Caused by Acute Occlusion of a Superior Vena Cava Stent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sofue, Keitaro, E-mail: keitarosofue@yahoo.co.jp; Takeuchi, Yoshito, E-mail: yotake62@qg8.so-net.ne.jp; Arai, Yasuaki, E-mail: arai-y3111@mvh.biglobe.ne.jp

A71-year-old man with advanced lung cancer developed a life-threatening cerebral edema caused by the acute occlusion of a superior vena cava (SVC) stent and was successfully treated by an additional stent placement. Although stent occlusion is a common early complication, no life-threatening situations have been reported until now. Our experience highlights the fact that acute stent occlusion can potentially lead to the complete venous shutdown of the SVC, resulting in life-threatening cerebral edema, after SVC stent placement. Immediate diagnosis and countermeasures are required.

Rapamycin alleviates brain edema after focal cerebral ischemia reperfusion in rats.

PubMed

Guo, Wei; Feng, Guoying; Miao, Yanying; Liu, Guixiang; Xu, Chunsheng

2014-06-01

Brain edema is a major consequence of cerebral ischemia reperfusion. However, few effective therapeutic options are available for retarding the brain edema progression after cerebral ischemia. Recently, rapamycin has been shown to produce neuroprotective effects in rats after cerebral ischemia reperfusion. Whether rapamycin could alleviate this brain edema injury is still unclear. In this study, the rat stroke model was induced by a 1-h left transient middle cerebral artery occlusion using an intraluminal filament, followed by 48 h of reperfusion. The effects of rapamycin (250 μg/kg body weight, intraperitoneal; i.p.) on brain edema progression were evaluated. The results showed that rapamycin treatment significantly reduced the infarct volume, the water content of the brain tissue and the Evans blue extravasation through the blood-brain barrier (BBB). Rapamycin treatment could improve histological appearance of the brain tissue, increased the capillary lumen space and maintain the integrity of BBB. Rapamycin also inhibited matrix metalloproteinase 9 (MMP9) and aquaporin 4 (AQP4) expression. These data imply that rapamycin could improve brain edema progression after reperfusion injury through maintaining BBB integrity and inhibiting MMP9 and AQP4 expression. The data of this study provide a new possible approach for improving brain edema after cerebral ischemia reperfusion by administration of rapamycin.

Inhibition of Cathepsin B Alleviates Secondary Degeneration in Ipsilateral Thalamus After Focal Cerebral Infarction in Adult Rats.

PubMed

Zuo, Xialin; Hou, Qinghua; Jin, Jizi; Zhan, Lixuan; Li, Xinyu; Sun, Weiwen; Lin, Kunqin; Xu, En

2016-09-01

Secondary degeneration in areas beyond ischemic foci can inhibit poststroke recovery. The cysteine protease Cathepsin B (CathB) regulates cell death and intracellular protein catabolism. To investigate the roles of CathB in the development of secondary degeneration in the ventroposterior nucleus (VPN) of the ipsilateral thalamus after focal cerebral infarction, infarct volumes, immunohistochemistry and immunofluorescence, and Western blotting analyses were conducted in a distal middle cerebral artery occlusion (dMCAO) stroke model in adult rats. We observed marked neuron loss and gliosis in the ipsilateral thalamus after dMCAO, and the expression of CathB and cleaved caspase-3 in the VPN was significantly upregulated; glial cells were the major source of CathB. Although it had no effect on infarct volume, delayed intracerebroventricular treatment with the membrane-permeable CathB inhibitor CA-074Me suppressed the expression of CathB and cleaved caspase-3 in ipsilateral VPN and accordingly alleviated the secondary degeneration. These data indicate that CathB mediates a novel mechanism of secondary degeneration in the VPN of the ipsilateral thalamus after focal cortical infarction and suggest that CathB might be a therapeutic target for the prevention of secondary degeneration in patients after stroke. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Neuroprotection of Osthole against Cerebral Ischemia/Reperfusion Injury through an Anti-apoptotic Pathway in Rats.

PubMed

Li, Kang; Ding, Dun; Zhang, Ming

2016-01-01

Cerebral ischemia/reperfusion (I/R) injury is a major cause of acute brain injury. The pathogenetic mechanisms underlying I/R injury involve apoptosis, inflammation and oxidative stress. Osthole-a plant coumarin compound-has been reported to protect against focal cerebral I/R-induced injury in rats. However, the mechanism remains unknown. Here we hypothesize that osthole acts through inhibition of apoptosis during focal cerebral I/R injury in rats. We induced cerebral I/R injury by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. We randomly assigned 60 rats to three groups (20 rats per group): sham-operated, vehicle-treated I/R, and osthole-treated I/R. We treated rats intraperitoneally with osthole (40 mg/kg) or vehicle 30 min before cerebral ischemia. We harvested the brains for infarct volume, brain water content, histological changes and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining as well as cleaved caspase-3, bax, and bcl-2 levels 24 h after reperfusion. Osthole treatment significantly attenuated cerebral dysfunction and histologic damage induced by I/R injury. Moreover, osthole-treated rats had a dramatic decrease in apoptotic neuronal cells along with a decrease in bax and cleaved caspase-3. The bcl-2 levels increased. Osthole treatment protects the brain from cerebral I/R injury by suppressing cell apoptosis. Thus, osthole may represent a novel practical strategy to prevent cerebral I/R injury.

Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice

PubMed Central

Chaparro, Rafael E; Izutsu, Miwa; Sasaki, Toshihiro; Sheng, Huaxin; Zheng, Yi; Sadeghian, Homa; Qin, Tao; von Bornstadt, Daniel; Herisson, Fanny; Duan, Bin; Li, Jing-Song; Jiang, Kai; Pearlstein, Molly; Pearlstein, Robert D; Smith, David E; Goldberg, Itzhak D; Ayata, Cenk; Warner, David S

2015-01-01

Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood–brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke. PMID:25712497

Methylene Blue Ameliorates Ischemia/Reperfusion-Induced Cerebral Edema: An MRI and Transmission Electron Microscope Study.

PubMed

Fang, Qing; Yan, Xu; Li, Shaowu; Sun, Yilin; Xu, Lixin; Shi, Zhongfang; Wu, Min; Lu, Yi; Dong, Liping; Liu, Ran; Yuan, Fang; Yang, Shao-Hua

2016-01-01

The neuroprotective effect of methylene blue (MB) has been identified against various brain disorders, including ischemic stroke. In the present study, we evaluated the effects of MB on postischemic brain edema using magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Adult male rats were subjected to transient focal cerebral ischemia induced by 1 h middle cerebral artery occlusion (MCAO), followed by reperfusion. MB was infused intravenously immediately after reperfusion (3 mg/kg) and again at 3 h post-occlusion (1.5 mg/kg). Normal saline was administered as vehicle control. Sequential MRIs, including apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI), were obtained at 0.5, 2.5, and 48 h after the onset of stroke. Separated groups of animals were sacrificed at 2.5 and 48 h after stroke for ultrastructural analysis by TEM. In addition, final lesion volumes were analyzed by triphenyltetrazolium chloride (TTC) staining at 48 h after stroke. Ischemic stroke induced ADC lesion volume at 0.5 h during MCAOs that were temporally recovered at 1.5 h after reperfusion. No significant difference in ADC-defined lesion was observed between vehicle and MB treatment groups. At 48 h after stroke, MB significantly reduced ADC lesion and T2WI lesion volume and attenuated cerebral swelling. Consistently, MB treatment significantly decreased TTC-defined lesion volume at 48 h after stroke. TEM revealed remarkable swollen astrocytes, astrocytic perivascular end-feet, and concurrent shrunken neurons in the penumbra at 2.5 and 48 h after MCAO. MB treatment attenuated astrocyte swelling, the perivascular astrocytic foot process, and endothelium and also alleviated neuron degeneration. This study demonstrated that MB could decrease postischemic brain edema and provided additional evidence that future clinical investigation of MB for the treatment of ischemic stroke is warrented.

EMBOLIC MIDDLE CEREBRAL ARTERY OCCLUSION MODEL USING THROMBIN AND FIBRINOGEN COMPOSED CLOTS IN RAT

PubMed Central

Ren, Ming; Lin, Zi-Jing; Qian, Hai; Gourav, Choudhury Roy; liu, Ran; Liu, Hanli; Yang, Shao-Hua

2012-01-01

Ischemic stroke accounts for over 80% in total human stroke which mostly affect middle cerebral artery (MCA) territory. Embolic stroke models induced by injection of homologous clots into the internal carotid artery and MCA closely mimic human stroke and have been commonly used in stroke research. Studies indicate that the size and composition of clots are critical for the reproducibility of the stroke model. In the present study, we modified the homologous clots formation by addition of thrombin and fibrinogen which produced even distribution of fibrin with tight cross linkage of red blood cells. We optimized the embolic MCA occlusion model in rats using different size of the mixed clots. A precise lodgment of the clots at the MCA bifurcation and highly reproducible ischemic lesion in the MCA territory were demonstrated in the embolic MCA occlusion model induced by injection of 10 pieces of 1-mm long mixed clots made in PE-60 catheter. We further tested the effect of recombinant tissue plasminogen activator (rtPA) in this embolic MCA occlusion model. rtPA induced thrombolysis, improved neurological outcome, and significantly reduced ischemic lesion volume when administered at 1 hour after embolism as compared with control. In summary, we have established a reproducible embolic MCA occlusion model using clots made of homologous blood, thrombin and fibrinogen. The mixed clots enable precise lodgment at the MCA bifurcation which is responsive to thrombolytic therapy of rtPA. PMID:22985597

Embolic middle cerebral artery occlusion model using thrombin and fibrinogen composed clots in rat.

PubMed

Ren, Ming; Lin, Zi-Jing; Qian, Hai; Choudhury, Gourav Roy; Liu, Ran; Liu, Hanli; Yang, Shao-Hua

2012-11-15

Ischemic stroke accounts for over 80% in total human stroke which mostly affect middle cerebral artery (MCA) territory. Embolic stroke models induced by injection of homologous clots into the internal carotid artery and MCA closely mimic human stroke and have been commonly used in stroke research. Studies indicate that the size and composition of clots are critical for the reproducibility of the stroke model. In the present study, we modified the homologous clots formation by addition of thrombin and fibrinogen which produced even distribution of fibrin with tight cross linkage of red blood cells. We optimized the embolic MCA occlusion model in rats using different size of the mixed clots. A precise lodgment of the clots at the MCA bifurcation and highly reproducible ischemic lesion in the MCA territory were demonstrated in the embolic MCA occlusion model induced by injection of 10 pieces of 1-mm long mixed clots made in PE-60 catheter. We further tested the effect of recombinant tissue plasminogen activator (rtPA) in this embolic MCA occlusion model. rtPA induced thrombolysis, improved neurological outcome, and significantly reduced ischemic lesion volume when administered at 1h after embolism as compared with control. In summary, we have established a reproducible embolic MCA occlusion model using clots made of homologous blood, thrombin and fibrinogen. The mixed clots enable precise lodgment at the MCA bifurcation which is responsive to thrombolytic therapy of rtPA. Copyright © 2012 Elsevier B.V. All rights reserved.

Bilateral ophthalmic artery occlusion in rhino-orbito-cerebral mucormycosis.

PubMed

Song, Yoo Mi; Shin, Sun Young

2008-03-01

To report a case of bilateral ophthalmic artery occlusion in rhino-orbito-cerebral mucormycosis. Reviewed clinical charts, photographs, and fluorescein angiography An 89-year-old man with poorly controlled diabetes developed sudden bilateral ptosis, complete ophthalmoplegia of the right eye, and superior rectus palsy of the left eye. Brain and orbit magnetic resonance imaging showed midbrain infarction and mild diffuse sinusitis. On the 2nd day of hospitalization, sudden visual loss and light reflex loss developed. There were retinal whitening, absence of retinal arterial filling, and a total lack of choroidal perfusion on fluorescein angiography of the right eye. The left eye showed a cherry red spot in the retina and the absence of retinal arterial filling and partial choroidal perfusion on fluorescein angiography. On rhinologic examination, mucormyosis was noticed. Despite treatment, visual acuity and light reflex did not recover and he died 4 days after admission. Bilateral ophthalmic artery occlusion can occur in rhino-orbital-cerebral mucormycosis.

Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation.

PubMed

Lin, Yun; Zhang, Jian-Cheng; Fu, Jun; Chen, Fang; Wang, Jie; Wu, Zhi-Lin; Yuan, Shi-Ying

2013-02-01

Hyperforin, a lipophilic constituent of medicinal herb St John's wort, has been identified as the main active ingredient of St John's wort extract for antidepressant action by experimental and clinical studies. Hyperforin is currently known to activate transient receptor potential canonical (subtype) 6 (TRPC6) channel, increase the phosphorylated CREB (p-CREB), and has N-methyl-D-aspartate receptor-antagonistic effect that convert potential neuroprotective effects in vitro. However, the protective effects of hyperforin on ischemic stroke in vivo remain controversial and its neuroprotective mechanisms are still unclear. This study was designed to examine the effects of intracerebroventricular (i.c.v.) injection of hyperforin on transient focal cerebral ischemia in rats. Hyperforin, when applied immediately after middle cerebral artery occlusion (MCAO) onset, significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores at 24 hours after reperfusion accompanied by elevated TRPC6 and p-CREB activity and decreased SBDP145 activity. When MEK or CaMKIV activity was specifically inhibited, the neuroprotective effect of hyperforin was attenuated, and we observed a correlated decrease in CREB activity. In conclusion, our results clearly showed that i.c.v. injection of hyperforin immediately after MCAO onset blocked calpain-mediated TRPC6 channels degradation, and then to stimulate the Ras/MEK/ERK and CaMKIV pathways that converge on CREB activation, contributed to neuroprotection.

Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation

PubMed Central

Lin, Yun; Zhang, Jian-Cheng; Fu, Jun; Chen, Fang; Wang, Jie; Wu, Zhi-Lin; Yuan, Shi-Ying

2013-01-01

Hyperforin, a lipophilic constituent of medicinal herb St John's wort, has been identified as the main active ingredient of St John's wort extract for antidepressant action by experimental and clinical studies. Hyperforin is currently known to activate transient receptor potential canonical (subtype) 6 (TRPC6) channel, increase the phosphorylated CREB (p-CREB), and has N-methyl-𝒟-aspartate receptor-antagonistic effect that convert potential neuroprotective effects in vitro. However, the protective effects of hyperforin on ischemic stroke in vivo remain controversial and its neuroprotective mechanisms are still unclear. This study was designed to examine the effects of intracerebroventricular (ICV) injection of hyperforin on transient focal cerebral ischemia in rats. Hyperforin, when applied immediately after middle cerebral artery occlusion (MCAO) onset, significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores at 24 hours after reperfusion accompanied by elevated TRPC6 and p-CREB activity and decreased SBDP145 activity. When MEK or CaMKIV activity was specifically inhibited, the neuroprotective effect of hyperforin was attenuated, and we observed a correlated decrease in CREB activity. In conclusion, our results clearly showed that ICV injection of hyperforin immediately after MCAO onset blocked calpain-mediated TRPC6 channels degradation, and then to stimulate the Ras/MEK/ERK and CaMKIV pathways that converge on CREB activation, contributed to neuroprotection. PMID:23149561

Protective effect of tetraethyl pyrazine against focal cerebral ischemia/reperfusion injury in rats: therapeutic time window and its mechanism.

PubMed

Jia, Jie; Zhang, Xi; Hu, Yong-Shan; Wu, Yi; Wang, Qing-Zhi; Li, Na-Na; Wu, Cai-Qin; Yu, Hui-Xian; Guo, Qing-Chuan

2009-03-01

Tetramethyl pyrazine has been considered an effective agent in treating neurons ischemia/reperfusion injury, but the mechanism of its therapeutic effect remains unclear. This study was to explore the therapeutic time window and mechanism of tetramethyl pyrazine on temporary focal cerebral ischemia/reperfusion injury. Middle cerebral artery occlusion was conducted in male Sprague-Dawley rats and 20 mg/kg of tetramethyl pyrazine was intraperitoneally injected at different time points. At 72 h after reperfusion, all animals' neurologic deficit scores were evaluated. Cerebrums were removed and cerebral infarction volume was measured. The expression of thioredoxin and thioredoxin reductase mRNA was determined at 6 and 24 h after reperfusion. Cerebral infarction volume and neurological deficit scores were significantly decreased in the group with tetramethyl pyrazine treatment. The expression of thioredoxin-1/thioredoxin-2 and thioredoxin reductase-1/thioredoxin reductase-2 was significantly decreased in rats with ischemia/reperfusion injury, while it was increased by tetramethyl pyrazine administration. Treatment with tetramethyl pyrazine, within 4 h after reperfusion, protects the brain from ischemic reperfusion injury in rats. The neuroprotective mechanism of tetramethyl pyrazine treatment is, in part, mediated through the upregulation of thioredoxin transcription.

Delayed brain ischemia tolerance induced by electroacupuncture pretreatment is mediated via MCP-induced protein 1

PubMed Central

2013-01-01

Background Emerging studies have demonstrated that pretreatment with electroacupuncture (EA) induces significant tolerance to focal cerebral ischemia. The present study seeks to determine the involvement of monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified novel modulator of inflammatory reactions, in the cerebral neuroprotection conferred by EA pretreatment in the animal model of focal cerebral ischemia and to elucidate the mechanisms of EA pretreatment-induced ischemic brain tolerance. Methods Twenty-four hours after the end of the last EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes in male C57BL/6 mice and MCPIP1 knockout mice. Transcription and expression of MCPIP1 gene was monitored by qRT-PCR, Western blot and immunohistochemistry. The neurobehavioral scores, infarction volumes, proinflammatory cytokines and leukocyte infiltration in brain and NF-κB signaling were evaluated after ischemia/reperfusion. Results MCPIP1 protein and mRNA levels significantly increased specifically in mouse brain undergoing EA pretreatment. EA pretreatment significantly attenuated the infarct volume, neurological deficits, upregulation of proinflammatory cytokines and leukocyte infiltration in the brain of wild-type mice after MCAO compared with that of the non-EA group. MCPIP1-deficient mice failed to evoke EA pretreatment-induced tolerance compared with that of the control MCPIP1 knockout group without EA treatment. Furthermore, the activation of NF-κB signaling was significantly reduced in EA-pretreated wild-type mice after MCAO compared to that of the non-EA control group and MCPIP1-deficient mice failed to confer the EA pretreatment-induced inhibition of NF-κB signaling after MCAO. Conclusions Our data demonstrated that MCPIP1 deficiency caused significant lack of EA pretreatment-induced cerebral protective effects after MCAO compared with the control group and that MCPIP1 is

PARK2-dependent mitophagy induced by acidic postconditioning protects against focal cerebral ischemia and extends the reperfusion window.

PubMed

Shen, Zhe; Zheng, Yanrong; Wu, Jiaying; Chen, Ying; Wu, Xiaoli; Zhou, Yiting; Yuan, Yang; Lu, Shousheng; Jiang, Lei; Qin, Zhenghong; Chen, Zhong; Hu, Weiwei; Zhang, Xiangnan

2017-03-04

Prompt reperfusion after cerebral ischemia is critical for neuronal survival. Any strategies that extend the limited reperfusion window will be of great importance. Acidic postconditioning (APC) is a mild acidosis treatment that involves inhaling CO 2 during reperfusion following ischemia. APC attenuates ischemic brain injury although the underlying mechanisms have not been elucidated. Here we report that APC reinforces ischemia-reperfusion-induced mitophagy in middle cortical artery occlusion (MCAO)-treated mice, and in oxygen-glucose deprivation (OGD)-treated brain slices and neurons. Inhibition of mitophagy compromises neuroprotection conferred by APC. Furthermore, mitophagy and neuroprotection are abolished in Park2 knockout mice, indicating that APC-induced mitophagy is facilitated by the recruitment of PARK2 to mitochondria. Importantly, in MCAO mice, APC treatment extended the effective reperfusion window from 2 to 4 h, and this window was further extended to 6 h by exogenously expressing PARK2. Taken together, we found that PARK2-dependent APC-induced mitophagy renders the brain resistant to ischemic injury. APC treatment could be a favorable strategy to extend the thrombolytic time window for stroke therapy.

Clinical outcomes in middle cerebral artery trunk occlusions versus secondary division occlusions after mechanical thrombectomy: pooled analysis of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi MERCI trials.

PubMed

Shi, Zhong-Song; Loh, Yince; Walker, Gary; Duckwiler, Gary R

2010-05-01

The benefit of endovascular revascularization of patients with acute ischemic stroke with middle cerebral artery (MCA) secondary division (M2) occlusions as compared with MCA trunk (M1) occlusions is not known. In this analysis, we compared revascularization status and clinical outcomes in patients with angiographically confirmed MCA M1 versus isolated M2 occlusions treated with mechanical thrombectomy using the Merci Retriever devices. We retrospectively analyzed the pooled data of patients with MCA strokes from the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi MERCI trials. Patient data were dichotomized into 2 groups: MCA M1 occlusions and isolated M2 occlusions. Baseline characteristics, revascularization rates, hemorrhage rates, complications, outcomes, and mortality were evaluated for both groups. Of 178 patients with MCA occlusion treated in the MERCI and Multi MERCI trials, 84.3% had M1 lesions and 15.7% had isolated M2 lesions. Patients with isolated M2 occlusions were revascularized at a higher rate, required a lower mean number of passes, and were associated with a trend toward shorter mean procedure time than patients with M1 occlusions. No statistically significant differences were found between M2 and M1 groups for symptomatic hemorrhage, clinically significant procedural adverse events, favorable 90-day outcome, or 90-day mortality, although in all instances, the M2 outcomes were numerically better than those in M1 subjects. In multivariate analysis, final revascularization was the strongest independent predictor of good outcome at 90 days. Patients with both MCA M1 occlusions and isolated M2 occlusions can achieve a relatively high rate of revascularization and favorable clinical outcomes after mechanical thrombectomy. In fact, patients with isolated M2 occlusions had a higher rate of revascularization, required fewer passes, and had no increased complications compared with patients with M1 occlusions.

Chronic photoperiod disruption does not increase vulnerability to focal cerebral ischemia in young normotensive rats.

PubMed

Ku Mohd Noor, Ku Mastura; Wyse, Cathy; Roy, Lisa A; Biello, Stephany M; McCabe, Christopher; Dewar, Deborah

2017-11-01

Photoperiod disruption, which occurs during shift work, is associated with changes in metabolism or physiology (e.g. hypertension and hyperglycaemia) that have the potential to adversely affect stroke outcome. We sought to investigate if photoperiod disruption affects vulnerability to stroke by determining the impact of photoperiod disruption on infarct size following permanent middle cerebral artery occlusion. Adult male Wistar rats (210-290 g) were housed singly under two different light/dark cycle conditions ( n = 12 each). Controls were maintained on a standard 12:12 light/dark cycle for nine weeks. For rats exposed to photoperiod disruption, every three days for nine weeks, the lights were switched on 6 h earlier than in the previous photoperiod. T 2 -weighted magnetic resonance imaging was performed at 48 h after middle cerebral artery occlusion. Disruption of photoperiod in young healthy rats for nine weeks did not alter key physiological variables that can impact on ischaemic damage, e.g. blood pressure and blood glucose immediately prior to middle cerebral artery occlusion. There was no effect of photoperiod disruption on infarct size after middle cerebral artery occlusion. We conclude that any potentially adverse effect of photoperiod disruption on stroke outcome may require additional factors such as high fat/high sugar diet or pre-existing co-morbidities.

Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia.

PubMed

Han, Lijuan; Cai, Wei; Mao, Leilei; Liu, Jia; Li, Peiying; Leak, Rehana K; Xu, Yun; Hu, Xiaoming; Chen, Jun

2015-09-01

Oligodendrogenesis is essential for white matter repair after stroke. Although agonists of peroxisome proliferator-activated receptors γ confer neuroprotection in models of cerebral ischemia, it is not known whether this effect extends to white matter protection. This study tested the hypothesis that the peroxisome proliferator-activated receptors γ agonist rosiglitazone enhances oligodendrogenesis and improves long-term white matter integrity after ischemia/reperfusion. Male adult C57/BL6 mice (25-30 g) were subjected to 60-minute middle cerebral artery occlusion and reperfusion. Rosiglitazone (3 mg/kg) was injected intraperitoneally once daily for 14 days beginning 2 hours after reperfusion. Sensorimotor and cognitive functions were evaluated ≤21 days after middle cerebral artery occlusion. Immunostaining was used to assess infarct volume, myelin loss, and microglial activation. Bromodeoxyuridine (BrdU) was injected for measurements of proliferating NG2(+) oligodendrocyte precursor cells (OPCs) and newly generated adenomatous polyposis coli(+) oligodendrocytes. Mixed glial cultures were used to confirm the effect of rosiglitazone on oligodendrocyte differentiation and microglial polarization. Rosiglitazone significantly reduced brain tissue loss, ameliorated white matter injury, and improved sensorimotor and cognitive functions for at least 21 days after middle cerebral artery occlusion. Rosiglitazone enhanced OPC proliferation and increased the numbers of newly generated mature oligodendrocytes after middle cerebral artery occlusion. Rosiglitazone treatment also reduced the numbers of Iba1(+)/CD16(+) M1 microglia and increased the numbers of Iba1(+)/CD206(+) M2 microglia after stroke. Glial culture experiments confirmed that rosiglitazone promoted oligodendrocyte differentiation, perhaps by promoting microglial M2 polarization. Rosiglitazone treatment improves long-term white matter integrity after cerebral ischemia, at least, in part, by promoting

Protective effect of zinc against ischemic neuronal injury in a middle cerebral artery occlusion model.

PubMed

Kitamura, Youji; Iida, Yasuhiko; Abe, Jun; Ueda, Masashi; Mifune, Masaki; Kasuya, Fumiyo; Ohta, Masayuki; Igarashi, Kazuo; Saito, Yutaka; Saji, Hideo

2006-02-01

In this study, we investigated the effect of vesicular zinc on ischemic neuronal injury. In cultured neurons, addition of a low concentration (under 100 microM) of zinc inhibited both glutamate-induced calcium influx and neuronal death. In contrast, a higher concentration (over 150 microM) of zinc decreased neuronal viability, although calcium influx was inhibited. These results indicate that zinc exhibits biphasic effects depending on its concentration. Furthermore, in cultured neurons, co-addition of glutamate and CaEDTA, which binds extra-cellular zinc, increased glutamate-induced calcium influx and aggravated the neurotoxicity of glutamate. In a rat transient middle cerebral artery occlusion (MCAO) model, the infarction volume, which is related to the neurotoxicity of glutamate, increased rapidly on the intracerebral ventricular injection of CaEDTA 30 min prior to occlusion. These results suggest that zinc released from synaptic vesicles may provide a protective effect against ischemic neuronal injury.

Length of occlusion predicts recanalization and outcome after intravenous thrombolysis in middle cerebral artery stroke.

PubMed

Rohan, Vladimir; Baxa, Jan; Tupy, Radek; Cerna, Lenka; Sevcik, Petr; Friesl, Michal; Polivka, Jiri; Polivka, Jiri; Ferda, Jiri

2014-07-01

The length of large vessel occlusion is considered a major factor for therapy in patients with ischemic stroke. We used 4D-CT angiography evaluation of middle cerebral artery occlusion in prediction of recanalization and favorable clinical outcome and after intravenous thrombolysis (IV-tPA). In 80 patients treated with IV-tPA for acute complete middle cerebral artery/M1 occlusion determined using CT angiography and temporal maximum intensity projection, calculated from 4D-CT angiography, the length of middle cerebral artery proximal stump, occlusion in M1 or M1 and M2 segment were measured. Univariate and multivariate analyses were performed to define independent predictors of successful recanalization after 24 hours and favorable outcome after 3 months. The length of occlusion was measureable in all patients using temporal maximum intensity projection. Recanalization thrombolysis in myocardial infarction 2 to 3 was achieved in 37 individuals (46%). The extension to M2 segment as a category (odds ratio, 4.58; 95% confidence interval, 1.39-15.05; P=0.012) and the length of M1 segment occlusion (odds ratio, 0.82; 95% confidence interval, 0.73-0.92; P=0.0007) with an optimal cutoff value of 12 mm (sensitivity 0.67; specificity 0.71) were significant independent predictors of recanalization. Favorable outcome (modified Rankin scale 0-2) was achieved in 25 patients (31%), baseline National Institutes of Health Stroke Scale (odds ratio, 0.82; 95% confidence interval, 0.72-0.93; P=0.003) and the length of occlusion M1 in segment (odds ratio, 0.79; 95% confidence interval, 0.69-0.91; P=0.0008) with an optimal cutoff value of 11 mm (sensitivity 0.74; specificity 0.76) were significant independent predictors of favorable outcome. The length of middle cerebral artery occlusion is an independent predictor of successful IV-tPA treatment. © 2014 American Heart Association, Inc.

Hexane extracts of Polygonum multiflorum improve tissue and functional outcome following focal cerebral ischemia in mice.

PubMed

Lee, Soo Vin; Choi, Kyung Ha; Choi, Young Whan; Hong, Jin Woo; Baek, Jin Ung; Choi, Byung Tae; Shin, Hwa Kyoung

2014-04-01

Polygonum multiflorum is a traditional Korean medicine that has been utilized widely in East Asian countries as a longevity agent. Clinical studies have demonstrated that Polygonum multiflorum improves hypercholesterolemia, coronary heart disease, neurosis and other diseases commonly associated with aging. However, scientific evidence defining the protective effects and mechanisms of Polygonum multiflorum against ischemic stroke is incomplete. In the present study, we investigated the cerebrovascular protective effects of Polygonum multiflorum against ischemic brain injury using an in vivo photothrombotic mouse model. To examine the underlying mechanism of action, we utilized an in vitro human brain microvascular endothelial cell (HBMEC) culture system. Hexane extracts (HEPM), ethyl acetate extracts (EAEPM) and methanol extracts (MEPM) of Polygonum multiflorum (100 mg/kg) were administered intraperitoneally 30 min prior to ischemic insult. Focal cerebral ischemia was induced in C57BL/6J mice and endothelial nitric oxide synthase knockout (eNOS KO) mice by photothrombotic cortical occlusion. We evaluated the infarct volume, as well as neurological and motor function, 24 h after ischemic brain injury. Following ischemic insult, HEPM induced a significant reduction in infarct volume and subsequent neurological deficits, compared with EAEPM and MEPM. HEPM significantly decreased infarct size and improved neurological and motor function, which was not observed in eNOS KO mice, suggesting that this cerebroprotective effect is primarily an eNOS-dependent mechanism. In vitro, HEPM effectively promoted NO production, however these effects were inhibited by the NOS inhibitor, L-NAME and the PI3K/Akt inhibitor, LY-294002. Furthermore, HEPM treatment resulted in increased phosphorylation-dependent activation of Akt and eNOS in HBMEC, suggesting that HEPM increased NO production via phosphorylation-dependent activation of Akt and eNOS. In conclusion, HEPM prevents cerebral

Spatiotemporal characterization of brain infarction by sequential multimodal MR imaging following transient focal ischemia in a Rat model of intra-arterial middle cerebral artery occlusion.

PubMed

Gory, Benjamin; Chauveau, Fabien; Bolbos, Radu; Langlois, Jean-Baptiste; Labeyrie, Paul-Emile; Signorelli, Francesco; Turjman, Alexis; Turjman, Francis

2016-12-01

To assess spatiotemporal brain infarction evolution by sequential multimodal magnetic resonance (MR) imaging in an endovascular model of acute stroke in rats. A microwire was selectively placed in the middle cerebral artery (MCA) in 16 consecutives rats during 90 minutes occlusion. Longitudinal 7-T MR imaging, including angiography, diffusion, and perfusion was performed during ischemia, immediately after reperfusion, 3 h and 24 h after subsequent reperfusion. MCA occlusion was complete in 75 % and partial in 18.7 %. Hypoperfusion (mean ± SD) was observed in all animals during ischemia (-59 ± 18 % of contralateral hemisphere, area 31 ± 5 mm 2 ). Infarction volume (mean ± SD) was 90 ± 64 mm 3 during ischemia and 57 ± 67 mm 3 at 24 h. Brain infarction was fronto-parietal cortical in five animals (31 %), striatal in four animals (25 %), and cortico-striatal in seven animals (44 %) at 24 h. All rats survived at 24 h. This model is suitable to neuroprotection studies because of possible acute and close characterization of spatiotemporal evolution of brain infarction by MR imaging techniques, and evidence of ischemic penumbra, the target of neuroprotection agents. However, optimization of the brain infarct reproducibility needs further technical and neurointerventional tools improvements. • Nitinol microwire is MRI compatible allowing spatiotemporal characterization of brain infarction in rats. • Microwire selective placement in middle cerebral artery allows complete artery occlusion in 75 %. • A diffusion/perfusion mismatch during arterial occlusion is observed in 77 % of rats.

Role of phosphoinositide 3-kinase in ischemic postconditioning-induced attenuation of cerebral ischemia-evoked behavioral deficits in mice.

PubMed

Rehni, Ashish K; Singh, Nirmal

2007-01-01

The present study has been designed to pharmacologically investigate the role of phosphoinositide 3-kinase in ischemic postconditioning-induced reversal of global cerebral ischemia and reperfusion-induced behavioral dysfunction in mice. Bilateral carotid artery occlusion for 10 min followed by reperfusion for 24 h was employed in the present study to produce ischemia and reperfusion-induced cerebral injury in mice. Short-term memory was evaluated using the elevated plus maze test. The inclined beam walking test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced impaired short-term memory, motor co-ordination and lateral push response. Three episodes of carotid artery occlusion for a period of 10 s and reperfusion of 10 s (ischemic postconditioning) significantly prevented ischemia-reperfusion-induced behavioral deficit measured in terms of loss of short-term memory, motor coordination and lateral push response. Wortmannin (2 mg/kg, iv), a phosphoinositide 3-kinase inhibitor given 10 min before ischemia attenuated the beneficial effects of ischemic postconditioning. It may be concluded that beneficial effects of ischemic postconditioning on global cerebral ischemia and reperfusion-induced behavioral deficits may involve activation of phosphoinositide 3-kinase-linked pathway.

Prevention of Glutamate Accumulation and Upregulation of Phospho-Akt may Account for Neuroprotection Afforded by Bergamot Essential Oil against Brain Injury Induced by Focal Cerebral Ischemia in Rat.

PubMed

Amantea, Diana; Fratto, Vincenza; Maida, Simona; Rotiroti, Domenicantonio; Ragusa, Salvatore; Nappi, Giuseppe; Bagetta, Giacinto; Corasaniti, Maria Tiziana

2009-01-01

The effects of bergamot essential oil (BEO; Citrus bergamia, Risso) on brain damage caused by permanent focal cerebral ischemia in rat were investigated. Administration of BEO (0.1-0.5 ml/kg but not 1 ml/kg, given intraperitoneally 1 h before occlusion of the middle cerebral artery, MCAo) significantly reduced infarct size after 24 h permanent MCAo. The most effective dose (0.5 ml/kg) resulted in a significant reduction of infarct extension throughout the brain, especially in the medial striatum and the motor cortex as revealed by TTC staining of tissue slices. Microdialysis experiments show that BEO (0.5 ml/kg) did not affect basal amino acid levels, whereas it significantly reduced excitatory amino acid, namely aspartate and glutamate, efflux in the frontoparietal cortex typically observed following MCAo. Western blotting experiments demonstrated that these early effects were associated, 24 h after permanent MCAo, to a significant increase in the phosphorylation and activity of the prosurvival kinase, Akt. Indeed, BEO significantly enhanced the phosphorylation of the deleterious downstream kinase, GSK-3beta, whose activity is negatively regulated via phosphorylation by Akt.

Blood -brain barrier disruption was less under isoflurane than pentobarbital anesthesia via a PI3K/Akt pathway in early cerebral ischemia.

PubMed

Chi, Oak Z; Mellender, Scott J; Kiss, Geza K; Liu, Xia; Weiss, Harvey R

2017-05-01

One of the important factors altering the degree of blood-brain barrier (BBB) disruption in cerebral ischemia is the anesthetic used. The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been reported to be involved in modulating BBB permeability and in isoflurane induced neuroprotection. This study was performed to compare the degree of BBB disruption in focal cerebral ischemia under isoflurane vs pentobarbital anesthesia and to determine whether inhibition of PI3K/Akt would affect the disruption in the early stage of focal cerebral ischemia. Permanent middle cerebral artery (MCA) occlusion was performed in rats under 1.4% isoflurane or pentobarbital (50mg/kg i.p.) anesthesia with controlled ventilation. In half of each group LY294002, which is a PI3K/Akt inhibitor, was applied on the ischemic cortex immediately after MCA occlusion. After one hour of MCA occlusion, the transfer coefficient (K i ) of 14 C-α-aminoisobutyric acid ( 14 C-AIB) was determined to quantify the degree of BBB disruption. MCA occlusion increased the K i both in the isoflurane and pentobarbital anesthetized rats. However, the value of K i was lower under isoflurane (11.5±6.0μL/g/min) than under pentobarbital (18.3±7.1μL/g/min) anesthesia. The K i of the contralateral cortex of the pentobarbital group was higher (+74%) than that of the isoflurane group. Application of LY294002 on the ischemic cortex increased the K i (+99%) only in the isoflurane group. The degree of BBB disruption by MCA occlusion was significantly lower under isoflurane than pentobarbital anesthesia in the early stage of cerebral ischemia. Our data demonstrated the importance of choice of anesthetics and suggest that PI3K/Akt signaling pathway plays a significant role in altering BBB disruption in cerebral ischemia during isoflurane but not during pentobarbital anesthesia. Copyright © 2017 Elsevier Inc. All rights reserved.

Focal retinal phlebitis.

PubMed

Hoang, Quan V; Freund, K Bailey; Klancnik, James M; Sorenson, John A; Cunningham, Emmett T; Yannuzzi, Lawrence A

2012-01-01

To report three cases of solitary, focal retinal phlebitis. An observational case series. Three eyes in three patients were noted to have unilateral decreased vision, macular edema, and a focal retinal phlebitis, which was not at an arteriovenous crossing. All three patients developed a branch retinal vein occlusion at the site of inflammation. These patients had no other evidence of intraocular inflammation, including vitritis, retinitis, retinal vasculitis, or choroiditis, nor was there any systemic disorder associated with inflammation, infection, or coagulation identified. Focal retinal phlebitis appears to be an uncommon and unique entity that produces macular edema and ultimately branch retinal vein occlusion. In our patients, the focal phlebitis and venous occlusion did not occur at an arteriovenous crossing, which is the typical site for branch retinal venous occlusive disease. This suggests that our cases represent a distinct clinical entity, which starts with a focal abnormality in the wall of a retinal venule, resulting in surrounding exudation and, ultimately, ends with branch retinal vein occlusion.

Intraluminal Middle Cerebral Artery Occlusion (MCAO) Model for Ischemic Stroke with Laser Doppler Flowmetry Guidance in Mice

PubMed Central

McConnell, Douglas J.; Afzal, Aqeela; Mocco, J

2011-01-01

Stroke is the third leading cause of death and the leading cause of disability in the world, with an estimated cost of near $70 billion in the United States in 20091,2. The intraluminal middle cerebral artery occlusion (MCAO) model was developed by Koizumi4 in 1986 to simulate this impactful human pathology in the rat. A modification of the MCAO method was later presented by Longa3. Both techniques have been widely used to identify molecular mechanisms of brain injury resulting from ischemic stroke and potential therapeutic modalities5. This relatively noninvasive method in rats has been extended to use in mice to take advantage of transgenic and knockout strains6,7. To model focal cerebral ischemia, an intraluminal suture is advanced via the internal carotid artery to occlude the base of the MCA. Retracting the suture after a specified period of time mimics spontaneous reperfusion, but the suture can also be permanently retained. This video will be demonstrating the two major approaches for performing intraluminal MCAO procedure in mice in a stepwise fashion, as well as providing insights for potential drawbacks and pitfalls. The ischemic brain tissue will subsequently be stained by 2,3,5-triphenyltetrazolium chloride (TTC) to evaluate the extent of cerebral infarction8. PMID:21587164

Effects of the methylene chloride fraction from modified Boyang-Hwan-o-Tang, a polyherbal medicine on transient middle cerebral artery occlusion-induced ischemia in rats.

PubMed

Oh, Tae Woo; Jung, Hyo Won; Shin, Gil Jo; Park, Yong-Ki

2014-01-28

To study the neuroprotective effect of the methylene chloride fraction from modified Boyang-Hwan-o-Tang (mBHT-MC), especially against neuronal apoptosis. mBHT-MC (10, 25 or 50 mg/kg) was orally administered once per day for 7 days in transient middle cerebral artery occlusion (MCAO)-induced ischemic rats. Infarction volumes was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining, neurological deficit score and the expression of apoptotic proteins such as Bcl-2, Bax and caspase-3 by Western blot in MCAO-induced ischemic brain. Neuronal apoptosis in ischemic phenumbra was also investigated by staining with hematoxylin and eosin, Nissl and Hoechst 33342. mBHT-MC administration in MCAO rats significantly decreased infarction volume and neurological deficit scores. mBHT-MC significantly enhanced Bcl-2 expression, and inhibited Bax and caspase-3 expression in ischemic brain. In addition, mBHT-MC significantly decreased the number of apoptotic neuronal cells in ischemic brains. mBHT-MC administration inhibits neuronal death induced by cerebral ischemia in rats, suggesting that mBHT-MC has a neuroprotective property in brain ischemia.

Role of Multimodal Evaluation of Cerebral Hemodynamics in Selecting Patients with Symptomatic Carotid or Middle Cerebral Artery Steno-occlusive Disease for Revascularization

PubMed Central

Sharma, Vijay K; Tsivgoulis, Georgios; Ning, Chou; Teoh, Hock L; Bairaktaris, Chrisostomos; Chong, Vincent FH; Ong, Benjamin KC; Chan, Bernard PL; Sinha, Arvind K

2008-01-01

Background: The circle of Willis provides collateral pathways to perfuse the affected vascular territories in patients with severe stenoocclusive disease of major arteries. The collateral perfusion may become insufficient in certain physiological circumstances due to failed vasodilatory reserve and intracranial steal phenomenon, so-called ‘Reversed-Robinhood syndrome’. We evaluated cerebral hemodynamics and vasodilatory reserve in patients with symptomatic distal internal carotid (ICA) or middle cerebral artery (MCA) severe steno-occlusive disease. Methods: Diagnostic transcranial Doppler (TCD) and TCD-monitoring with voluntary breath-holding according to a standard scanning protocol were performed in patients with severe ICA or MCA steno-occlusive disease. The steal phenomenon was detected as transient, spontaneous, or vasodilatory stimuli-induced velocity reductions in affected arteries at the time of velocity increase in normal vessels. Patients with exhausted vasomotor reactivity and intracranial steal phenomenon during breath-holding were further evaluated by 99technetiumm-hexamethyl propylene amine oxime single photon emission computed tomography (HMPAO-SPECT) with acetazolamide challenge. Results: Sixteen patients (age 27–74 years, 11 men) fulfilled our TCD criteria for exhausted vasomotor reactivity and intracranial steal phenomenon during the standard vasomotor testing by breath holding. Acetazolamide-challenged HMPAO-SPECT demonstrated significant hypoperfusion in 12 patients in affected arterial territories, suggestive of failed vasodilatory reserve. A breath-holding index of ≤0.3 on TCD was associated with an abnormal HMPAO-SPECT with acetazolamide challenge. TCD findings of a breath holding index of ≤0.3 and intracranial steal during the procedure were determinants of a significant abnormality on HMPAO-SPECT with acetazolamide challenge. Conclusion: Multimodal evaluation of cerebral hemodynamics in symptomatic patients with severe steno-occlusive

Tanshinone IIA attenuates the cerebral ischemic injury-induced increase in levels of GFAP and of caspases-3 and -8.

PubMed

Zhou, L; Bondy, S C; Jian, L; Wen, P; Yang, F; Luo, H; Li, W; Zhou, Jun

2015-03-12

Tanshinone IIA (TSA) is a lipid soluble agent derived from the root of Salvia miltiorrhiza (Danshen). This plant is a traditional Chinese herb, which has been used widely in China especially for enhancing circulation. However mechanisms underlying its efficacy remain poorly understood. The present study was designed to illuminate events that may underlie the apparently neuroprotective effects of TSA following ischemic insult. Adult Sprague-Dawley rats were subjected to transient focal cerebral ischemia by use of a middle cerebral artery occlusion model. They were then randomly divided into a sham-operated control group, and cerebral ischemia/reperfusion groups receiving a two-hour occlusion. Further subsets of groups received the same durations of occlusion or were sham-operated but then received daily i.p. injections of high or low doses of TSA, for seven or 15days. Hematoxylin and eosin staining revealed lesions in the entorhinal cortex of both rats subject to ischemia and to a lesser extent to those receiving TSA after surgery. Levels of glial fibrillary acidic protein (GFAP), caspase-3 and caspase-8, were quantified by both immunohistochemistry and Western blotting. TSA treatment after middle cerebral artery occlusion, markedly reduced infarct size, and reduced the expression of caspase-3 and caspase-8. These changes were considered protective and were generally proportional to the dose of TSA used. These results suggest that TSA may effect neuroprotection by way of reduction of the extent of cell inflammation and death within affected regions. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Semi-quantitative analyses of hippocampal heat shock protein-70 expression based on the duration of ischemia and the volume of cerebral infarction in mice.

PubMed

Choi, Jong-Il; Kim, Sang-Dae; Kim, Se-Hoon; Lim, Dong-Jun; Ha, Sung-Kon

2014-06-01

We investigated the expression of hippocampal heat shock protein 70 (HSP-70) infarction volume after different durations of experimental ischemic stroke in mice. Focal cerebral ischemia was induced in mice by occluding the middle cerebral artery with the modified intraluminal filament technique. Twenty-four hours after ischemia induction, both hippocampi were extracted for HSP-70 protein analyses. Slices from each hemisphere were stained with 2,3,5-triphenyltetrazolium chloride (2%), and infarction volumes were calculated. HSP-70 levels were evaluated using western blot and enzyme-linked immunosorbent assay (ELISA). HSP-70 subtype (hsp70.1, hspa1a, hspa1b) mRNA levels in the hippocampus were measured using reverse transcription-polymerase chain reaction (RT-PCR). Cerebral infarctions were found ipsilateral to the occlusion in 10 mice exposed to transient ischemia (5 each in the 30-min and 60-min occlusion groups), whereas no focal infarctions were noted in any of the sham mice. The average infarct volumes of the 2 ischemic groups were 22.28±7.31 mm(3) [30-min group±standard deviation (SD)] and 38.06±9.53 mm(3) (60-min group±SD). Western blot analyses and ELISA showed that HSP-70 in hippocampal tissues increased in the infarction groups than in the sham group. However, differences in HSP-70 levels between the 2 infarction groups were statistically insignificant. Moreover, RT-PCR results demonstrated no relationship between the mRNA expression of HSP-70 subtypes and occlusion time or infarction volume. Our results indicated no significant difference in HSP-70 expression between the 30- and 60-min occlusion groups despite the statistical difference in infarction volumes. Furthermore, HSP-70 subtype mRNA expression was independent of both occlusion duration and cerebral infarction volume.

A New Approach of Short Wave Protection against Middle Cerebral Artery Occlusion/Reperfusion Injury via Attenuation of Golgi Apparatus Stress by Inhibition of Downregulation of Secretory Pathway Ca(2+)-ATPase Isoform 1 in Rats.

PubMed

Fan, Yongmei; Zhang, Changjie; Li, Ting; Peng, Wenna; Yin, Jing; Li, Xiaofao; Kong, Ying; Lan, Chunna; Wang, Rumi; Hu, Zhiping

2016-07-01

Short wave (SW), a pattern of electromagnetic therapy, achieves an oscillating electromagnetic field. It has been reported that it may have a potential effect on cerebral injury. The present study was designed to investigate the potential role and possible mechanism of SW in focal cerebral ischemia/reperfusion (I/R) injury in rats. Secretory pathway Ca(2+)/Mn(2+) ATPase isoform 1 is a major component of Golgi apparatus stress. It has been reported as representative of Golgi apparatus stress. Up to 120 minutes of middle cerebral artery occlusion (MCAO) and reperfusion injury was induced in male Sprague-Dawley rats. Different sessions of SW daily were administered over head after reperfusion from day 1 to day 7. Functional recovery scores, survival rates, infarct volume analysis, electron microscope test, and western blotting studies were used to analyze the therapy. SW protected against neuronal death and apoptosis in cornu ammon 1 region of hippocampus by reducing neuronal deficit, infarct volume, and ultrastructure. SW partly inhibited upregulation of caspase3. In addition, the expression of secretory pathway Ca(2+)-ATPase isoform 1 (SPCA1) was upregulated by SW. Our data indicate that SW can be protected against focal cerebral I/R injury, and the influence on Golgi apparatus stress might provide us a new perspective in further study. To the authors' knowledge, this is the first report using SW to increase expression of SPCA1 indicating modulate Golgi apparatus stress in MCAO and reperfusion model. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Protective effect of chlorogenic acid on the focal cerebral ischemia reperfusion rat models.

PubMed

Miao, Mingsan; Cao, Lihua; Li, Ruiqi; Fang, Xiaoyan; Miao, Yanyan

2017-05-01

The aim of the study was to investigate the protective characteristic of chlorogenic acid, a natural glucosyl xanthone found in Lonicera Japonica on the cerebral ischemia reperfusion injury and the underlying mechanism. Focal cerebral ischemia reperfusion model was built by blocking the left middle cerebral artery in rats by using the suture-occluded method. Before operation, the corresponding drugs were given for each group once a day for 7 days. After 1 h of final administration, the model was built, after operation, reperfusion was conducted for 22 h, Before the reperfusion 10 min tail vein injection of large, medium and small dose of chlorogenic acid and then mortality was calculated, and Neurological deficit score (NDS) was conducted, and serum was collected to measure the NSE level; a 2 mm thick brain slice located at the intersection of optic nerves was collected for TTC staining, and the percentage of cerebral infarction area was calculated; brain homogenate was collected to measure the ICAM-1, VCAM-1, EPO and HIF-1α levels in brain tissue of cerebral ischemia reperfusion rat models; NGF was detected using immunohistochemical method; the morphological changes in brain tissue was observed with HE staining. All focal cerebral ischemia reperfusion rat models were duplicated successfully. Every chlorogenic acid group with different dosage can significantly reduce the mortality, NDS and cerebral infarction area of rats, and significantly increase the EPO, HIF-1α and NGF levels in brain tissue; significantly improve the pathological lesions of hippocampus and cortex in brain tissue. The results showed that chlorogenic acid could protect the focal cerebral ischemia reperfusion injury rat models by adjusting the inflammatory factor, hypoxia factor and nerve growth factor.

Progesterone induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in rats.

PubMed

Andrabi, Syed Suhail; Parvez, Suhel; Tabassum, Heena

2017-06-01

Organelle damage and increases in mitochondrial permeabilization are key events in the development of cerebral ischemic tissue injury because they cause both modifications in ATP turnover and cellular apoptosis/necrosis. Early restoration of blood flow and improvement of mitochondrial function might reverse the situation and help in recovery following an onset of stroke. Mitochondria and related bioenergetic processes can be effectively used as pharmacological targets. Progesterone (P4), one of the promising neurosteroids, has been found to be neuroprotective in various models of neurological diseases, through a number of mechanisms. This influenced us to investigate the possible role of P4 in the mitochondria-mediated neuroprotective mechanism in an ischemic stroke model of rat. In this study, we have shown the positive effect of P4 administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). After induction of tMCAO, the rats received an initial intraperitoneal injection of P4 (8 mg/kg body weight) or vehicle at 1 h post-occlusion followed by subcutaneous injections at 6, 12 and 18 h. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Findings revealed a significant improvement with P4 treatment in tMCAO animals. Staining of isolated brain slices from P4-treated rats with 2,3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. P4 treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that P4 has

Effects of the Oral Ingestion of Probiotics on Brain Damage in a Transient Model of Focal Cerebral Ischemia in Mice

PubMed Central

Akhoundzadeh, Kobra; Vakili, Abedin; Shadnoush, Mahdi; Sadeghzadeh, Jafar

2018-01-01

Background: Probiotics are microorganisms that may influence brain function via altering brain neurochemistry. New research evidence suggests that probiotic bacteria might protect tissue damage through diminishing the production of free radicals and/or inflammatory cytokines. Therefore, this study was designed to evaluate the effects of probiotic bacteria on the prevention or reduction of brain damage in an experimental model of stroke in mice. Methods: In this study, 30 male BLC57 mice were randomly divided into 6 equal groups. Focal cerebral ischemia was induced via middle cerebral artery occlusion for 45 minutes, followed by 24 hours of reperfusion, in the mice. Probiotics at a concentration of 107 CFU/mL were administered by oral gavage daily for 14 days before ischemia. Infarct size, neurological outcome, and biochemical markers were measured 24 hours after brain ischemia. Statistical analysis were performed using the one-way ANOVA and/or Kruskal–Wallis ANOVA on rank by Sigma Stat (2.0; Jandel Scientific) software. Results: Our results indicated that pretreatment with probiotics significantly reduced infarct size by 52% (P=0.001) but could not improve neurological function (P=0.26). Moreover, the administration of probiotics significantly decreased the malondialdehyde content (P=0.001) and the tumor necrosis factor-alpha level (P=0.004) in the ischemic brain tissue. Conclusion: The findings of the present study showed that probiotic supplements might be useful in the prevention or attenuation of brain ischemic injury in patients at risk of stroke. Probiotics may open new therapeutic alternatives for the prevention of stroke. More preclinical and clinical studies are, however, needed to clarify their efficacy in cerebral stroke. PMID:29398750

PPAR{gamma} agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Seong-Ryong; Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Taegu; Kim, Hahn-Young

2009-02-27

Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist, has shown protective effects against ischemic insult in various tissues. Pioglitazone is also reported to reduce matrix metalloproteinase (MMP) activity. MMPs can remodel extracellular matrix components in many pathological conditions. The current study was designed to investigate whether the neuroprotection of pioglitazone is related to its MMP inhibition in focal cerebral ischemia. Mice were subjected to 90 min focal ischemia and reperfusion. In gel zymography, pioglitazone reduced the upregulation of active form of MMP-9 after ischemia. In in situ zymograms, pioglitazone also reduced the gelatinase activity induced by ischemia. After co-incubation withmore » pioglitazone, in situ gelatinase activity was directly reduced. Pioglitazone reduced the infarct volume significantly compared with controls. These results demonstrate that pioglitazone may reduce MMP-9 activity and neuronal damage following focal ischemia. The reduction of MMP-9 activity may have a possible therapeutic effect for the management of brain injury after focal ischemia.« less

Rationale of cerebral protection devices in left atrial appendage occlusion.

PubMed

Meincke, Felix; Spangenberg, Tobias; Kreidel, Felix; Frerker, Christian; Virmani, Renu; Ladich, Elena; Kuck, Karl-Heinz; Ghanem, Alexander

2017-01-01

Aims of this case-series were to assess the feasibility of cerebral protection devices in interventional left atrial appendage occlusion (iLAAO) procedures and to yield insight into the pathomorphological correlate of early, procedural cerebral embolization during iLAAO. Five consecutive patients underwent iLLO flanked by the Sentinel CPS® (Claret Medical, Inc., Santa Rosa, CA) cerebral protection system. Placement and recapture of the Sentinel ® device as well as the iLAAO were successful and safe in all cases. Histomorphometric analysis of the collected filters showed embolized debris in all patients. Acute thrombus was found in three patients, organizing thrombus in four. Interestingly, two patients had endocardial or myocardial tissue in their filters. Cerebral protection during iLAAO with the Sentinel CPS ® device is feasible. Furthermore, this dataset identifies the formation and embolization of thrombus and cardiac tissue as emboligeneic sources and potential future targets to reduce procedural complications. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Green tea polyphenols alleviate early BBB damage during experimental focal cerebral ischemia through regulating tight junctions and PKCalpha signaling.

PubMed

Liu, Xiaobai; Wang, Zhenhua; Wang, Ping; Yu, Bo; Liu, Yunhui; Xue, Yixue

2013-07-21

It has been supposed that green tea polyphenols (GTPs) have neuroprotective effects on brain damage after brain ischemia in animal experiments. Little is known regarding GTPs' protective effects against the blood-brain barrier (BBB) disruption after ischemic stroke. We investigated the effects of GTPs on the expression of claudin-5, occludin, and ZO-1, and the corresponding cellular mechanisms involved in the early stage of cerebral ischemia. Male Wistar rats were subjected to a middle cerebral artery occlusion (MCAO) for 0, 30, 60, and 120 min. GTPs (400 mg/kg/day) or vehicle was administered by intragastric gavage twice a day for 30 days prior to MCAO. At different time points, the expression of claudin-5, occludin, ZO-1, and PKCα signaling pathway in microvessel fragments of cerebral ischemic tissue were evaluated. GTPs reduced BBB permeability at 60 min and 120 min after ischemia as compared with the vehicle group. Transmission electron microscopy also revealed that GTPs could reverse the opening of tight junction (TJ) barrier at 60 min and 120 min after MACO. The decreased mRNA and protein expression levels of claudin-5, occludin, and ZO-1 in microvessel fragments of cerebral ischemic tissue were significantly prevented by treatment with GTPs at the same time points after ischemia in rats. Furthermore, GTPs could attenuate the increase in the expression levels of PKCα mRNA and protein caused by cerebral ischemia. These results demonstrate that GTPs may act as a potential neuroprotective agent against BBB damage at the early stage of focal cerebral ischemia through the regulation of TJ and PKCα signaling.

The use of in vivo fluorescence image sequences to indicate the occurrence and propagation of transient focal depolarizations in cerebral ischemia.

PubMed

Strong, A J; Harland, S P; Meldrum, B S; Whittington, D J

1996-05-01

A method for the detection and tracking of propagated fluorescence transients as indicators of depolarizations in focal cerebral ischemia is described, together with initial results indicating the potential of the method. The cortex of the right cerebral hemisphere was exposed for nonrecovery experiments in five cats anesthetized with chloralose and subjected to permanent middle cerebral artery (MCA) occlusion. Fluorescence with 370-nm excitation (attributed to the degree of reduction of the NAD/H couple) was imaged with an intensified charge-coupled device camera and digitized. Sequences of images representing changes in gray level from a baseline image were examined, together with the time courses of mean gray levels in specified regions of interest. Spontaneous increases in fluorescence occurred, starting most commonly at the edge of areas of core ischemia; they propagated usually throughout the periinfarct zone and resolved to varying degrees and at varying rates, depending on proximity of the locus to the MCA input. When a fluorescence transient reached the anterior cerebral artery territory, its initial polarity reversed from an increase to a decrease in fluorescence. An initial increase in fluorescence in response to the arrival of a transient may characterize cortex that will become infarcted, if pathophysiological changes in the periinfarct zone are allowed to evolve naturally.

Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning

PubMed Central

Ren, Chuancheng; Gao, Xuwen; Steinberg, Gary K.; Zhao, Heng

2009-01-01

Remote ischemic preconditioning is an emerging concept for stroke treatment, but its protection against focal stroke has not been established. We tested whether remote preconditioning, performed in the ipsilateral hind limb, protects against focal stroke and explored its protective parameters. Stroke was generated by a permanent occlusion of the left distal middle cerebral artery (MCA) combined with a 30 minute occlusion of the bilateral common carotid arteries (CCA) in male rats. Limb preconditioning was generated by 5 or 15 minute occlusion followed with the same period of reperfusion of the left hind femoral artery, and repeated for 2 or 3 cycles. Infarct was measured 2 days later. The results showed that rapid preconditioning with 3 cycles of 15 minutes performed immediately before stroke reduced infarct size from 47.7±7.6% of control ischemia to 9.8±8.6%; at 2 cycles of 15 minutes, infarct was reduced to 24.7±7.3%; at 2 cycles of 5 minutes, infarct was not reduced. Delayed preconditioning with 3 cycles of 15 minutes conducted 2 days before stroke also reduced infarct to 23.0 ±10.9%, but with 2 cycles of 15 minutes it offered no protection. The protective effects at these two therapeutic time windows of remote preconditioning are consistent with those of conventional preconditioning, in which the preconditioning ischemia is induced in the brain itself. Unexpectedly, intermediate preconditioning with 3 cycles of 15 minutes performed 12 hours before stroke also reduced infarct to 24.7±4.7%, which contradicts the current dogma for therapeutic time windows for the conventional preconditioning that has no protection at this time point. In conclusion, remote preconditioning performed in one limb protected against ischemic damage after focal cerebral ischemia. PMID:18201834

Near-infrared diffuse reflectance imaging of infarct core and peri-infarct depolarization in a rat middle cerebral artery occlusion model

NASA Astrophysics Data System (ADS)

Kawauchi, Satoko; Nishidate, Izumi; Nawashiro, Hiroshi; Sato, Shunichi

2014-03-01

To understand the pathophysiology of ischemic stroke, in vivo imaging of the brain tissue viability and related spreading depolarization is crucial. In the infarct core, impairment of energy metabolism causes anoxic depolarization (AD), which considerably increases energy consumption, accelerating irreversible neuronal damage. In the peri-infarct penumbra region, where tissue is still reversible despite limited blood flow, peri-infarct depolarization (PID) occurs, exacerbating energy deficit and hence expanding the infarct area. We previously showed that light-scattering signal, which is sensitive to cellular/subcellular structural integrity, was correlated with AD and brain tissue viability in a rat hypoxia-reoxygenation model. In the present study, we performed transcranial NIR diffuse reflectance imaging of the rat brain during middle cerebral artery (MCA) occlusion and examined whether the infarct core and PIDs can be detected. Immediately after occluding the left MCA, light scattering started to increase focally in the occlusion site and a bright region was generated near the occlusion site and spread over the left entire cortex, which was followed by a dark region, showing the occurrence of PID. The PID was generated repetitively and the number of times of occurrence in a rat ranged from four to ten within 1 hour after occlusion (n=4). The scattering increase in the occlusion site was irreversible and the area with increased scattering expanded with increasing the number of PIDs, indicating an expansion of the infarct core. These results suggest the usefulness of NIR diffuse reflectance signal to visualize spatiotemporal changes in the infarct area and PIDs.

Nuclear factor-kappaB activation and postischemic inflammation are suppressed in CD36-null mice after middle cerebral artery occlusion.

PubMed

Kunz, Alexander; Abe, Takato; Hochrainer, Karin; Shimamura, Munehisa; Anrather, Josef; Racchumi, Gianfranco; Zhou, Ping; Iadecola, Costantino

2008-02-13

CD36, a class-B scavenger receptor involved in multiple functions, including inflammatory signaling, may also contribute to ischemic brain injury through yet unidentified mechanisms. We investigated whether CD36 participates in the molecular events underlying the inflammatory reaction that accompanies cerebral ischemia and may contribute to the tissue damage. We found that activation of nuclear factor-kappaB, a transcription factor that coordinates postischemic gene expression, is attenuated in CD36-null mice subjected to middle cerebral artery occlusion. The infiltration of neutrophils and the glial reaction induced by cerebral ischemia were suppressed. Treatment with an inhibitor of inducible nitric oxide synthase, an enzyme that contributes to the tissue damage, reduced ischemic brain injury in wild-type mice, but not in CD36 nulls. In contrast to cerebral ischemia, the molecular and cellular inflammatory changes induced by intracerebroventricular injection of interleukin-1beta were not attenuated in CD36-null mice. The findings unveil a novel role of CD36 in early molecular events leading to nuclear factor-kappaB activation and postischemic inflammation. Inhibition of CD36 signaling may be a valuable therapeutic approach to counteract the deleterious effects of postischemic inflammation.

In vivo MRI assessment of permanent middle cerebral artery occlusion by electrocoagulation: pitfalls of procedure

PubMed Central

2010-01-01

Permanent middle cerebral artery (MCA) occlusion (pMCAO) by electrocoagulation is a commonly used model but with potential traumatic lesions. Early MRI monitoring may assess pMCAO for non-specific brain damage. The surgical steps of pMCAO were evaluated for traumatic cerebral injury in 22 Swiss mice using diffusion and T2-weighted MRI (7T) performed within 1 h and 24 h after surgery. Temporal muscle cauterization without MCA occlusion produced an early T2 hyperintensity mimicking an infarct. No lesion was visible after temporal muscle incision or craniotomy. Early MRI monitoring is useful to identify non-specific brain injury that could hamper neuroprotective drugs assessment. PMID:20298536

Nicotine-induced neuroprotection against ischemic injury involves activation of endocannabinoid system in rats.

PubMed

Chen, Yu; Nie, Huang; Tian, Li; Tong, Li; Yang, Lujia; Lao, Ning; Dong, Hailong; Sang, Hanfei; Xiong, Lize

2013-02-01

Nicotine has been reported to exert certain protective effect in the Parkinson's and Alzheimer's diseases. Whether it has a similar action in focal cerebral ischemia was unclear. In the present study, rats received either an injection of (-)-nicotine hydrogen tartrate salt (1.2 mg/kg, i.p.) or the vehicle 2 h before the 120 min middle cerebral artery occlusion. Neurological deficits and histological injury were assessed at 24 h after reperfusion. The content of endocannabinoids and the expression of cannabinoid receptor CB1 in brain tissues were determined at different time points after nicotine administration. Results showed that nicotine administration ameliorated neurological deficits and reduced infarct volume induced by cerebral ischemia in the rats. The neuroprotective effect was partially reversed by CB1 blockage. The content of the endocannabinoids N-arachidonylethanolamine and 2-arachidonoylglycerol, as well as the expression of cannabinoid receptor CB1 were up-regulated in brain tissues after nicotine delivery. These results suggest that endogenous cannabinoid system is involved in the nicotine-induced neuroprotection against transient focal cerebral ischemia.

Ferulic acid prevents cerebral ischemic injury-induced reduction of hippocalcin expression.

PubMed

Koh, Phil-Ok

2013-07-01

Intracellular calcium overload is a critical pathophysiological factor in ischemic injury. Hippocalcin is a neuronal calcium sensor protein that buffers intracellular calcium levels and protects cells from apoptotic stimuli. Ferulic acid exerts a neuroprotective effect in cerebral ischemia through its anti-oxidant and anti-inflammation activity. This study investigated whether ferulic acid contributes to hippocalcin expression during cerebral ischemia and glutamate exposure-induced neuronal cell death. Rats were immediately treated with vehicle or ferulic acid (100 mg/kg, i.v.) after middle cerebral artery occlusion (MCAO). Brain tissues were collected 24 h after MCAO and followed by assessment of cerebral infarct. Ferulic acid reduced MCAO-induced infarct regions. A proteomics approach elucidated a decrease in hippocalcin in MCAO-operated animals, ferulic acid attenuates the injury-induced decrease in hippocalcin expression. Reverse transcription-polymerase chain reaction and Western blot analyses confirmed that ferulic acid prevents the injury-induced decrease in hippocalcin. In cultured HT22 hippocampal cells, glutamate exposure increased the intracellular Ca(2+) levels, whereas ferulic acid attenuated this increase. Moreover, ferulic acid attenuated the glutamate toxicity-induced decrease in hippocalcin expression. These findings can suggest the possibility that ferulic acid exerts a neuroprotective effect through modulating hippocalcine expression and regulating intracellular calcium levels. Copyright © 2013 Wiley Periodicals, Inc.

Critical role of matrix metalloprotease-9 in chronic high fat diet-induced cerebral vascular remodelling and increase of ischaemic brain injury in mice†

PubMed Central

Deng, Jiao; Zhang, Junfeng; Feng, Chenzhuo; Xiong, Lize; Zuo, Zhiyi

2014-01-01

Aims About one-third of American adults and 20% of teenagers are obese. Obesity and its associated metabolic disturbances including hyperlipidaemia are risk factors for cardiovascular diseases including stroke. They can worsen neurological outcome after stroke. We determined whether obesity and hyperlipidaemia could induce cerebral vascular remodelling via matrix metalloproteases (MMP) and whether this remodelling affected neurological outcome after brain ischaemia. Methods and results Six-week-old male CD1, C57BL/6J, and MMP-9−/− mice were fed regular diet (RD) or high-fat diet (HFD) for 10 weeks. They were subjected to vascular casting or a 90 min middle cerebral arterial occlusion (MCAO). Mice on HFD were heavier and had higher blood glucose and lipid levels than those on RD. HFD-fed CD1 and C57BL/6J mice had an increased cerebral vascular tortuosity index and decreased inner diameters of the middle cerebral arterial root. HFD increased microvessel density in CD1 mouse cerebral cortex. After MCAO, CD1 and C57BL/6J mice on HFD had a bigger infarct volume, more severe brain oedema and blood–brain barrier damage, higher haemorrhagic transformation rate, greater haemorrhagic volume, and worse neurological function. HFD increased MMP-9 activity in the ischaemic and non-ischaemic brain tissues. Although HFD increased the body weights, blood glucose, and lipid levels in the MMP-9−/− mice on a C57BL/6J genetic background, the HFD-induced cerebral vascular remodelling and worsening of neurological outcome did not occur in these mice. Conclusion HFD induces cerebral vascular remodelling and worsens neurological outcome after transient focal brain ischaemia. MMP-9 activation plays a critical role in these HFD effects. PMID:24935427

Ferulic acid attenuates the down-regulation of MEK/ERK/p90RSK signaling pathway in focal cerebral ischemic injury.

PubMed

Koh, Phil-Ok

2015-02-19

Ferulic acid provides neuroprotective effects against a middle cerebral artery occlusion (MCAO)-induced cerebral ischemia. Mitogen-activated protein kinases can regulate extensive intracellular processes including cell differentiation, growth, and death. This study further investigated whether ferulic acid modulates a protective mechanism through the activation of Raf-MEK-ERK and its downstream targets, including 90 ribosomal S6 kinase (p90RSK) and Bad during cerebral ischemic injury. Male Sprague-Dawley rats were treated with ferulic acid (100mg/kg) or vehicle after the onset of MCAO and brain tissues were collected 24h after MCAO. These results indicated that ferulic acid decreases the volume of the infarct area and the number of cells positive in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Although MCAO injury induces a decrease in the phosphorylation of Raf-1, MEK1/2, and ERK1/2, ferulic acid treatment prevents the injury-induced decrease in these phosphorylation levels. Ferulic acid also attenuates the injury-induced decrease in p90RSK and Bad phosphorylation levels. These findings suggest that ferulic acid prevents MCAO-induced neuronal cell death and that the MEK-ERK-p90RSK-Bad signaling pathway is involved in these neuroprotective effects. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Middle Cerebral Artery Occlusion Model of Stroke in Rodents: A Step-by-Step Approach

PubMed Central

Shahjouei, Shima; Cai, Peter Y.; Ansari, Saeed; Sharififar, Sharareh; Azari, Hassan; Ganji, Sarah; Zand, Ramin

2016-01-01

Stroke is one of the leading causes of morbidity and mortality in developed countries and an immense amount of medical care resources are devoted to combat the poststroke debilitating consequences. The key to develop effective and clinically applicable treatment methodologies is a better understanding of the pathophysiology of the disease, including the root causes and targets for pharmacology. Developing these foundations requires the use of standard animal models that mimic the physicochemical process of the diseases that can reliably replicate results in order to test and fine-tune therapeutic modalities. Middle cerebral artery occlusion (MCAO), endothelin-1-induced ischemic stroke, photothrombosis, devascularization, embolization, and spontaneous infarction using hemorrhage are some examples of different animal models. Reliability of MCAO has been proved and due to the ability to induce reperfusion similar to tissue plasminogen activator (tPA) therapy, this model is widely used in preclinical studies. Here, we describe a detailed methodology on how to develop MCAO stroke in rodents using intra-arterial insertion of filament to occlude the middle cerebral artery. This approach allows for the study of a wide array of basic pathophysiology mechanisms, regenerative medicine and rehabilitation therapy. PMID:26958146

A protocol for characterizing the impact of collateral flow after distal middle cerebral artery occlusion

PubMed Central

DeFazio, R. Anthony; Levy, Sean; Morales, Carmen L.; Levy, Rebecca V.; Dave, Kunjan R.; Lin, Hung W.; Abaffy, Tatjana; Watson, Brant D.; Perez-Pinzon, Miguel A.; Ohanna, Victoria

2010-01-01

I. SUMMARY In humans and in animal models of stroke, collateral blood flow between territories of the major pial arteries has a profound impact on cortical infarct size. However, there is a gap in our understanding of the genetic determinants of collateral formation and flow, as well as the signaling pathways and neurovascular interactions regulating this flow. Previous studies have demonstrated that collateral flow between branches of the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) can protect mouse cortex from infarction after middle cerebral artery occlusion. Because the number and diameter of collaterals varies among mouse strains and after transgenic manipulations, a combination of methods is required to control for these variations. Here, we report an inexpensive approach to characterizing the cerebrovascular anatomy, and in vivo monitoring of cerebral blood flow as well. Further, we introduce a new, minimally invasive method for the occlusion of distal MCA branches. These methods will permit a new generation of studies on the mechanisms regulating collateral remodeling and cortical blood flow after stroke. PMID:21593993

Interleukin-6 mediates enhanced thrombus development in cerebral arterioles following a brief period of focal brain ischemia

PubMed Central

Tang, Ya Hui; Vital, Shantel; Russell, Janice; Seifert, Hilary; Granger, D. Neil

2015-01-01

Objective The cerebral microvasculature is rendered more vulnerable to thrombus formation following a brief (5.0 min) period of focal ischemia. This study examined the contribution of interleukin-6 (IL-6), a neuroprotective and prothrombotic cytokine produced by the brain, to transient ischemia-induced thrombosis in cerebral arterioles. Approach & results The middle cerebral artery of C57BL/6J mice was occluded for 5 minutes, followed by 24 hrs of reperfusion (MCAo/R). Intravital fluorescence microscopy was used to monitor thrombus development in cerebral arterioles induced by light/dye photoactivation. Thrombosis was quantified as the time of onset of platelet aggregation on the vessel wall and the time for complete blood flow cessation. MCAo/R in wild type (WT) mice yielded an acceleration of thrombus formation that was accompanied by increased IL-6 levels in plasma and in post-ischemic brain tissue. The exaggerated thrombosis response to MCAo/R was blunted in WT mice receiving an IL-6 receptor-blocking antibody and in IL-6 deficient (IL-6−/−) mice. Bone marrow chimeras, produced by transplanting IL-6−/− marrow into WT recipients, did not exhibit protection against MCAo/R-induced thrombosis. Conclusions The increased vulnerability of the cerebral vasculature to thrombus development after MCAo/R is mediated by IL-6, which is likely derived from brain cells rather than circulating blood cells. These findings suggest that anti-IL-6 therapy may reduce the likelihood of cerebral thrombus development after a transient ischemic attack. PMID:26054883

Arctigenin protects focal cerebral ischemia-reperfusion rats through inhibiting neuroinflammation.

PubMed

Fan, Tao; Jiang, Wei Long; Zhu, Jian; Feng Zhang, Yu

2012-01-01

Stroke is the third leading cause of death in industrialized countries and the most important cause of acquired adult disability. Many evidences suggest that inflammation accounts for the progression of cerebral ischemic injury. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignin isolated from certain plants, has shown anti-inflammatory activity against diabetes and Alzheimer's disease. In this study, we tested whether arctigenin can protect middle cerebral artery occluded (MCAO) rats. Male Sprague-Dawley rats were pretreated with arctigenin or vehicle for 7 d before being subjected to transient occlusion of middle cerebral artery and reperfusion. Rats were evaluated at 24 h after MCAO for neurological deficit scoring. Furthermore, the mechanism of the anti-inflammatory effect of arctigenin was investigated with a focus on inflammatory cells, proinflammatory cytokines, and transcriptional factors. Arctigenin significantly reduced cerebral infarction and improved neurological outcome. Arctigenin suppressed the activation of microglia and decreased the expression of interleukin (IL)- 1β and tumor necrosis factor (TNF)-α. These results revealed that arctigenin has a promising therapeutic effect in ischemic stroke treatment through an anti-inflammatory mechanism.

MORIN MITIGATES OXIDATIVE STRESS, APOPTOSIS AND INFLAMMATION IN CEREBRAL ISCHEMIC RATS

PubMed Central

Chen, Yanrong; Li, Yanke; Xu, Huali; Li, Gang; Ma, Yunxia; Pang, Yu Jun

2017-01-01

Background: Morin is a flavanoid which exhibits potent antioxidant activity in various oxidative stress related diseases. The current study was attempted to scrutinize the preclinical bio-efficacy of morin on focal ischemia. Methods: The animal model of focal cerebral ischemic injury was done by midbrain carotid artery occlusion (MCAO) method, followed by Morin (30mg/kg) administration for seven days. Results: The outcome of the study showed that treatment with morin displayed positive effects in reducing the focal cerebral ischemia. This effect was evident with the improvements in neurological deficits, reduction in MDA content and elevation of antioxidant levels (SOD, GSH and Gpx). Furthermore, protein expression of Bax and caspase-3 were effectively down-regulated, whilst the expression of Bcl-2 was significantly elevated. On the other hand, the mRNA expression of proinflammatory cytokines was significantly reduced in focal cerebral ischemic rats upon morin intervention. Conclusion: Thus, the beneficial effects of morin on cerebral ischemia assault may result from the reduction of oxidative stress, inhibition of apoptosis and inflammation. The neuroprotective effects of morin supplement may serve as potent adjuvant in the amelioration of ischemic stroke. PMID:28573251

Ebselen reduces autophagic activation and cell death in the ipsilateral thalamus following focal cerebral infarction.

PubMed

Li, Yiliang; Zhang, Jian; Chen, Li; Xing, Shihui; Li, Jingjing; Zhang, Yusheng; Li, Chuo; Pei, Zhong; Zeng, Jinsheng

2015-07-23

Previous studies have demonstrated that both oxidative stress and autophagy play important roles in secondary neuronal degeneration in the ipsilateral thalamus after distal middle cerebral artery occlusion (MCAO). This study aimed to investigate whether oxidative stress is associated with autophagy activation within the ipsilateral thalamus after distal MCAO. Sixty stroke-prone renovascular hypertensive rats were subjected to distal MCAO or sham operation, and were killed at 14 days after MCAO. Mn-SOD, LC3-II, Beclin-1 and p62 expression were evaluated by immunostaining and immunoblotting. Secondary damage in the thalamus was assessed with Nissl staining and immunostaining. The association of oxidative stress with autophagy activation was investigated by the antioxidant, ebselen. We found that treatment with ebselen at 24h after MCAO significantly reduced the expression of Mn-SOD in the ipsilateral thalamus at 14 days following focal cerebral infarction. In parallel, it prevented the elevation of LC3-II and Beclin-1, and the reduction of p62. Furthermore, ebselen attenuated the neuronal loss and gliosis in the ipsilateral thalamus. These results suggested that ebselen reduced oxidative stress, autophagy activation and secondary damage in the ipsilateral thalamus following MCAO. There are associations between oxidative stress, autophagy activation and secondary damage in the thalamus after MCAO. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Pre-treatment with the synthetic antioxidant T-butyl bisphenol protects cerebral tissues from experimental ischemia reperfusion injury.

PubMed

Duong, Thi Thuy Hong; Chami, Belal; McMahon, Aisling C; Fong, Genevieve M; Dennis, Joanne M; Freedman, Saul B; Witting, Paul K

2014-09-01

Treatments to inhibit or repair neuronal cell damage sustained during focal ischemia/reperfusion injury in stroke are largely unavailable. We demonstrate that dietary supplementation with the antioxidant di-tert-butyl-bisphenol (BP) before injury decreases infarction and vascular complications in experimental stroke in an animal model. We confirm that BP, a synthetic polyphenol with superior radical-scavenging activity than vitamin E, crosses the blood-brain barrier and accumulates in rat brain. Supplementation with BP did not affect blood pressure or endogenous vitamin E levels in plasma or cerebral tissue. Pre-treatment with BP significantly lowered lipid, protein and thiol oxidation and decreased infarct size in animals subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. This neuroprotective action was accompanied by down-regulation of hypoxia inducible factor-1α and glucose transporter-1 mRNA levels, maintenance of neuronal tissue ATP concentration and inhibition of pro-apoptotic factors that together enhanced cerebral tissue viability after injury. That pre-treatment with BP ameliorates oxidative damage and preserves cerebral tissue during focal ischemic insult indicates that oxidative stress plays at least some causal role in promoting tissue damage in experimental stroke. The data strongly suggest that inhibition of oxidative stress through BP scavenging free radicals in vivo contributes significantly to neuroprotection. We demonstrate that pre-treatment with ditert-butyl bisphenol(Di-t-Bu-BP) inhibits lipid, protein, and total thiol oxidation and decreases caspase activation and infarct size in rats subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. These data suggest that inhibition of oxidative stress contributes significantly to neuroprotection. © 2014 International Society for Neurochemistry.

Cerebral hemodynamics and metabolism in patients with symptomatic occlusion of the internal carotid artery.

PubMed

Rutgers, D R; van Osch, M J P; Kappelle, L J; Mali, W P T M; van der Grond, J

2003-03-01

The goals of this study were to investigate (1) whether the concentrations of choline, creatine, and N-acetyl aspartate (NAA) in cerebral white matter are changed in patients with symptomatic occlusion of the internal carotid artery (ICA) and (2) whether possible changes in metabolite concentration are related to regional cerebral perfusion or cerebral vasoreactivity. In 19 patients (mean+/-SD age, 60+/-9 years), white matter metabolite concentrations were measured with proton MR spectroscopic imaging on average 4+/-2 months after symptoms occurred. In selected voxels, corresponding cerebral blood flow and volume, mean transit time, and time-to-bolus peak were determined with dynamic susceptibility contrast MRI. Cerebral CO2 reactivity was determined with transcranial Doppler sonography. No significant changes in choline and creatine concentrations were observed. NAA concentration was significantly reduced in the hemisphere on the side of the symptomatic ICA (9.1+/-1.7 mmol/L) compared with the contralateral hemisphere (10.5+/-1.7 mmol/L, P<0.005) and control subjects (10.5+/-0.9 mmol/L, P<0.01). Although no significant interhemispheric difference in NAA concentration was found in patients who presented with retinal ischemia, patients with cerebral ischemia had a significantly lower NAA concentration in the symptomatic hemisphere (9.0+/-1.7 mmol/L) compared with the asymptomatic hemisphere (10.4+/-1.6 mmol/L, P<0.05). In all patients, NAA concentration was not significantly correlated with quantitative cerebral perfusion parameters or CO2 reactivity. Patients with symptomatic ICA occlusion may show chronic neuronal damage in cerebral white matter as evidenced by reduced NAA concentration. This seems to be related to previous symptomatology rather than to the cerebral hemodynamic status in a chronic stage.

Two-photon imaging during prolonged middle cerebral artery occlusion in mice reveals recovery of dendritic structure after reperfusion.

PubMed

Li, Ping; Murphy, Timothy H

2008-11-12

Filament occlusion of the middle cerebral artery (MCA) is a well accepted animal model of focal ischemia. Advantages of the model are relatively long occlusion times and a large penumbra region that simulates aspects of human stroke. Here, we use two-photon and confocal microscopy in combination with regional measurement of blood flow using laser speckle to assess the spatial relationship between the borders of the MCA ischemic territory and loss of dendrite structure, as well as the effect of reperfusion on dendritic damage in adult YFP (yellow fluorescent protein) and GFP (green fluorescent protein) C57BL/6 transgenic mice with fluorescent (predominantly layer 5) neurons. By examining the spatial extent of dendritic damage, we determined that 60 min of MCA occlusion produced a core with severe structural damage that did not recover after reperfusion (begins approximately 3.8 mm lateral to midline), a reversibly damaged area up to 0.6 mm medial to the core that recovered after reperfusion (penumbra), and a relatively structurally intact area ( approximately 1 mm wide; medial penumbra) with hypoperfusion. Loss of structure was preceded by a single ischemic depolarization 122.1 +/- 10.2 s after occlusion onset. Reperfusion of animals after 60 min of ischemia was not associated with exacerbation of damage (reperfusion injury) and resulted in a significant restoration of blebbed dendritic structure, but only within approximately 0.6 mm lateral of the dendritic damage structural border. In summary, we find that recovery of dendritic structure can occur after reperfusion after even 60 min of ischemia, but is likely restricted to a relatively small penumbra region with partial blood flow or oxygenation.

Regional cerebral blood flow changes associated with focal electrically administered seizure therapy (FEAST).

PubMed

Chahine, George; Short, Baron; Spicer, Ken; Schmidt, Matthew; Burns, Carol; Atoui, Mia; George, Mark S; Sackeim, Harold A; Nahas, Ziad

2014-01-01

Use of electroconvulsive therapy (ECT) is limited by cognitive disturbance. Focal electrically-administered seizure therapy (FEAST) is designed to initiate focal seizures in the prefrontal cortex. To date, no studies have documented the effects of FEAST on regional cerebral blood flow (rCBF). A 72 year old depressed man underwent three single photon emission computed tomography (SPECT) scans to capture the onset and resolution of seizures triggered with right unilateral FEAST. We used Bioimage Suite for within-subject statistical analyses of perfusion differences ictally and post-ictally compared with the baseline scan. Early ictal increases in regional cerebral blood flow (rCBF) were limited to the right prefrontal cortex. Post-ictally, perfusion was reduced in bilateral frontal and occipital cortices and increased in left motor and precuneus cortex. FEAST appears to triggers focal onsets of seizure activity in the right prefrontal cortex with subsequent generalization. Future studies are needed on a larger sample. Copyright © 2014 Elsevier Inc. All rights reserved.

Physical exercise induces expression of CD31 and facilitates neural function recovery in rats with focal cerebral infarction.

PubMed

Hu, Xiquan; Zheng, Haiqing; Yan, Tiebin; Pan, Sanqiang; Fang, Jie; Jiang, Ruishu; Ma, Shangfeng

2010-05-01

The present study was aimed at examining the role of physical exercise in the improvement of damaged neural function and the induction of angiogenesis. An infarction model was induced by ligating the left middle cerebral artery occlusion (MCAO) in a total of 66 adult Sprague-Dawley rats that were further randomly divided into three groups: the physical exercise group (n=30), which was given running wheel exercise every day after MCAO, the control group (n=30) and sham-operated group (n=6), which were fed in standard cages without any special training exercise. The rats were killed on the third, seventh and fourteenth days and the neurological severity scores were examined for evaluating the neural function. And the neogenetic microvessels around the peri-infarction region were checked with the specific marker CD31. Although neogenetic microvessels in the peri-infarction region were observed in both control group and physical exercise group, which showed the highest signal on the seventh day after ischemia, the number of CD31 positive cells significantly increased in physical exercise group in comparison with those in control group on the seventh and fourteenth days after ischemia (p<0.01). Moreover, the neurological severity scores in the physical exercise group showed more quick declination as compared to those in control group from the seventh day after ischemic. Our results suggested that physical exercise plays an important role in the recovery of damaged neural function and induction of angiogenesis after cerebral infarction in rats.

Effect of enriched environment on angiogenesis and neurological functions in rats with focal cerebral ischemia.

PubMed

Zhang, Xin; Chen, Xiu-Ping; Lin, Jun-Bin; Xiong, Yu; Liao, Wei-Jing; Wan, Qi

2017-01-15

The purpose of this study was to investigate the effect of enriched environment (EE) on cerebral angiogenesis after ischemia-reperfusion injury. Middle cerebral artery occlusion (MCAO) followed by reperfusion was performed in rats to set up an animal model of ischemia-reperfusion injury. In a set of behavioral tests, we demonstrated that the animals in the IEE (ischemia + enriched environment) group exhibited significantly improved neurological functions compared to those in the standard housing condition group. In consistent with the functional tests, smaller infarction volumes were observed in the animals of IEE group. Laser scanning confocal microscopy and 3D quantitative analysis of cerebral microvessels revealed that EE treatment increased the total vessel surface area and number of branch point in the ischemic boundary zone. IgG extraction assay showed that the blood brain barrier (BBB) leakage in the ischemic brain was attenuated after EE treatment. EE treatment also enhanced endothelial cells (ECs) proliferation and increased the expression levels of VEGF and its receptor Flk-1 after ischemia-reperfusion injury. Analyses of Spearman's correlation coefficients indicated a correlation of mNSS scores with enhanced cerebral angiogenesis. Together, the results suggest that EE treatment-induced cerebral angiogenesis may contribute to the improved neurological outcome of stroke animals after ischemia-reperfusion injury. Copyright © 2016 Elsevier B.V. All rights reserved.

Pretreatment of 6-shogaol attenuates oxidative stress and inflammation in middle cerebral artery occlusion-induced mice.

PubMed

Na, Ji-Young; Song, Kibbeum; Lee, Ju-Woon; Kim, Sokho; Kwon, Jungkee

2016-10-05

6-Shogaol can be extracted from ginger and has been shown to exert anti-inflammatory and antioxidant activities, which are potentially relevant to the treatment of central nervous system disorders. Oxidative stress and inflammation are closely associated with ischemic injury and can eventually result in neuronal death. The aim of this study was to evaluate if 6-shogaol exerts neuroprotective activity. To this end, we determined its effects on oxidative stress and inflammation in a mouse model of middle cerebral artery occlusion (MCAO)-induced brain damage. In this model, MCAO was induced in C57BL/6 mice (30-35g, 9 weeks) for 1h, followed by 24h reperfusion. Mice were treated orally with 6-shogaol (0.1ml, 5 or 20mg/kg) once daily for 7 consecutive days prior to MCAO. We found that 6-shogaol significantly reduced neurological deficit scores and the mean infarct area. Moreover, 6-shogaol improved the behavioral deficits in the MCAO group. In addition, 6-shogaol pretreatment dampened MCAO-mediated production of reactive oxygen species and inflammatory cytokines. Mechanistic studies revealed that 6-shogaol inhibits the cysteinyl leukotriene 1 receptor (CysLT1R) and mitogen-activated protein kinase (MAPK) signaling proteins, thus providing a potential pharmacological mechanism for our observations. These results suggest that 6-shogaol can ameliorate the outcomes of MCAO and could thus be used as a potential preventive of stroke. Copyright © 2016 Elsevier B.V. All rights reserved.

Hyperphosphorylation of tau protein in the ipsilateral thalamus after focal cortical infarction in rats.

PubMed

Dong, Da-Wei; Zhang, Yu-Sheng; Yang, Wan-Yong; Wang-Qin, Run-Qi; Xu, An-Ding; Ruan, Yi-Wen

2014-01-16

Hyperphosphorylation of tau has been considered as an important risk factor for neurodegenerative diseases. It has been found also in the cortex after focal cerebral ischemia. The present study is aimed at investigating changes of tau protein expression in the ipsilateral thalamus remote from the primary ischemic lesion site after distal middle cerebral artery occlusion (MCAO). The number of neurons in the ventroposterior thalamic nucleus (VPN) was evaluated using Nissl staining and neuronal nuclei (NeuN) immunostaining. Total tau and phosphorylated tau at threonine 231 (p-T231-tau) and serine 199 (p-S199-tau) levels, respectively, in the thalamus were measured using immunostaining and immunoblotting. Moreover, apoptosis was detected with terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling (TUNEL) assay. It was found that the numbers of intact neurons and NeuN(+) cells within the ipsilateral VPN were reduced significantly compared with the sham-operated group, but the levels of p-T231-tau and p-S199-tau in the ipsilateral thalamus were increased significantly in rats subjected to ischemia for 3 days, 7 days and 28 days. Furthermore, the number of TUNEL-positive cells was increased in the ipsilateral VPN at 7 days and 28 days after MCAO. Thus, hyperphosphorylated tau protein is observed in ipsilateral thalamus after focal cerebral infarction in this study. Our findings suggest that the expression of hyperphosphorylated tau protein induced by ischemia may be associated with the secondary thalamic damage after focal cortical infarction via an apoptotic pathway. © 2013 Published by Elsevier B.V.

Chronic hyperperfusion and angiogenesis follow subacute hypoperfusion in the thalamus of rats with focal cerebral ischemia

PubMed Central

Hayward, Nick MEA; Yanev, Pavel; Haapasalo, Annakaisa; Miettinen, Riitta; Hiltunen, Mikko; Gröhn, Olli; Jolkkonen, Jukka

2011-01-01

Cerebral blood flow (CBF) is disrupted after focal ischemia in rats. We examined long-term hemodynamic and cerebrovascular changes in the rat thalamus after focal cerebral ischemia. Cerebral blood flow quantified by arterial spin labeling magnetic resonance imaging was decreased in the ipsilateral and contralateral thalamus 2 days after cerebral ischemia. Partial thalamic CBF recovery occurred by day 7, then the ipsilateral thalamus was chronically hyperperfused at 30 days and 3 months compared with its contralateral side. This contrasted with permanent hypoperfusion in the ipsilateral cortex. Angiogenesis was indicated by endothelial cell (RECA-1) immunohistochemistry that showed increased blood vessel branching in the ipsilateral thalamus at the end of the 3-month follow-up. Only transient thalamic IgG extravasation was observed, indicating that the blood–brain barrier was intact after day 2. Angiogenesis was preceded by transiently altered expression levels of cadherin family adhesion molecules, cadherin-7, protocadherin-1, and protocadherin-17. In conclusion, thalamic pathology after focal cerebral ischemia involved long-term hemodynamic changes and angiogenesis preceded by altered expression of vascular adhesion factors. Postischemic angiogenesis in the thalamus represents a novel type of remote plasticity, which may support removal of necrotic brain tissue and aid functional recovery. PMID:21081957

Posttraumatic cerebral infarction due to progressive occlusion of the internal carotid artery after minor head injury in childhood: a case report.

PubMed

Matsumoto, Hiroaki; Kohno, Kanehisa

2011-07-01

Although minor head injury in childhood is a common occurrence and usually no complications, posttraumatic cerebral infarction has rarely been reported. Such infarction is characterized by occlusion of the lateral lenticulostriate artery. The authors report an atypical case of posttraumatic occlusion of the internal carotid artery (ICA) after minor head injury in childhood. A healthy 16-year-old boy was hit on the head by a pitch while playing baseball. He developed a transient ischemic attack involving the left extremities 15 min after the accident. Initial magnetic resonance imaging revealed neither hemorrhage nor infarction, and MR angiography demonstrated mild stenosis of the right carotid fork. Conservative therapy was started. However, 24 h after the accident, he suddenly developed left hemiparesis. Emergent neuroimaging demonstrated progressive occlusion of the supraclinoid portion of the right ICA and cerebral infarction of the deep white matter in the right frontal lobe. The hemiparesis deteriorated and the infarction area continued to expand on a daily. The patient underwent emergent superficial temporally artery-middle cerebral artery (STA-MCA) bypass. Intraoperative observation demonstrated that the supraclinoid portion of the right ICA was not thrombosed but pale with low tension and did not appear dissected. He fully recovered by 2 weeks after the operation. Postoperative investigations showed gradual improvement of the ICA occlusion. Minor head injury can cause cerebral infarction in childhood, although this is rare. If conservative therapy cannot prevent progressive cerebral infarction, STA-MCA bypass should be considered in case of the ICA occlusion.

Electroacupuncture modulates stromal cell-derived factor-1α expression and mobilization of bone marrow endothelial progenitor cells in focal cerebral ischemia/reperfusion model rats.

PubMed

Xie, Chenchen; Gao, Xiang; Luo, Yong; Pang, Yueshan; Li, Man

2016-10-01

Stromal cell-derived factor-1α(SDF-1α) plays a crucial role in regulating the mobilization, migration and homing of endothelial progenitor cells(EPCs). Electroacupuncture(EA), a modern version of Traditional Chinese Medicine, can improve neurological recovery and angiogenesis in cerebral ischemic area. This study aimed to investigate the effects of electroacupuncture(EA) on the mobilization and migration of bone marrow EPCs and neurological functional recovery in rats model after focal cerebral ischemia/reperfusion and the potentially involved mechanisms. Sprague-Dawley rats received filament occlusion of the right middle cerebral artery for 2h followed by reperfusion for 12h, 1d, 2d, 3d, 7d respectively. Rats were randomly divided into sham group, model group and EA group. After 2h of the reperfusion, EA was given at the "Baihui" (GV 20)/Siguan ("Hegu" (LI 4)/"Taichong" (LR 3)) acupoints in the EA group. Modified neurological severity score (mNSS) was used to assess the neurological functional recovery. EPCs number and SDF-1α level in bone marrow(BM) and peripheral blood(PB) were detected by using fluorescence-activated cell sorting (FACS) analysis and quantitative real time polymerase chain reaction (qRT-PCR) respectively. An mNSS test showed that EA treatment significantly improved the neurological functional outcome. EPCs number in PB and BM were obviously increased in the EA group. After cerebral ischemia, the SDF-1α level was decreased in BM while it was increased in PB, which implied a gradient of SDF-1α among BM and PB after ischemia. It suggested that the forming of SDF-1α concentration gradient can induce the mobilization and homing of EPCs. Eletroacupuncture as a treatment can accelerate and increase the forming of SDF-1α concentration gradient to further induce the mobilization of EPCs and angiogenesis in ischemic brain and improve the neurological function recovery. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of activation of the Ca(2+)-permeable acid-sensing ion channel 1a on focal cerebral ischemia in diabetic rats.

PubMed

Wang, Jie; Wen, Chun-Yan; Cui, Cui-Cui; Xing, Ying

2015-01-01

We investigated the role of acid-sensing ion channel Ia (ASIC1a) expression and changes in intracellular Ca(2+) concentration ([Ca(2+)]) in focal cerebral ischemia after middle cerebral artery occlusion (MCAO) in a rat model of diabetes mellitus (DM). Male Wistar rats (n = 108) were divided into three groups: the MCAO, DM + MCAO, and DM + MCAO + fasudil groups (n = 36 each). Samples were obtained 1, 3, 6, and 24 h after ischemia induction (n = 9). Rats in the DM + MCAO + fasudil group were treated with 1 mg/kg fasudil, a Rho-kinase inhibitor, by caudal vein injection 30 min after MCAO was performed. ASIC1a expression gradually increased with time in the MCAO and DM + MCAO groups (0.71 ± 0.10 nM, 0.80 ± 0.11 nM, 0.86 ± 0.08 nM, 0.93 ± 0.09 nM; 0.86 ± 0.11 nM, 1.05 ± 0.51 nM, 2.42 ± 0.08 nM, 2.78 ± 0.04 nM; pairwise comparisons at each time point, P < 0.05), and was higher in the DM + MCAO than the MCAO group (P < 0.05). [Ca(2+)] gradually increased in the DM + MCAO group (106.32 ± 18.6 nM, 137.84 ± 14.32 nM, 151.94 ± 18.38 nM, 183.61 ± 7.96 nM, P < 0.05). ASIC1a expression and calcium currents were reduced in the DM + MCAO + fasudil group. The overload of intracellular [Ca(2+)] caused by ASIC1a activation could be one mechanism for the aggravation of focal cerebral ischemia in diabetes.

Photothrombosis-Induced Infarction of the Mouse Cerebral Cortex Is Not Affected by the Nrf2-Activator Sulforaphane

PubMed Central

Hou, Linda; Nilsson, Åsa; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

2012-01-01

Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2) and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p.) after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage. PMID:22911746

Photothrombosis-induced infarction of the mouse cerebral cortex is not affected by the Nrf2-activator sulforaphane.

PubMed

Porritt, Michelle J; Andersson, Helene C; Hou, Linda; Nilsson, Åsa; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

2012-01-01

Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2) and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p.) after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage.

Zinc translocation accelerates infarction after mild transient focal ischemia.

PubMed

Lee, J-M; Zipfel, G J; Park, K H; He, Y Y; Hsu, C Y; Choi, D W

2002-01-01

Excess release of chelatable zinc (Zn(2+)) from central synaptic vesicles may contribute to the pathogenesis of selective neuronal cell death following transient forebrain ischemia, but a role in neurodegeneration after focal ischemia has not been defined. Adult male Long-Evans rats subjected to middle cerebral artery occlusion (MCAO) for 30 min followed by reperfusion developed delayed cerebral infarction reaching completion 3 days after the insult. One day after the insult, many degenerating cerebral neurons exhibited increased intracellular Zn(2+), and some labeled with the antibody against activated caspase-3. I.c.v. administration of the Zn(2+) chelator, EDTA saturated with equimolar Ca(2+) (CaEDTA), 15 min prior to ischemia attenuated subsequent Zn(2+) translocation into cortical neurons, and reduced infarct volume measured 3 days after ischemia. Although the protective effect of CaEDTA at this endpoint was substantial (about 70% infarct reduction), it was lost when insult severity was increased (from 30 to 60 min MCAO), or when infarct volume was measured at a much later time point (14 days instead of 3 days after ischemia). These data suggest that toxic Zn(2+) translocation, from presynaptic terminals to post-synaptic cell bodies, may accelerate the development of cerebral infarction following mild transient focal ischemia.

Evaluation of the cerebral vasodilatory capacity by the acetazolamide test before EC-IC bypass surgery in patients with occlusion of the internal carotid artery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vorstrup, S.; Brun, B.; Lassen, N.A.

1986-11-01

Cerebral blood flow (CBF) was measured by xenon-133 inhalation tomography in 18 patients with cerebrovascular disease before and 4 months after extracranial-intracranial bypass surgery. Only patients who showed a reduced CBF in areas that were intact on the CT scan and relevant to the clinical and angiographical findings were operated. The majority of the patients had suffered a minor stroke with or without subsequent transient ischemic attacks. They were studied at least 6 weeks following the stroke. All patients had an occlusion of the relevant internal carotid artery. To identify preoperatively the patients with a compromised collateral circulation and hencemore » reduced CBF due to reduced perfusion pressure, a cerebral vasodilatory stress test was performed using acetazolamide (Diamox). In normal subjects, Diamox has been shown to increase tomographic CBF without change of the flow distribution. In the present series 9 patients showed a significant redistribution of flow in favor of the non-occluded side (positive Diamox test). Two of these 9 patients showed even a paradoxical decrease in focal CBF preoperatively, i.e., a steal effect. These 2 patients were the only patients who improved in focal CBF after shunting. The remaining 9 patients all showed uniform flow responses (negative Diamox test), and none of these increased in focal CBF postoperatively. The finding of an unchanged flow map postoperatively confirmed that the low flow areas were not due to restricted flow via collateral pathways. However, an increase in the regional vasodilatory capacity was observed postoperatively in the majority of patients.« less

Neuroprotective effect of p-coumaric acid in rat model of embolic cerebral ischemia

PubMed Central

Guven, Mustafa; Aras, Adem Bozkurt; Akman, Tarik; Sen, Halil Murat; Ozkan, Adile; Salis, Osman; Sehitoglu, Ibrahim; Kalkan, Yildiray; Silan, Coskun; Deniz, Mustafa; Cosar, Murat

2015-01-01

Objective(s): Stroke poses a crucial risk for mortality and morbidity. Our study aimed to investigate the effect of p-coumaric acid on focal cerebral ischemia in rats. Material and Methods: Rats were randomly divided into four groups, namely Group I (control rats), Group II (ischemia rats), Group III (6 hr ischemia + p-coumaric acid rats) and Group IV (24 hr ischemia + p-coumaric acid rats). Cerebral ischemia was induced via intraluminal monofilament occlusion model. In all groups, the brain was removed after the procedure and rats were sacrificed. Malondialdehyde, superoxide dismutase and nuclear respiratory factor-1 were measured in the ischemic hemisphere. The histopathological changes were observed in the right hemisphere within the samples. Functional assessment was performed for neurological deficit scores. Results: Following the treatment, biochemical factors changed significantly. Histopathologically, it was shown that p-coumaric acid decreased the oxidative damage. The neurological deficit scores of p-coumaric acid-treated rats were significantly improved after cerebral ischemia. Conclusion: Our results showed that p-coumaric acid is a neuroprotective agent on account of its strong anti-oxidant and anti-apoptotic features. Moreover, p-coumaric acid decreased the focal ischemia. Extra effort should be made to introduce p-coumaric acid as a promising therapeutic agent to be utilized for treatment of human cerebral ischemia in the future. PMID:26019798

Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms.

PubMed

Shin, Hwa Kyoung; Salomone, Salvatore; Potts, E Michelle; Lee, Sae-Won; Millican, Eric; Noma, Kensuke; Huang, Paul L; Boas, David A; Liao, James K; Moskowitz, Michael A; Ayata, Cenk

2007-05-01

Rho-kinase is a serine threonine kinase that increases vasomotor tone via its effects on both endothelium and smooth muscle. Rho-kinase inhibition reduces cerebral infarct size in wild type, but not endothelial nitric oxide synthase deficient (eNOS-/-) mice. The mechanism may be related to Rho-kinase activation under hypoxic/ischemic conditions and impaired vasodilation because of downregulation of eNOS activity. To further implicate Rho-kinase in impaired vascular relaxation during hypoxia/ischemia, we exposed isolated vessels from rat and mouse to 60 mins of hypoxia, and showed that hypoxia reversibly abolished acetylcholine-induced eNOS-dependent relaxation, and that Rho-kinase inhibitor hydroxyfasudil partially preserved this relaxation during hypoxia. We, therefore, hypothesized that if hypoxia-induced Rho-kinase activation acutely impairs vasodilation in ischemic cortex, in vivo, then Rho-kinase inhibitors would acutely augment cerebral blood flow (CBF) as a mechanism by which they reduce infarct size. To test this, we studied the acute cerebral hemodynamic effects of Rho-kinase inhibitors in ischemic core and penumbra during distal middle cerebral artery occlusion (dMCAO) in wild-type and eNOS-/- mice using laser speckle flowmetry. When administered 60 mins before or immediately after dMCAO, Rho-kinase inhibitors hydroxyfasudil and Y-27632 reduced the area of severely ischemic cortex. However, hydroxyfasudil did not reduce the area of CBF deficit in eNOS-/- mice, suggesting that its effect on CBF within the ischemic cortex is primarily endothelium-dependent, and not mediated by its direct vasodilator effect on vascular smooth muscle. Our results suggest that Rho-kinase negatively regulates eNOS activity in acutely ischemic brain, thereby worsening the CBF deficit. Therefore, rapid nontranscriptional upregulation of eNOS activity by small molecule inhibitors of Rho-kinase may be a viable therapeutic approach in acute stroke.

Effect of activation of the Ca2+-permeable acid-sensing ion channel 1a on focal cerebral ischemia in diabetic rats

PubMed Central

Wang, Jie; Wen, Chun-Yan; Cui, Cui-Cui; Xing, Ying

2015-01-01

We investigated the role of acid-sensing ion channel Ia (ASIC1a) expression and changes in intracellular Ca2+ concentration ([Ca2+]) in focal cerebral ischemia after middle cerebral artery occlusion (MCAO) in a rat model of diabetes mellitus (DM). Male Wistar rats (n = 108) were divided into three groups: the MCAO, DM + MCAO, and DM + MCAO + fasudil groups (n = 36 each). Samples were obtained 1, 3, 6, and 24 h after ischemia induction (n = 9). Rats in the DM + MCAO + fasudil group were treated with 1 mg/kg fasudil, a Rho-kinase inhibitor, by caudal vein injection 30 min after MCAO was performed. ASIC1a expression gradually increased with time in the MCAO and DM + MCAO groups (0.71 ± 0.10 nM, 0.80 ± 0.11 nM, 0.86 ± 0.08 nM, 0.93 ± 0.09 nM; 0.86 ± 0.11 nM, 1.05 ± 0.51 nM, 2.42 ± 0.08 nM, 2.78 ± 0.04 nM; pairwise comparisons at each time point, P < 0.05), and was higher in the DM + MCAO than the MCAO group (P < 0.05). [Ca2+] gradually increased in the DM + MCAO group (106.32 ± 18.6 nM, 137.84 ± 14.32 nM, 151.94 ± 18.38 nM, 183.61 ± 7.96 nM, P < 0.05). ASIC1a expression and calcium currents were reduced in the DM + MCAO + fasudil group. The overload of intracellular [Ca2+] caused by ASIC1a activation could be one mechanism for the aggravation of focal cerebral ischemia in diabetes. PMID:26722526

PSD-93 deletion inhibits Fyn-mediated phosphorylation of NR2B and protects against focal cerebral ischemia.

PubMed

Zhang, Meijuan; Li, Qingjie; Chen, Ling; Li, Jie; Zhang, Xin; Chen, Xiang; Zhang, Qingxiu; Shao, Yuan; Xu, Yun

2014-08-01

Modification of N-methyl-d-aspartate receptor (NMDAR)-mediated excitotoxicity appears to be a potential target in the treatment of ischemic stroke. Postsynaptic density protein-93 (PSD-93) specifically binds the C-terminal tails of the NMDAR, which is critical to couple NMDAR activity to specific intracellular signaling. This study is to investigate whether PSD-93 disruption displays neuroprotection in a focal ischemic stroke model of adult mice and, if it does, to explore possible mechanisms. It was found that, following middle cerebral artery occlusion (MCAO), PSD-93 knockout (KO) mice manifested significant reductions in infarcted volume, neurological deficits and number of degenerated neurons. PSD-93 deletion also reduced cultured cortical neuronal death caused by glucose and oxygen deprivation (OGD). Ischemic long term potentiation (i-LTP) could not be induced in the PSD-93 KO group and wild type (WT) groups pretreated with either AP-5 (NMDAR inhibitor) or PP2 (Src family inhibitor). PSD-93 KO decreased the phosphorylation of the NR2B at Tyr1472 and the interaction between NR2B and Fyn after MCAO. Together, our study demonstrated that PSD-93 KO confers profound neuroprotection against ischemic brain injury, which probably links to the inhibitory effect on Fyn-mediated phosphorylation of NR2B caused by PSD-93 deletion. These findings may provide a novel avenue for the treatment of ischemic stroke. Copyright © 2014 Elsevier Inc. All rights reserved.

Systematic and detailed analysis of behavioural tests in the rat middle cerebral artery occlusion model of stroke: Tests for long-term assessment

PubMed Central

Diaz, Claris; Farr, Tracy D; Harrison, David J; Fuller, Anna; Tokarczuk, Paweł F; Stewart, Andrew J; Paisey, Stephen J; Dunnett, Stephen B

2016-01-01

In order to test therapeutics, functional assessments are required. In pre-clinical stroke research, there is little consensus regarding the most appropriate behavioural tasks to assess deficits, especially when testing over extended times in milder models with short occlusion times and small lesion volumes. In this study, we comprehensively assessed 16 different behavioural tests, with the aim of identifying those that show robust, reliable and stable deficits for up to two months. These tasks are regularly used in stroke research, as well as being useful for examining striatal dysfunction in models of Huntington’s and Parkinson’s disease. Two cohorts of male Wistar rats underwent the intraluminal filament model of middle cerebral artery occlusion (30 min) and were imaged 24 h later. This resulted in primarily subcortical infarcts, with a small amount of cortical damage. Animals were tested, along with sham and naïve groups at 24 h, seven days, and one and two months. Following behavioural testing, brains were processed and striatal neuronal counts were performed alongside measurements of total brain and white matter atrophy. The staircase, adjusting steps, rotarod and apomorphine-induced rotations were the most reliable for assessing long-term deficits in the 30 min transient middle cerebral artery occlusion model of stroke. PMID:27317655

Remote ischaemic preconditioning and prevention of cerebral injury.

PubMed

Rehni, Ashish K; Shri, Richa; Singh, Manjeet

2007-03-01

Bilateral carotid artery occlusion of 10 min followed by reperfusion for 24 hr was employed in present study to produce ischaemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Short-term memory was evaluated using elevated plus maze. Inclined beam walking test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired short-term memory, motor co-ordination and lateral push response. A preceding episode of mesenteric artery occlusion for 15 min and reperfusion of 15 min (remote mesenteric ischaemic preconditioning) prevented markedly ischaemia-reperfusion-induced cerebral injury measured in terms of infarct size, loss of short-term memory, motor coordination and lateral push response. Glibenclamide (5 mg/kg, iv) a KATP channel blocker and caffeine (7 mg/kg, iv) an adenosine receptor blocker attenuated the neuroprotective effect of remote mesenteric ischaemic preconditioning. It may be concluded that neuroprotective effect of remote mesenteric ischaemic preconditioning may be due to activation of adenosine receptors and consequent activation of KATP channels in mice.

[Effect of ginsenoside Rb1 on cerebral infarction volume and IL-1 beta in the brain tissue and sera of focal cerebral ischemia/reperfusion injury model rats].

PubMed

Liu, Jun-Wei; Ren, Ye-Long; Liu, Xu-Ling; Xia, Hong-Lian; Zhang, Hui-Ling; Jin, Shen-Hui; Dai, Qin-Xue; Wang, Jun-Lu

2013-12-01

To investigate the effect of ginsenoside Rb1 on cerebral infarction volume as well as IL-1 beta in the brain tissue and sera of focal cerebral ischemia/reperfusion (I/R) injury model rats. The I/R rat model was established by using thread according to Zea-Longa. SD rats were randomly divided into five groups, i.e., the sham-operation group, the model group, the low dose ginsenoside Rb1 (20 mg/kg) group, the medium dose ginsenoside Rb1 group (40 mg/kg), and the high dose ginsenoside Rb1 group (80 mg/kg), 12 in each group. Rats in the sham-operation group only received middle cerebral artery occlusion (MCAO) but without thread insertion. The MCAO model was prepared in the rest 4 groups, followed by MCAO2 h later. Ginsenoside Rb1 at each dose was peritoneally administrated to rats in corresponding groups immediately after cerebral ischemia. Equal volume of normal saline was administered to rats in the sham-operation group. Rats' cerebral infarction volume, integrals of neurologic defect degree, expression of IL-1 beta content in the brain tissue and sera were observed 24 h after 2-h cerebral I/R. In the model group, integrals of neurologic defect degree were improved (P < 0.01), IL-1 beta positive cells in the brain tissue increased and serum IL-1 beta content elevated (P < 0.05), when compared with the sham-operation group. In comparison of the model group, integrals of neurologic defect degree were lowered in the medium dose and high dose ginsenoside Rb1 groups (P < 0.05, P < 0.01). The cerebral infarction volume was all shrunken in each ginsenoside Rb1 group, IL-1 beta positive cells in the brain tissue decreased, and IL-1 beta content in serum reduced (P < 0.01, P < 0.05). Compared with the low dose ginsenoside Rb1 group, integrals of neurologic defect degree decreased, the cerebral infarction volume shrunken, and IL-1 beta content in serum reduced in the high dose ginsenoside Rb1 group (P < 0.01, P < 0.05). Ginsenoside Rb1 (20, 40, 80 mg/kg) might effectively

Inhibition of cerebral ischemia/reperfusion injury-induced apoptosis: nicotiflorin and JAK2/STAT3 pathway.

PubMed

Hu, Guang-Qiang; Du, Xi; Li, Yong-Jie; Gao, Xiao-Qing; Chen, Bi-Qiong; Yu, Lu

2017-01-01

Nicotiflorin is a flavonoid extracted from Carthamus tinctorius. Previous studies have shown its cerebral protective effect, but the mechanism is undefined. In this study, we aimed to determine whether nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis through the JAK2/STAT3 pathway. The cerebral ischemia/reperfusion injury model was established by middle cerebral artery occlusion/reperfusion. Nicotiflorin (10 mg/kg) was administered by tail vein injection. Cell apoptosis in the ischemic cerebral cortex was examined by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Bcl-2 and Bax expression levels in ischemic cerebral cortex were examined by immunohistochemial staining. Additionally, p-JAK2, p-STAT3, Bcl-2, Bax, and caspase-3 levels in ischemic cerebral cortex were examined by western blot assay. Nicotiflorin altered the shape and structure of injured neurons, decreased the number of apoptotic cells, down-regulates expression of p-JAK2, p-STAT3, caspase-3, and Bax, decreased Bax immunoredactivity, and increased Bcl-2 protein expression and immunoreactivity. These results suggest that nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis via the JAK2/STAT3 pathway.

Traumatic occlusion of the anterior cerebral artery--case report.

PubMed

Ishibashi, A; Kubota, Y; Yokokura, Y; Soejima, Y; Hiratsuka, T

1995-12-01

A 71-year-old female presented with posttraumatic occlusion of the anterior cerebral artery (ACA) after a road accident in which she was hit in the mid-frontal region. Initial computed tomography (CT) demonstrated frontal skull fractures and pneumocephalus. High density areas were also identified in the right basal cisterns, suggesting traumatic subarachnoid hemorrhage. She was alert on admission, but with attendant shock due to crush wounds. Her condition rapidly deteriorated and an emergency amputation of her left leg was performed. After aggressive treatment with transfusion and infusion, her systolic pressure increased to 120 mmHg. Her consciousness remained disturbed. Serial CT disclosed hemorrhagic infarction in the entire medial side of the right frontal lobe. Magnetic resonance angiography demonstrated decreased flow voids in the bilateral A1 segments and right ACA, and a basilar artery aneurysm, which was unruptured clinically. Three weeks after the injury, she regained consciousness. Six months later, she had motor aphasia and left upper extremity weakness. The clinicopathological mechanism causing the traumatic occlusion of the ACA in the present case was probably dissecting aneurysm.

The Dual Role of Cerebral Autoregulation and Collateral Flow in the Circle of Willis After Major Vessel Occlusion.

PubMed

Kennedy McConnell, Flora; Payne, Stephen

2017-08-01

Ischaemic stroke is a leading cause of death and disability. Autoregulation and collateral blood flow through the circle of Willis both play a role in preventing tissue infarction. To investigate the interaction of these mechanisms a one-dimensional steady-state model of the cerebral arterial network was created. Structural variants of the circle of Willis that present particular risk of stroke were recreated by using a network model coupled with: 1) a steady-state physiological model of cerebral autoregulation; and 2) one wherein the cerebral vascular bed was modeled as a passive resistance. Simulations were performed in various conditions of internal carotid and vertebral artery occlusion. Collateral flow alone is unable to ensure adequate blood flow ([Formula: see text] normal flow) to the cerebral arteries in several common variants during internal carotid artery occlusion. However, compared to a passive model, cerebral autoregulation is better able to exploit available collateral flow and maintain flows within [Formula: see text] of baseline. This is true for nearly all configurations. Hence, autoregulation is a crucial facilitator of collateral flow through the circle of Willis. Impairment of this response during ischemia will severely impact cerebral blood flows and tissue survival, and hence, autoregulation should be monitored in this situation.

The critical role of the external carotid artery in cerebral perfusion of patients with total occlusion of the internal carotid artery.

PubMed

Dalainas, I; Avgerinos, E D; Daskalopoulos, M E; Papapetrou, A; Papasideris, C P; Katsikas, V; Xiromeritis, K; Moulakakis, K; Gianakopoulos, T; Liapis, C D

2012-02-01

The ipsilateral external carotid artery (ECA) can potentially provide an important collateral pathway for cerebral blood flow in the presence of occlusion or severe stenosis of the internal carotid artery (ICA), recovering up to 15% of the middle cerebral arterial flow. The aim of the study is to elucidate the role of ECA in cerebral flow of patients with total ICA occlusion. Retrospective study of prospectively collected data of 139 patients with total ICA occlusions. The patients were divided to symptomatic and asymptomatic and were categorized in four subgroups according to the stenosis rates: A) ipsilateral ECA<70% and contralateral internal carotid artery stenosis <70%; B) ipsilateral ECA stenosis <70% and contralateral internal carotid artery stenosis ≥70%; C) ipsilateral ECA stenosis ≥70% and contralateral ICA stenosis <70%; D) ipsilateral ECA stenosis ≥70% and contralateral ICA stenosis ≥75%. Fifty eight (41.7%) patients were asymptomatic. The highest rate (48.2%) of asymptomatic patients was in Group A. Among patients with strokes, the highest rate belonged in groups C and D (44.4% and 50% respectively) where ipsilateral ECA stenosis was ≥70% irrespectively of the contralateral ICA patency. Ipsilateral external carotid artery stenosis ≥70% proved to be and independent risk factor for symptom presentation (P=0.013). The study reveals the significant role of ECA patency in cerebral flow in patients with ICA occlusion.

Super-selective Balloon Test Occlusion of the Posterior Communicating Artery in the Treatment of a Posterior Cerebral Artery Fusiform Aneurysm: a Case Report.

PubMed

Isozaki, Makoto; Arai, Hiroshi; Neishi, Hiroyuki; Kitai, Ryuhei; Kikuta, Ken-Ichiro

2016-10-01

We report the case of a 49-year-old man with underlying hypertension who developed diplopia lasting 2 months. Magnetic resonance imaging and digital subtraction angiography showed multi-lobular unruptured aneurysms in the P2 portion of the posterior cerebral artery (PCA) migrating into the interpeduncular cistern of the midbrain. Because the shapes of the aneurysms were serpentine fusiform and the posterior communicating artery (PCoA) was the fetal type, we planned anastomosis of the occipital artery to the P4 portion of the PCA followed by endovascular obliteration of the parent artery including the aneurysms. Endovascular treatment was performed via a femoral approach one week after the anastomosis. Super-selective balloon test occlusion (BTO) of the PCoA was performed by using an occlusion balloon microcatheter before endovascular treatment. Occlusion of the proximal segment of the PCoA induced disturbance of consciousness of the patient. Occlusion of the distal segment other than the first point of the PCoA did not induce any neurological symptoms. The information from this super-selective BTO helped us to perform precise endovascular obliteration. The aneurysm was successfully obliterated, and the diplopia almost disappeared in a few months. Super-selective BTO of the PCoA might be a useful method for preventing ischemic complications due to occlusion of invisible perforators.

Super-selective Balloon Test Occlusion of the Posterior Communicating Artery in the Treatment of a Posterior Cerebral Artery Fusiform Aneurysm: a Case Report

PubMed Central

Isozaki, Makoto; Arai, Hiroshi; Neishi, Hiroyuki; Kitai, Ryuhei; Kikuta, Ken-ichiro

2016-01-01

We report the case of a 49-year-old man with underlying hypertension who developed diplopia lasting 2 months. Magnetic resonance imaging and digital subtraction angiography showed multi-lobular unruptured aneurysms in the P2 portion of the posterior cerebral artery (PCA) migrating into the interpeduncular cistern of the midbrain. Because the shapes of the aneurysms were serpentine fusiform and the posterior communicating artery (PCoA) was the fetal type, we planned anastomosis of the occipital artery to the P4 portion of the PCA followed by endovascular obliteration of the parent artery including the aneurysms. Endovascular treatment was performed via a femoral approach one week after the anastomosis. Super-selective balloon test occlusion (BTO) of the PCoA was performed by using an occlusion balloon microcatheter before endovascular treatment. Occlusion of the proximal segment of the PCoA induced disturbance of consciousness of the patient. Occlusion of the distal segment other than the first point of the PCoA did not induce any neurological symptoms. The information from this super-selective BTO helped us to perform precise endovascular obliteration. The aneurysm was successfully obliterated, and the diplopia almost disappeared in a few months. Super-selective BTO of the PCoA might be a useful method for preventing ischemic complications due to occlusion of invisible perforators. PMID:28664014

Therapeutic effects of oral dimethyl fumarate on stroke induced by middle cerebral artery occlusion: An animal experimental study.

PubMed

Safari, Anahid; Fazeli, Mehdi; Namavar, Mohammad Reza; Tanideh, Nader; Jafari, Peyman; Borhani-Haghighi, Afshin

2017-01-01

Dimethyl fumarate (DMF) has immune-modulatory and neuro-protective characteristics that can be used for treatment of acute ischemic stroke. To investigate the therapeutic effects of DMF on histological and functional recovery of rats after transient middle cerebral artery (MCA) occlusion. 22 Sprague-Dawley male rats weighing 275-300 g were randomized into three groups by block randomization. In the sham group (n = 7), the neck was opened, but neither MCA was occluded, nor any drug was administered.The control group (n = 7) was treated with vehicle (methocel) by gavage for 14 days after MCA occlusion. In the DMF-treated group (n = 8), treatment was performed with 15 mg/kg body weight dimethyl fumarate twice a day for 14 days after MCA occlusion. Transient occlusion of the right MCA was performed by intraluminal thread method in the DMF-treated and the control group. Neurological deficit score (NDS), pole test, and adhesive removal test were performed before the surgery, and on post-operative Days 0, 3, 5, 7, 10, and 14. After the final behaviour test, the animals' brains were perfused and removed. Brains were frozen and sectioned serially and coronally using a cryostat. Infract volume and brain volume were estimated by stereology. The percentage of infarct volume was significantly lower in DMF-treated animals (5.76%) than in the control group (22.39%) (P < 0.0001). Regarding behavioural tests, the DMF-treated group showed better function in NDS on Days 7 (P = 0.041) and 10 (P = 0.046), but not in pole and adhesive removal tests. There was no significant correlation between behavioural tests and histological results. Dimethyl fumarate could be beneficial as a potential neuroprotective agent in the treatment of stroke.

Effects of noninvasive facial nerve stimulation in the dog middle cerebral artery occlusion model of ischemic stroke.

PubMed

Borsody, Mark K; Yamada, Chisa; Bielawski, Dawn; Heaton, Tamara; Castro Prado, Fernando; Garcia, Andrea; Azpiroz, Joaquín; Sacristan, Emilio

2014-04-01

Facial nerve stimulation has been proposed as a new treatment of ischemic stroke because autonomic components of the nerve dilate cerebral arteries and increase cerebral blood flow when activated. A noninvasive facial nerve stimulator device based on pulsed magnetic stimulation was tested in a dog middle cerebral artery occlusion model. We used an ischemic stroke dog model involving injection of autologous blood clot into the internal carotid artery that reliably embolizes to the middle cerebral artery. Thirty minutes after middle cerebral artery occlusion, the geniculate ganglion region of the facial nerve was stimulated for 5 minutes. Brain perfusion was measured using gadolinium-enhanced contrast MRI, and ATP and total phosphate levels were measured using 31P spectroscopy. Separately, a dog model of brain hemorrhage involving puncture of the intracranial internal carotid artery served as an initial examination of facial nerve stimulation safety. Facial nerve stimulation caused a significant improvement in perfusion in the hemisphere affected by ischemic stroke and a reduction in ischemic core volume in comparison to sham stimulation control. The ATP/total phosphate ratio showed a large decrease poststroke in the control group versus a normal level in the stimulation group. The same stimulation administered to dogs with brain hemorrhage did not cause hematoma enlargement. These results support the development and evaluation of a noninvasive facial nerve stimulator device as a treatment of ischemic stroke.

Effects of the combined treatment of bone marrow stromal cells with mild exercise and thyroid hormone on brain damage and apoptosis in a mouse focal cerebral ischemia model.

PubMed

Akhoundzadeh, Kobar; Vakili, Abedin; Sameni, Hamid Reza; Vafaei, Abbas Ali; Rashidy-Pour, Ali; Safari, Manouchehr; Mohammadkhani, Razieh

2017-08-01

This study examined whether post-stroke bone marrow stromal cells (BMSCs) therapy combined with exercise (EX) and/or thyroid hormone (TH) could reduce brain damage in an experimental ischemic stroke in mice. Focal cerebral ischemia was induced under Laser Doppler Flowmetry (LDF) guide by 45 min of middle cerebral artery occlusion (MCAO), followed by 7 days of reperfusion in albino mice. BMSCs were injected into the right cerebral ventricle 24 h after MCAO, followed by daily injection of T3 (20 μg/100 g weight S.C) and 6 days of running on a treadmill. Infarct size, neurobehavioral test, TUNEL and BrdU positive cells were evaluated at 7 days after MCAO. Treatment with BMSCs and mild EX alone significantly reduced the infarct volume by 23% and 44%, respectively (both, p < 0.001). The BMSCs + TH, BMSCs + EX, and BMSCs + EX + TH combination therapies significantly reduced the infarct volume by 26%, 51%, and 70%, respectively (all, p < 0.001). A significant improvement in the neurobehavioral functioning was observed in the EX, BMSCs + EX, and BMSCs + EX+ TH groups (p < 0.001). The number of TUNEL-positive cells (a marker of apoptosis) was significantly reduced in the EX, BMSCs, BMSCs + EX, BMSCs + TH, and BMSCs + EX + TH groups (all, p < 0.001). Moreover, the combination therapy considerably increased BrdU-labeled cells in the subventricular zone (SVZ) (p < 0.01). Our findings indicated that the combined treatment of BMSCs with mild EX and TH more efficiently reduces the cerebral infarct size after stroke. More likely, these effects mediate via enchaining generation of new neuronal cells and the attenuation of apoptosis in ischemia stroke in young mice.

Korean red ginseng protects against neuronal damage induced by transient focal ischemia in rats

PubMed Central

BAN, JU YEON; KANG, SUNG WOOK; LEE, JONG SEOK; CHUNG, JOO-HO; KO, YOUNG GWAN; CHOI, HAN SUNG

2012-01-01

In the present study, we investigated the neuroprotective effect of Korean red ginseng (KRG) following focal brain ischemia/reperfusion injury, in relation to its antioxidant activities. The middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats was employed. The KRG extract (100 mg/kg, perorally) was administered once daily for 7 days following MCAO/R. The elevated levels of lipid peroxidation in the MCAO/R group were attenuated significantly in the KRG-administered group. The significantly depleted activity of the antioxidant enzymes glutathione peroxidase, superoxide dismutase and catalase was prevented in the KRG-administered group. In the neurobehavioral evaluation expressed as the modified neurological severity score and corner-turn test, the daily intake of KRG showed consistent and significant improvement in the neurological deficits for 7 days following MCAO/R injury. These results indicate that KRG has a neuroprotective effect against ischemia/reperfusion brain injury by reducing the level of lipid peroxidation and increasing the endogenous antioxidant enzymatic activity. PMID:22969953

Different mechanisms of secondary neuronal damage in thalamic nuclei after focal cerebral ischemia in rats.

PubMed

Dihné, Marcel; Grommes, Christian; Lutzenburg, Michael; Witte, Otto W; Block, Frank

2002-12-01

After focal cerebral ischemia, depending on its localization and extent, secondary neuronal damage may occur that is remote from the initial lesion. In this study differences in secondary damage of the ventroposterior thalamic nucleus (VPN) and the reticular thalamic nucleus (RTN) were investigated with the use of different ischemia models. Transient middle cerebral artery occlusion (MCAO) leads to cortical infarction, including parts of the basal ganglia such as the globus pallidus, and to widespread edema. Photothrombotic ischemia generates pure cortical infarcts sparing the basal ganglia and with only minor edema. Neuronal degeneration was quantified within the ipsilateral RTN and VPN 14 days after ischemia. Glial reactions were studied with the use of immunohistochemistry. MCAO resulted in delayed neuronal cell loss of the ipsilateral VPN and RTN. Glial activation occurred in both nuclei beginning after 24 hours. Photothrombotic ischemia resulted in delayed neuronal cell loss only within the VPN. Even 2 weeks after photothrombotic ischemia, glial activation could only be seen within the VPN. Pure cortical infarcts after photothrombotic ischemia, without major edema and without effects on the globus pallidus of the basal ganglia, only lead to secondary VPN damage that is possibly due to retrograde degeneration. MCAO, which results in infarction of cortex and globus pallidus and which causes widespread edema, leads to secondary damage in the VPN and RTN. Thus, additional RTN damage may be due to loss of protective GABAergic input from the globus pallidus to the RTN or due to the extensive edema. Retrograde degeneration is not possible because the RTN, in contrast to the VPN, has no efferents to the cortex.

Down-regulation of NOX4 by betulinic acid protects against cerebral ischemia-reperfusion in mice.

PubMed

Lu, Pei; Zhang, Chen-Chen; Zhang, Xiao-Min; Li, Hui-Ge; Luo, Ai-Lin; Tian, Yu-Ke; Xu, Hui

2017-10-01

Ischemic stroke leads to high potentiality of mortality and disability. The current treatment for ischemic stroke is mainly focused on intravenous thrombolytic therapy. However, ischemia/ reperfusion induces neuronal damage, which significantly influences the outcome of patients with ischemic stroke, and the exact mechanism implicated in ischemia/reperfusion injury remains unclear, although evidence shows that oxidative stress is likely to be involved. Betulinic acid is mainly known for its anti-tumor and anti-inflammatory activities. Our previous study showed that betulinic acid could decrease the reactive oxygen species (ROS) production by regulating the expression of NADPH oxidase. Thus, we hypothesized that betulinic acid may protect against brain ischemic injury in the animal model of stroke. Focal cerebral ischemia was achieved by using the standard intraluminal occlusion method and reperfusion enabled after 2 h ischemia. Neurological deficits were scored. Infarct size was determined with 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining and the mRNA expression of NADPH oxidase 4 (NOX4) was determined by RT-PCR in infarct tissue. ROS generation and apoptosis in ischemic tissue were analyzed by measuring the oxidative conversion of cell permeable 2',7'-dichloro-fluorescein diacetate (DCF-DA) to fluorescent dichlorofluorescein (DCF) in fluorescence microplate reader and TUNEL assay, respectively. In Kunming mice, 2 h of middle cerebral artery (MCA) occlusion followed by 24 or 72 h of reperfusion led to an enhanced NOX4 expression in the ischemic hemisphere. This was associated with elevated levels of ROS generation and neuronal apoptosis. Pre-treatment with betulinic acid (50 mg/kg/day for 7 days via gavage) prior to MCA occlusion prevented the ischemia/reperfusion-induced up-regulation of NOX4 and ROS production. In addition, treatment with betulinic acid could markedly blunt the ischemia/reperfusion-induced neuronal apoptosis. Finally, betulinic

Diabetic microangiopathy: impact of impaired cerebral vasoreactivity and delayed angiogenesis after permanent middle cerebral artery occlusion on stroke damage and cerebral repair in mice.

PubMed

Poittevin, Marine; Bonnin, Philippe; Pimpie, Cynthia; Rivière, Léa; Sebrié, Catherine; Dohan, Anthony; Pocard, Marc; Charriaut-Marlangue, Christiane; Kubis, Nathalie

2015-03-01

Diabetes increases the risk of stroke by three, increases related mortality, and delays recovery. We aimed to characterize functional and structural alterations in cerebral microvasculature before and after experimental cerebral ischemia in a mouse model of type 1 diabetes. We hypothesized that preexisting brain microvascular disease in patients with diabetes might partly explain increased stroke severity and impact on outcome. Diabetes was induced in 4-week-old C57Bl/6J mice by intraperitoneal injections of streptozotocin (60 mg/kg). After 8 weeks of diabetes, the vasoreactivity of the neurovascular network to CO2 was abolished and was not reversed by nitric oxide (NO) donor administration; endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) mRNA, phospho-eNOS protein, nNOS, and phospho-nNOS protein were significantly decreased; angiogenic and vessel maturation factors (vascular endothelial growth factor a [VEGFa], angiopoietin 1 (Ang1), Ang2, transforming growth factor-β [TGF-β], and platelet-derived growth factor-β [PDGF-β]) and blood-brain barrier (BBB) occludin and zona occludens 1 (ZO-1) expression were significantly decreased; and microvessel density was increased without changes in ultrastructural imaging. After permanent focal cerebral ischemia induction, infarct volume and neurological deficit were significantly increased at D1 and D7, and neuronal death (TUNEL+ / NeuN+ cells) and BBB permeability (extravasation of Evans blue) at D1. At D7, CD31+ / Ki67+ double-immunolabeled cells and VEGFa and Ang2 expression were significantly increased, indicating delayed angiogenesis. We show that cerebral microangiopathy thus partly explains stroke severity in diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Hydroquinone Strongly Alleviates Focal Ischemic Brain Injury via Blockage of Blood-Brain Barrier Disruption in Rats.

PubMed

Ha Park, Joon; Yoo, Ki-Yeon; Hye Kim, In; Cho, Jeong-Hwi; Lee, Jae-Chul; Hyeon Ahn, Ji; Jin Tae, Hyun; Chun Yan, Bing; Won Kim, Dae; Kyu Park, Ok; Kwon, Seung-Hae; Her, Song; Su Kim, Jin; Hoon Choi, Jung; Hyun Lee, Choong; Koo Hwang, In; Youl Cho, Jae; Hwi Cho, Jun; Kwon, Young-Guen; Ryoo, Sungwoo; Kim, Young-Myeong; Won, Moo-Ho; Jun Kang, Il

2016-12-01

Hydroquinone (HQ), a major benzene metabolite, occurs naturally in various plants and is manufactured for commercial use. Although HQ displays various biological effects, its neuroprotective effects following ischemic insults have not been investigated. In this study, we first examined neuroprotective effects of HQ in a rat model of transient focal cerebral ischemia. Animals were subjected to transient middle cerebral artery occlusion for 120 min. HQ (50 or 100 mg/kg) or vehicle was intraperitoneally administered once at 30 min after ischemia-reperfusion. Neuroprotection by treatment with 100 mg/kg of HQ was shown using evaluation of neurological deficits, positron-emission tomography (PET) and 2,3,5-triphenyltetrazoliumchloride (TTC) staining. In addition, HQ treatment significantly attenuated ischemia-induced Evans blue dye extravasation from blood vessels and significantly increased immunoreactivities of SMI-71 (an endothelial BBB marker) and glucose transporter-1 (GLUT-1, an endothelial cell marker) in ischemic cortex compared to the vehicle-treated ischemia-operated group. Confocal microscopy and western blot analysis also showed that HQ treatment maintained expressions of tight junction proteins (zonula occludens-1 and occludin) in the ischemic cortex. Post-treatment with HQ protected neurons from transient focal cerebral ischemic injury and the neuroprotective effect of HQ might be closely associated with prevention of BBB disruption via maintaining SMI-71 and GLUT-1 expressions as well as prevention of the degradation of zonula occludens-1 and occludin proteins. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Netrin-1 rescues neuron loss by attenuating secondary apoptosis in ipsilateral thalamic nucleus following focal cerebral infarction in hypertensive rats.

PubMed

Liao, S-J; Gong, Q; Chen, X-R; Ye, L-X; Ding, Q; Zeng, J-S; Yu, J

2013-02-12

Neurological deficit following cerebral infarction correlates with not only primary injury, but also secondary neuronal apoptosis in remote loci connected to the infarction. Netrin-1 is crucial for axonal guidance by interacting with its receptors, deleted in colorectal cancer (DCC) and uncoordinated gene 5H (UNC5H). DCC and UNC5H are also dependence receptors inducing cell apoptosis when unbound by netrin-1. The present study is to investigate the role of netrin-1 and its receptors in ipsilateral ventroposterior thalamic nucleus (VPN) injury secondary to stroke in hypertensive rats. Renovascular hypertensive Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO). Continuous intracerebroventricular infusion of netrin-1 (600 ng/d for 7 days) or vehicle (IgG/Fc) was given 24h after MCAO. Neurological function was evaluated by postural reflex 8 and 14 days after MCAO. Then, immunoreactivity was determined in the ipsilateral VPN for NeuN, glial fibrillary acidic protein, netrin-1 and its receptors (DCC and UNC5H2), apoptosis was detected with Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling (TUNEL) assay, and the expressions of caspase-3, netrin-1, DCC, and UNC5H2 were quantified by western blot analysis. MCAO resulted in the impaired postural reflex after 8 and 14 days, with decreased NeuN marked neurons and increased TUNEL-positive cells, as well as an up-regulation in the levels of cleaved caspase-3 and UNC5H2 protein in the ipsilateral VPN, without significant change in DCC or netrin-1 expression. By exogenous netrin-1 infusion, the number of neurons was increased in the ipsilateral VPN, and both TUNEL-positive cell number and caspase-3 protein level were reduced, while UNC5H2 expression remained unaffected, simultaneously, the impairment of postural reflex was improved. Taken together, the present study indicates that exogenous netrin-1 could rescue neuron loss by attenuating secondary apoptosis in the

Nicotinamide attenuates the ischemic brain injury-induced decrease of Akt activation and Bad phosphorylation.

PubMed

Koh, Phil-Ok

2011-07-08

Nicotinamide protects cortical neuronal cells against cerebral ischemic injury through activation of various cytoprotective mechanisms. Here, this study confirmed the neuroprotective effects of nicotinamide in focal cerebral ischemic injury and investigated whether nicotinamide modulates a crucial survival pathway, Akt and its downstream targets. Adult male rats were treated with vehicle or nicotinamide (500 mg/kg) 2h after the onset of middle cerebral artery occlusion (MCAO). Brains were collected 24h after MCAO and infarct volumes were analyzed. Nicotinamide significantly reduced the infarct volume in the cerebral cortex. Potential activation was measured by phosphorylation of PDK1 at Ser(241), Akt at Ser(473), and Bad at Ser(136) using Western blot analysis. Nicotinamide prevented the injury-induced decrease of pPDK1, pAkt, and pBad levels. 14-3-3 levels were not different between vehicle- and nicotinamide-treated animals. However, pBad and 14-3-3 interaction levels decreased during MCAO, but were maintained in the presence of nicotinamide, compared to levels in control animals. These findings suggest that nicotinamide attenuates cell death due to focal cerebral ischemic injury and that neuroprotective effects are mediated through the Akt signaling pathway, thus enhancing neuronal survival. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Effects of laser acupoint irradiation on energy metabolism of brain tissue of rats with cerebral ischemia-reperfusion

NASA Astrophysics Data System (ADS)

Xiong, Guoxin; Li, Xinzhong

2017-12-01

The protective effect and mechanism of low-intensity laser acupoint irradiation on focal cerebral ischemia-reperfusion (CIR) injury in rats were investigated. Male Sprague-Dawley rats were randomly divided into a sham group, a CIR model (model) group, and a model plus laser irradiation (laser) group. The focal CIR model was induced by middle cerebral artery occlusion in all except the rats in the sham group. After modeling, the Baihui, Mingmen, and left Zusanli points of the rats in the laser group were irradiated with 15 mW using a semiconductor laser, and each point was irradiated for 15 min once a day for 7 d. The treatments used in the sham and model groups were the same as in the laser group except that the laser output power was zero. After treatment, the expressions of serum superoxide dismutase (SOD) activity and serum malonaldehyde (MDA) content, the expression of growth-associated protein (GAP-43), the activities of succinic dehydrogenase and lactic dehydrogenase in brain tissue, were measured. The results showed that acupoint irradiation with a semiconductor laser can improve energy metabolism, enhance the expression of GAP-43, increase the levels of expression of serum SOD, and decrease the serum MDA content in a rat model of focal CIR, suggesting the mechanism for reduction of CIR injury.

Regional cerebral (18)FDG uptake during subarachnoid hemorrhage induced vasospasm.

PubMed

Novak, Laszlo; Emri, Miklos; Molnar, Peter; Balkay, Laszlo; Szabo, Sandor; Rozsa, Laszlo; Lengyel, Zsolt; Tron, Lajos

2006-12-01

The aim was to elucidate whether aneurysmal subarachnoid hemorrhage (SAH)-induced vasospasm induces changes of regional glucose uptake in surgically treated, asymptomatic cases. (18)FDG uptake (standardized uptake value, SUV) was analysed with PET in eight surgically treated aneurismal patients with a mean middle cerebral artery flow velocity >120 cm/seconds measured with transcranial Doppler ultrasound. Data were compared with a healthy control group using Statistical Parametric Mapping (SPM99b). Six of the eight patients had no focal neurological signs. The inhomogeneous bilateral increase in SUV (p<0.0001) was asymmetrical, with an almost 70% larger volume on the operated side. Reduced glucose uptake was found in the frontal and temporobasal regions of the two patients with neurological deficits (p<0.0001); the affected volume was 40% larger on the operated side. SAH-induced vasospasm results in widespread increase of glucose uptake-probably reflecting increased glycolysis. This was earlier than neurological focal signs appear. Decreased glucose uptake can be detected in severe cases of vasospasm reflected by neurological deficit. Although the changes are more prominent where surgery had taken place our results suggest that not only the surgery, but also subarachnoid blood might have resulted in our findings.

Comparison of the anti-apoptotic effects of 15- and 35-minute suspended moxibustion after focal cerebral ischemia/reperfusion injury.

PubMed

Xiao, Ai-Jiao; He, Lin; Ouyang, Xin; Liu, Jie-Min; Chen, Ming-Ren

2018-02-01

Heat-sensitive suspended moxibustion has a neuroprotective effect against focal cerebral ischemia/reperfusion injury, but the underlying mechanisms remain unclear. The duration of heat-sensitive suspended moxibustion (usually from 30 minutes to 1 hour) is longer than traditional suspended moxibustion (usually 15 minutes). However, the effects of 15- and 35-minute suspended moxibustion in rats with cerebral ischemia/reperfusion injury are poorly understood. In this study, we performed 15- or 35-minute suspended moxibustion at acupoint Dazhui (GV14) in an adult rat model of focal cerebral ischemia/reperfusion injury. Infarct volume was evaluated with the 2,3,5-triphenyltetrazolium chloride assay. Histopathological changes and neuronal apoptosis at the injury site were assessed by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Caspase-9 and caspase-3 expression at the injury site was detected using immunofluorescent staining. Bax and Bcl-2 expression at the injury site was assessed using western blot assay. In the 35-minute moxibustion group, infarct volume was decreased, neuronal apoptosis was reduced, caspase-9, caspase-3 and Bax expression was lower, and Bcl-2 expression was increased, compared with the 15-minute moxibustion group. Our findings show that 35-minute moxibustion has a greater anti-apoptotic effect than 15-minute moxibustion after focal cerebral ischemia/reperfusion injury.

TIA model is attainable in Wistar rats by intraluminal occlusion of the MCA for 10min or shorter.

PubMed

Durukan Tolvanen, A; Tatlisumak, E; Pedrono, E; Abo-Ramadan, U; Tatlisumak, T

2017-05-15

Transient ischemic attack (TIA) has received only little attention in the experimental research field. Recently, we introduced a TIA model for mice, and here we set similar principles for simulating this human condition in Wistar rats. In the model: 1) transient nature of the event is ensured, and 2) 24h after the event animals are free from any sensorimotor deficit and from any detectable lesion by magnetic resonance imaging (MRI). Animals experienced varying durations of ischemia (5, 10, 12.5, 15, 25, and 30min, n=6-8pergroup) by intraluminal middle cerebral artery occlusion (MCAO). Ischemia severity and reperfusion rates were controlled by cerebral blood flow measurements. Sensorimotor neurological evaluations and MRI at 24h differentiated between TIA and ischemic stroke. Hematoxylin and eosin staining and apoptotic cell counts revealed pathological correlates of the event. We found that already 12.5min of ischemia was long enough to induce ischemic stroke in Wistar rats. Ten min or shorter durations induced neither gross neurological deficits nor infarcts visible on MRI, but histologically caused selective neuronal necrosis. A separate group of animals with 10min of ischemia followed up to 1week after reperfusion remained free of infarction and any MRI signal change. Thus, 10min or shorter focal cerebral ischemia induced by intraluminal MCAO in Wistar rats provides a clinically relevant TIA the rat. This model is useful for studying molecular correlates of TIA. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuroprotection by dimethyloxalylglycine following permanent and transient focal cerebral ischemia in rats

PubMed Central

Nagel, Simon; Papadakis, Michalis; Chen, Ruoli; Hoyte, Lisa C; Brooks, Keith J; Gallichan, Daniel; Sibson, Nicola R; Pugh, Chris; Buchan, Alastair M

2011-01-01

Dimethyloxalylglycine (DMOG) is an inhibitor of prolyl-4-hydroxylase domain (PHD) enzymes that regulate the stability of hypoxia-inducible factor (HIF). We investigated the effect of DMOG on the outcome after permanent and transient middle cerebral artery occlusion (p/tMCAO) in the rat. Before and after pMCAO, rats were treated with 40 mg/kg, 200 mg/kg DMOG, or vehicle, and with 40 mg/kg or vehicle after tMCAO. Serial magnetic resonance imaging (MRI) was performed to assess infarct evolution and regional cerebral blood flow (rCBF). Both doses significantly reduced infarct volumes, but only 40 mg/kg improved the behavior after 24 hours of pMCAO. Animals receiving 40 mg/kg were more likely to maintain rCBF values above 30% from the contralateral hemisphere within 24 hours of pMCAO. DMOG after tMCAO significantly reduced the infarct volumes and improved behavior at 24 hours and 8 days and also improved the rCBF after 24 hours. A consistent and significant upregulation of both mRNA and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) was associated with the observed neuroprotection, although this was not consistently related to HIF-1α levels at 24 hours and 8 days. Thus, DMOG afforded neuroprotection both at 24 hours after pMCAO and at 24 hours and 8 days after tMCAO. This effect was associated with an increase of VEGF and eNOS and was mediated by improved rCBF after DMOG treatment. PMID:20407463

Does Preinterventional Flat-Panel Computer Tomography Pooled Blood Volume Mapping Predict Final Infarct Volume After Mechanical Thrombectomy in Acute Cerebral Artery Occlusion?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wagner, Marlies, E-mail: marlies.wagner@kgu.de; Kyriakou, Yiannis, E-mail: yiannis.kyriakou@siemens.com; Mesnil de Rochemont, Richard du, E-mail: mesnil@em.uni-frankfurt.de

2013-08-01

PurposeDecreased cerebral blood volume is known to be a predictor for final infarct volume in acute cerebral artery occlusion. To evaluate the predictability of final infarct volume in patients with acute occlusion of the middle cerebral artery (MCA) or the distal internal carotid artery (ICA) and successful endovascular recanalization, pooled blood volume (PBV) was measured using flat-panel detector computed tomography (FPD CT).Materials and MethodsTwenty patients with acute unilateral occlusion of the MCA or distal ACI without demarcated infarction, as proven by CT at admission, and successful Thrombolysis in cerebral infarction score (TICI 2b or 3) endovascular thrombectomy were included. Cerebralmore » PBV maps were acquired from each patient immediately before endovascular thrombectomy. Twenty-four hours after recanalization, each patient underwent multislice CT to visualize final infarct volume. Extent of the areas of decreased PBV was compared with the final infarct volume proven by follow-up CT the next day.ResultsIn 15 of 20 patients, areas of distinct PBV decrease corresponded to final infarct volume. In 5 patients, areas of decreased PBV overestimated final extension of ischemia probably due to inappropriate timing of data acquisition and misery perfusion.ConclusionPBV mapping using FPD CT is a promising tool to predict areas of irrecoverable brain parenchyma in acute thromboembolic stroke. Further validation is necessary before routine use for decision making for interventional thrombectomy.« less

The Immune Response to Acute Focal Cerebral Ischemia and Associated Post-stroke Immunodepression: A Focused Review

PubMed Central

Famakin, Bolanle M.

2014-01-01

It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to recruitment of inflammatory cells and the production of more inflammatory mediators that result in activation of the adaptive immune response. Under ideal conditions, this inflammation gives way to tissue repair and attempts at regeneration. However, for reasons that are just being understood, immunosuppression occurs following acute stroke leading to post-stroke immunodepression. This review focuses on the current state of knowledge regarding innate and adaptive immune activation in response to focal cerebral ischemia as well as the immunodepression that can occur following stroke. A better understanding of the intricate and complex events that take place following immune response activation, to acute cerebral ischemia, is imperative for the development of effective novel immunomodulatory therapies for the treatment of acute stroke. PMID:25276490

Protective effects of alkaloid extract from Leonurus heterophyllus on cerebral ischemia reperfusion injury by middle cerebral ischemic injury (MCAO) in rats.

PubMed

Liang, Hao; Liu, Ping; Wang, Yunshan; Song, Shuliang; Ji, Aiguo

2011-07-15

The neuronal damage following cerebral ischemia is a serious risk to stroke patients. The aim of this study was to investigate the neuroprotective effects of alkaloid extract from Leonurus heterophyllus (LHAE) on cerebral ischemic injury. After 24 h of reperfusion following ischemia for 2 h induced by middle cerebral artery occlusion (MCAO), some rats were intraperitoneally administered different doses of LHAE (3.6, 7.2, 14.4 mg/kg, respectively). Neurological examination was measured in all animals. Infarct volume, myeloperoxidase (MPO) activity, levels of nitrate/nitrite metabolite (NO) and apoptosis ratio of nerve fiber in brain were determined. The results showed that LHAE at 7.2 mg/kg or 14.4 mg/kg exerted significantly decreasing neurological deficit scores and reducing the infarct volume on rats with focal cerebral ischemic injury (p<0.05). At those dose, the MPO content were significantly decreased in ischemic brain as compared with model group (p<0.05). LHAE at 14.4 mg/kg significantly decreased the NO level compared with the model group (p<0.05). In addition, LHAE significantly decreased the apoptosis ratio of nerve fiber compared with the model group (p<0.05). This study suggests that LHAE may be used for treatment of ischemic stroke as a neuroprotective agent. Further studies are warranted to assess the efficacy and safety of LHAE in patients. Copyright © 2011 Elsevier GmbH. All rights reserved.

Buprenorphine does not aggravate ischemic neuronal injury in experimental focal cerebral ischemia.

PubMed

Yulug, Burak; Cam, Ertugrul; Yildiz, Aysegul; Kilic, Ertugrul

2007-01-01

Buprenorphine has been increasingly used as maintenance therapy in opioid dependence as an alternative to methadone and other pharmacological therapies. However, available data suggest increased risk of cerebrovascular events in opioid-dependent patients. Therefore, an opioid that provides safety with regard to neurological function should be considered by opioid-dependent patients. The evidence for the in vitro neurotoxic effects of buprenorphine is rapidly increasing. In order to clarify whether buprenorphine is also neurotoxic under the condition of cerebral ischemia in vivo, we applied an acute dose of buprenorphine in a transient model of focal cerebral ischemia in rats. Our study provides preclinical evidence for the usage of buprenorphine during the postoperative period following ischemic events as well as for the maintenance therapy of opioid-dependent patients wherein the risk of cerebrovascular events is increased.

Middle Cerebral Artery, Ophthalmic Artery, and Multibranch Retinal Vessel Occlusion After Cosmetic Autologous Fat Transfer to Forehead.

PubMed

Roshandel, Danial; Soheilian, Masoud; Pakravan, Mohammad; Aghayan, Sara; Peyman, Gholam A

2015-05-01

A 65-year-old woman with left hemiparesis and sudden loss of visual acuity in her right eye presented a few hours after cosmetic injection of autologous fat to her forehead. Right eye visual acuity was no light perception. Funduscopy revealed widespread retinal whitening and multibranch retinal vessel occlusion. Fluorescein angiography showed markedly delayed choroidal and retinal filling together with occlusion of multiple branches of retinal arteries and veins. On magnetic resonance imaging of the brain, multiple lesions compatible with recent infarction were detected. The authors diagnosed multibranch retinal artery and vein occlusion in the right ophthalmic and middle cerebral arteries due to fat emboli. This case emphasizes the need to reevaluate the safety of such aesthetic procedures, particularly in the facial zone to prevent devastating complications. Copyright 2015, SLACK Incorporated.

Role of Ocimum basilicum L. in prevention of ischemia and reperfusion-induced cerebral damage, and motor dysfunctions in mice brain.

PubMed

Bora, Kundan Singh; Arora, Shruti; Shri, Richa

2011-10-11

The genus Ocimum (Lamiaceae) has a long history of use as culinary and medicinal herbs. Many species are used for their antioxidant and neuroprotective activity in various parts of the world. Ocimum basilicum Linn. has been used traditionally for the treatment of anxiety, diabetes, cardiovascular diseases, headaches, nerve pain, as anticonvulsant and anti-inflammatory, and used in a variety of neurodegenerative disorders. The present study is designed to investigate the effect of ethyl acetate extract of Ocimum basilicum leaves on ischemia and reperfusion-induced cerebral damage, and motor dysfunctions in mice. Global cerebral ischemia was induced by bilateral carotid artery occlusion for 15 min followed by reperfusion for 24h. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. The concentration of thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) content was determined by colorimetric assay. Short-term memory was evaluated using elevated plus-maze. Inclined beam walking was employed to assess motor coordination. Bilateral carotid artery occlusion followed by reperfusion produced significant increase in cerebral infarct size and lipid peroxidation (TBARS), and reduced GSH content, and impaired short-term memory and motor coordination. Pre-treatment with standardized ethyl acetate extract of Ocimum basilicum (100 and 200mg/kg, p.o.) markedly reduced cerebral infarct size and lipid peroxidation, restored GSH content, and attenuated impairment in short-term memory and motor coordination. The results of the study suggest that Ocimum basilicum could be useful clinically in the prevention of stroke. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Ferulic acid attenuates the cerebral ischemic injury-induced decrease in peroxiredoxin-2 and thioredoxin expression.

PubMed

Sung, Jin-Hee; Gim, Sang-Ah; Koh, Phil-Ok

2014-04-30

Ferulic acid, a phenolic phytochemical compound found in various plants, has a neuroprotective effect through its anti-oxidant and anti-inflammation functions. Peroxiredoxin-2 and thioredoxin play a potent neuroprotective function against oxidative stress. We investigated whether ferulic acid regulates peroxiredoxin-2 and thioredoxin levels in cerebral ischemia. Sprague-Dawley rats (male, 210-230g) were treated with vehicle or ferulic acid (100mg/kg) after middle cerebral artery occlusion (MCAO), and cerebral cortex tissues were collected 24h after MCAO. Decreases in peroxiredoxin-2 and thioredoxin levels were elucidated in MCAO-operated animals using a proteomics approach. We found that ferulic acid treatment prevented the MCAO-induced decrease in the expression of peroxiredoxin-2 and thioredoxin. RT-PCR and Western blot analyses confirmed that ferulic acid treatment attenuated the MCAO-induced decrease in peroxiredoxin-2 and thioredoxin levels. Moreover, immunoprecipitation analysis showed that the interaction between thioredoxin and apoptosis signal-regulating kinase 1 (ASK1) decreased during MCAO, whereas ferulic acid prevented the MCAO-induced decrease in this interaction. Our findings suggest that ferulic acid plays a neuroprotective role by attenuating injury-induced decreases in peroxiredoxin-2 and thioredoxin levels in neuronal cell injury. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Combination of blood flow asymmetry in the cerebral and cerebellar hemispheres on brain perfusion SPECT predicts 5-year outcome in patients with symptomatic unilateral major cerebral artery occlusion.

PubMed

Nomura, Jun-ichi; Ogasawara, Kuniaki; Saito, Hideo; Terasaki, Kazunori; Matsumoto, Yoshiyasu; Takahashi, Yoshihiro; Ogasawara, Yasushi; Saura, Hiroaki; Yoshida, Koji; Sato, Yuiko; Kubo, Yoshitaka; Ogawa, Akira

2014-03-01

Misery perfusion increases the risk of stroke recurrence in patients with symptomatic major cerebral artery occlusion. The ratio of brain perfusion contralateral-to-affected asymmetry in the cerebellar hemisphere to brain perfusion affected-to-contralateral asymmetry in the cerebral hemisphere (CblPR/CbrPR) indicates affected-to-contralateral asymmetry of oxygen extraction fraction (OEF) in the cerebral hemisphere. The purpose of the present study was to determine whether the CblPR/CbrPR on brain perfusion single-photon emission computed tomography (SPECT) predicts 5-year outcomes in patients with symptomatic unilateral occlusion of the middle cerebral artery (MCA) or internal carotid artery (ICA). Brain perfusion was assessed using N-isopropyl-p-[123I]-iodoamphetamine (123I-IMP) SPECT in 70 patients. A region of interest (ROI) was manually placed in the bilateral MCA territories and in the bilateral cerebellar hemispheres, and the CblPR/CbrPR was calculated. All patients were prospectively followed for 5 years. The primary end points were stroke recurrence or death. A total of 17 patients exhibited the primary end points, 11 of whom experienced subsequent ipsilateral strokes. Multivariate analysis revealed that only high CblPR/CbrPR was significantly associated with the development of the primary end point or subsequent ipsilateral strokes (95% confidential limits [CIs], 1.130-3.145; P  =  0.0114 or 95% CIs, 2.558-5.140; P  =  0.0045, respectively). The CblPR/CbrPR provided 65% (11/17) or 91% (10/11) sensitivity and 88% (47/53) or 88% (52/59) specificity in predicting the primary end point or subsequent ipsilateral strokes, respectively. The CblPR/CbrPR on brain perfusion SPECT predicts 5-year outcomes in patients with symptomatic unilateral occlusion of the MCA or ICA.

Neuroprotective effects of scutellarin against hypoxic-ischemic-induced cerebral injury via augmentation of antioxidant defense capacity.

PubMed

Guo, Hong; Hu, Li-Min; Wang, Shao-Xia; Wang, Yu-Lin; Shi, Fang; Li, Hui; Liu, Yang; Kang, Li-Yuan; Gao, Xiu-Mei

2011-12-31

An increasing number of studies has indicated that hypoxic-ischemic-induced cerebral injury is partly mediated via oxidative stress. Recent researches have focused on searching for drug and herbal manipulations to protect against hypoxic-ischemic-induced oxidative cell damage. Scutellarin is a flavonoid derived from the Erigeron breviscapus (vant.) and has been reported to exhibit neuroprotective properties. However, its precise mechanism, particularly its antioxidation mechanism, remains elusive. In the present study, we investigated the neuroprotective effects of scutellarin on middle cerebral artery occlusion (MCAO)-induced brain damage in rats, and oxygen-glucose deprivation (OGD)-induced toxicity in primary culture of rat cortical neurons. In vivo, intraperitoneal injections of scutellarin (20 and 60 mg/kg) improved the neurological score and diminished the percentage of brain infarct volume. At the same time, scutellarin significantly increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) level in ischemic brain tissues, enhancing endogenous antioxidant activity. Moreover, pretreatment of scutellarin (25, 50 and 100 μM) protected neurons against lethal stimuli, decreased the percentage of apoptotic cells and inhibited reactive oxygen species (ROS) generation in OGD-induced primary cortical neurons in vitro. These results suggest that the preventive and therapeutic potential of scutellarin in cerebral injury patients is, at least in part, ascribed to augmentation of cellular antioxidant defense capacity.

Relevance of Occlusion Test in Endovascular Coiling of Posterior Cerebral Artery (P2 Segment) Aneurysms

PubMed Central

Jayakumar, P. N.; Desai, S.; Srikanth, S. G.; Ravishankar, S.; Kovoor, J. M. E.

2004-01-01

Summary P2 segment aneurysms are located on the posterior cerebral artery (PCA) between the junction of the posterior communicating artery with the PCA and the quadrigeminal cisternal part of the PCA. We reviewed our experience with endovascular coiling in such aneurysms. Clinical and pre-procedural data from four patients, referred for endovascular treatment of P2 segment aneurysms, were retrospectively studied for factors influencing post-interventional neurological deficits caused by ischemia of the PCA distal territory. Balloon occlusion was done in three patients and patient tolerance was assessed using clinical and anatomic criteria. Embryologic and anatomic features of the PCA were reviewed. Balloon occlusion test and endovascular coiling of aneurysms was possible in three patients. Control angiogram after embolization showed elimination of aneurysms from the circulation and the distal PCA filled through leptomeningeal anastomoses. One patient deteriorated due to aneurysmal rupture soon after the balloon occlusion test and coiling could not be done. In the other three patients post-intervention CT and MRI images showed PCA territory infarcts in spite of demonstration of good collateral circulation distal to the occluded PCA. In conclusion, P2 aneurysms can be effectively treated by endovascular coiling without a balloon occlusion test. While the balloon occlusion test does not contribute to clinical decision-making it may be associated with potential morbidity and mortality. PMID:20587236

DCPIB, a potent volume-regulated anion channel antagonist, attenuates microglia-mediated inflammatory response and neuronal injury following focal cerebral ischemia.

PubMed

Han, Qingdong; Liu, Shengwen; Li, Zhengwei; Hu, Feng; Zhang, Qiang; Zhou, Min; Chen, Jingcao; Lei, Ting; Zhang, Huaqiu

2014-01-13

Accumulating evidence indicates that extensive microglia activation-mediated local inflammation contributes to neuronal injury in cerebral ischemia. We have previously shown that 4-(2-butyl-6, 7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), a potent volume-regulated anion channel (VRAC) inhibitor, suppresses pathological glutamate release and excitatory neurotoxicity in reversible middle cerebral artery occlusion (rMCAO) model in vivo. In the present study, we sought to determine whether DCPIB also attenuates microglia activation that could contribute to neuronal injury in the cerebral ischemia/reperfusion pathology. We show that oxygen-glucose deprivation (OGD) induced microglia proliferation, migration, and secretion of cytokines and all these pathological changes were effectively inhibited by DCPIB in vitro. In the microglia/neuron co-cultures, OGD induced neuronal damage was reduced markedly in the presence of DCPIB. In rat rMCAO animal model, DCPIB significantly attenuated microglia activation and neuronal death. Activation of mitogen-activated protein kinase (MAPK) signaling pathway is known to be a critical signaling pathway for microglia activation. We further explored a potential involvement of DCPIB in this pathway by western blot analysis. Under the conditions that MAPK pathway was activated either by lipopolysaccharides (LPS) or OGD, the levels of phosphorylated ERK1/2, JNK and p38 were reduced significantly in the presence of DCPIB. Altogether, our study demonstrated that DCPIB inhibits microglia activation potently under ischemic conditions both in vitro and in vivo. The DCPIB effect is likely attributable to both direct inhibition VRAC and indirect inhibition of MAPK pathway in microglia that are beneficial for the survival of neurons in cerebral ischemic conditions. © 2013 Elsevier B.V. All rights reserved.

Normobaric hyperoxia retards the evolution of ischemic brain tissue toward infarction in a rat model of transient focal cerebral ischemia.

PubMed

Xu, Ji; Zhang, Yuan; Liang, Zhouyuan; Wang, Ting; Li, Weiping; Ren, Lijie; Huang, Shaonong; Liu, Wenlan

2016-01-01

Oxygen therapy has been long considered a logical therapy for ischemic stroke. Our previous studies showed that normobaric hyperoxia (normobaric hyperoxia (NBO), 95% O2 with 5% CO2) treatment during ischemia reduced ischemic neuronal death and cerebromicrovascular injury in animal stroke models. In this study, we studied the effects of NBO on the evolution of ischemic brain tissue to infarction in a rat model of transient focal cerebral ischemia. Male Sprague-Dawley rats were given NBO (95% O2) or normoxia (21% O2) during 90-min filament occlusion of the middle cerebral artery (MCAO), followed by 3 or 22.5 h of reperfusion. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to evaluate the longitudinal evolution of tissue infarction. Results： In normoxic rats, MCA-supplied cortical and striatal tissue was infarcted after 90-min MCAO with 22.5 h of reperfusion. NBO-treated rats showed a 61.4% reduction in infarct size and tissue infarction mainly occurred in the ischemic striatum. When infarction was assessed at an earlier time point, i.e. at 3 h of reperfusion, normoxic rats showed significantly smaller but mature infarction (no TTC staining, white color), with the infarction mainly occurring in the striatum. Unexpectedly, NBO-treated rats only showed immature lesion (partially stained by TTC, light white color) in the ischemic striatum, indicating that NBO treatment also retarded the process of neuronal death in the ischemic core. Of note, NBO-preserved striatal tissue underwent infarction after prolonged reperfusion. Conclusions： Our results demonstrate that NBO treatment given during cerebral ischemia retards the evolution of ischemic brain tissue toward infarction and NBO-preserved cortical tissue survives better than NBO-preserved striatal tissue during the phase of reperfusion.

Evaluation of Aged Garlic Extract Neuroprotective Effect in a Focal Model of Cerebral Ischemia

NASA Astrophysics Data System (ADS)

Aguilera, Penélope; Maldonado, Perla D.; Ortiz-Plata, Alma; Barrera, Diana; Chánez-Cárdenas, María Elena

2008-02-01

The oxidant species generated in cerebral ischemia have been implicated as important mediators of neuronal injury through damage to lipids, DNA, and proteins. Since ischemia as well as reperfusion insults generate oxidative stress, the administration of antioxidants may limit oxidative damage and ameliorate disease progression. The present work shows the transitory neuroprotective effect of the aged garlic extract (AGE) administration (a proposed antioxidant compound) in a middle cerebral artery occlusion (MCAO) model in rats and established its therapeutic window. To determine the optimal time of administration, animal received AGE (1.2 mL/kg) intraperitoneally 30 min before onset of reperfusion (-0.5 R), at the beginning of reperfusion (0R), or 1 h after onset of reperfusion (1R). Additional doses were administrated after 1, 2, or 3 h after onset of reperfusion. To establish the therapeutic window of AGE, the infarct area was determined for each treatment after different times of reperfusion. Results show that the administration of AGE at the onset of reperfusion reduced the infarct area by 70% (evaluated after 2 h reperfusion). The therapeutic window of AGE was determined. Repeated doses did not extend the temporal window of protection. A significant reduction in the nitrotyrosine level was observed in the brain tissue subjected to MCAO after AGE treatment at the onset of reperfusion. Data in the present work show that AGE exerts a transitory neuroprotective effect in response to ischemia/reperfusion-induced neuronal injury.

The protective effect of SCR(15-18) on cerebral ischemia-reperfusion injury.

PubMed

Li, Shu; Xian, Jinhong; He, Li; Luo, Xue; Tan, Bing; Yang, Yongtao; Liu, Gaoke; Wang, Zhengqing

2011-10-01

Soluble complement receptor type 1 (sCR1), a potent inhibitor of complement activation, has been shown to protect brain cells against cerebral ischemic/reperfusion (CI/R) injury due to its decay-accelerating activity for C3/C5 convertase and co-factor activity for C3b/C4b degradation. However, the effect of short consensus repeats (SCRs) 15-18, one of active domains of sCR1 with high C3b/C4b degradability, has not been demonstrated. Here, we investigated the protective effect of recombinant SCR(15-18) protein in middle cerebral artery occlusion (MCAO)-induced focal CI/R injury. Recombinant SCR(15-18) protein was successfully expressed in Escherichia coli and refolded to its optimal bioactivity. Seventy-five Sprague-Dawley rats were randomly assigned into three groups: sham-operated group, CI/R group, and SCR(15-18)+CI/R group pretreated with 20 mg/kg SCR(15-18) protein. After 2 hours of MCAO and subsequent 24 hours of reperfusion, rats were evaluated for neurological deficits and cerebral infarction. Polymorphonuclear leukocyte accumulation, C3b deposition, and morphological changes in cerebral tissue were also estimated. SCR(15-18) pretreatment induced a 20% reduction of infarct size and an improvement of neurological function with 22·2% decrease of neurological deficit scores. Inhibition of cerebral neutrophils infiltration by SCR(15-18) was indicated from the reduction of myeloperoxidase activity in SCR(15-18)+CI/R rats. Decreased C3b deposition and improved morphological changes were also found in cerebral tissue of SCR(15-18)-treated rats. Our studies suggest a definitive moderately protective effect of SCR(15-18) against CI/R damage and provide preclinical experimental evidence supporting the possibility of using it as a small anti-complement therapeutic agent for CI/R injury therapy.

Extra-anatomic revascularization for preoperative cerebral malperfusion due to distal carotid artery occlusion in acute type A aortic dissection.

PubMed

Luehr, Maximilian; Etz, Christian D; Nozdrzykowski, Michal; Lehmkuhl, Lukas; Misfeld, Martin; Bakhtiary, Farhad; Borger, Michael A; Mohr, Friedrich-Wilhelm

2016-02-01

Management of patients with acute aortic dissection type A (AADA) and cerebral malperfusion secondary to occlusion or stenosis of the left common carotid artery (LCCA) or right common carotid artery (RCCA) is a significant challenge. The aim of this study is to present our institutional strategy and postoperative results for this high-risk patient cohort. Between November 2005 and July 2013, 23 of 354 consecutively operated AADA patients [median age: 66.3; interquartile range (IQR): 55.2-69.9] suffered from cerebral malperfusion due to bilateral (n = 1) or unilateral occlusion of the LCCA/RCCA (n = 22). AADA repair comprised hemi- (n = 14) or total (n = 9) arch replacement in combination with aortic valve repair (n = 7) or replacement (n = 11), root replacement (n = 15) and coronary bypass (n = 3). Extra-anatomic aorto-carotid bypass was performed in all patients. Aorto-carotid bypass was performed at the beginning of the procedure to allow for unilateral selective cerebral perfusion (n = 17; 73.9%) or during the procedure if persisting malperfusion was suspected by near-infrared spectroscopy (n = 6; 26.1%). The median follow-up was 15.2 months (IQR: 4.8-34.1) and 100% complete. Median hospital stay and ICU stay were 16.0 (IQR: 12.5-26.0) and 13.7 (IQR: 2.0-16.5) days, respectively. Rethoracotomy for haemorrhage or cardiac tamponade was performed in 6 (26.1%) patients. Other postoperative complications comprised low cardiac output with extracorporeal membrane oxygenation (n = 2; 8.7%), sepsis (n = 4; 17.4%), respiratory insufficiency (n = 10; 43.5%), renal failure with temporary dialysis (n = 7; 30.4%) and visceral malperfusion (n = 2; 8.7%) requiring stent grafting (n = 1) or laparotomy with intestinal resection (n = 1). New stroke with or without permanent sensory or motor deficit was diagnosed in 8 (34.8%) patients. Temporary neurological deficits were seen in 9 (39.1%) individuals. Hospital and 1-year mortality rates were 13.0 and 30.4%, respectively. Overall

Upregulation of heme oxygenase-1 protected against brain damage induced by transient cerebral ischemia-reperfusion injury in rats.

PubMed

Lu, Xiufang; Gu, Renjun; Hu, Weimin; Sun, Zhitang; Wang, Gaiqing; Wang, Li; Xu, Yuming

2018-06-01

The aim of the present study was to identify the effect of heme oxygenase (HO)-1 gene on cerebral ischemia-reperfusion injury. Sprague-Dawley rats were divided randomly into four groups: Sham group, vehicle group, empty adenovirus vector (Ad) group and recombinant HO-1 adenovirus (Ad-HO-1) transfection group. Rats in the vehicle, Ad and Ad-HO-1 groups were respectively injected with saline, Ad or Ad-HO-1 for 3 days prior to cerebral ischemia-reperfusion injury. Subsequently, the middle cerebral artery occlusion method was used to establish the model of cerebral ischemia-reperfusion injury. Following the assessment of neurological function, rats were sacrificed, and the infarction volume and apoptotic index in rat brains were measured. Furthermore, the protein expression levels of HO-1 in brain tissues were detected using western blot analysis. Results indicated that the neurological score of the Ad-HO-1 group was significantly increased compared with the Ad or vehicle groups, respectively (P<0.001). The volume of cerebral infarction and the index score of neuronal apoptosis in the vehicle and Ad groups was significantly increased compared with the Ad-HO-1 group (P<0.01). The death of neuronal cells following cerebral ischemia-reperfusion injury reduced remarkably induced by over-expression of HO-1. These findings suggest a neuroprotective role of HO-1 against brain injury induced by transient cerebral ischemia-reperfusion injury.

Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies.

PubMed

Beretta, Simone; Versace, Alessandro; Carone, Davide; Riva, Matteo; Dell'Era, Valentina; Cuccione, Elisa; Cai, Ruiyao; Monza, Laura; Pirovano, Silvia; Padovano, Giada; Stiro, Fabio; Presotto, Luca; Paternò, Giovanni; Rossi, Emanuela; Giussani, Carlo; Sganzerla, Erik P; Ferrarese, Carlo

2017-10-01

Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm 3 absolute mean difference; p < 0.001) and higher chance of good functional outcome (OR 4.58, p < 0.001). Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p < 0.001) and lateral (+19.2%; p = 0.016) MCA territory compared to pretreatment during MCA occlusion. Safety indicators were treatment-related mortality and cardiorespiratory effects. The highest efficacy and safety profile was observed for HDT. Our findings suggest that acute modulation of cerebral collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.

[Adipose-derived stem cell transplantation promotes the expression of netrin-1 in the rat cortex after focal cerebral ischemia].

PubMed

Wang, Jiehua; Hong, Zhuquan; Pan, Ying; Li, Guoqian

2017-01-01

Objective To observe the effect of adipose-derived stem cells (ADSCs) transplantation on the expression of netrin-1 in rats after focal cerebral ischemia. Methods Male SD rats were randomly divided into control group, model group and ADSC group. ADSCs were harvested and purified. Focal cerebral ischemia models were established in rats by the suture method. ADSCs were injected into the lateral ventricle of ADSC group rats and the same does of PBS was given to model group rats. At day 4, 7 and 14 after reperfusion, six rats were sacrificed to remove the brain tissues at each time point. The expression of netrin-1 was detected by reverse-transcription PCR, Western blotting and immunohistochemistry. Results Compared with the control group, the expression of netrin-1 in the brain tissues of the model group increased after focal cerebral ischemia, reached the peak at 4 days, and the expression of netrin-1 was significantly higher than that of the control group at each time point. Compared with the model group, the expression of netrin-1 in the ADSC group increased further, reached the peak at 7 days, and the expression of netrin-1 in the ADSC group was significantly higher than that of the model group at each time point. Conclusion ADSC transplantation could up-regulate the expression of netrin-1, and promote axon regeneration and the recovery of neurological functions.

Neuropilin 2 deficiency does not affect cortical neuronal viability in response to oxygen-glucose-deprivation and transient middle cerebral artery occlusion.

PubMed

Hou, Sheng T; Jiang, Susan X; Slinn, Jacqueline; O'Hare, Michael; Karchewski, Laurie

2010-04-01

Neuropilin 2 (NRP2) is a type I transmembrane protein that binds to distinct members of the class III secreted Semaphorin subfamily. NRP2 plays important roles in repulsive axon guidance, angiogenesis and vasculogenesis through partnering with co-receptors such as vascular endothelial growth factor receptors (VEGFRs) during development. Emerging evidence also suggests that NRP2 contributes to injury response and environment changes in adult brains. In this study, we examined the contribution of NRP2 gene to cerebral ischemia-induced brain injury using NRP2 deficient mouse. To our surprise, the lack of NRP2 expression does not affect the outcome of brain injury induced by transient occlusion of the middle cerebral artery (MCAO) in mouse. The cerebral vasculature in terms of the middle cerebral artery anatomy and microvessel density in the cerebral cortex of NRP2 deficient homozygous (NRP2(-/-)) mice are normal and almost identical to those of the heterozygous (NRP2(+/-)) and wild type (NRP2(+/+)) littermates. MCAO (1h) and 24h reperfusion caused a brain infarction of 23% (compared to the contralateral side) in NRP2(-/-) mice, which is not different from those in NRP2(+/- and +/+) mice at 22 and 21%, respectively (n=19, p>0.05). Correspondingly, NRP2(-/-) mouse also showed a similar level of deterioration of neurological functions after stroke compared with their NRP2(+/- and +/+) littermates. Oxygen-glucose-deprivation (OGD) caused a significant neuronal death in NRP2(-/-) cortical neurons, at the level similar to that in NRP(+/+) cortical neurons (72% death in NRP(-/-) neurons vs. 75% death in NRP2(+/+) neurons; n=4; p>0.05). Together, these loss-of-function studies demonstrated that despite of its critical role in neuronal guidance and vascular formation during development, NRP2 expression dose not affect adult brain response to cerebral ischemia. Crown Copyright 2009. Published by Elsevier Ireland Ltd. All rights reserved.

COMMUNICATION: Electrophysiological response dynamics during focal cortical infarction

NASA Astrophysics Data System (ADS)

Chiganos, Terry C., Jr.; Jensen, Winnie; Rousche, Patrick J.

2006-12-01

While the intracellular processes of hypoxia-induced necrosis and the intercellular mechanisms of post-ischemic neurotoxicity associated with stroke are well documented, the dynamic electrophysiological (EP) response of neurons within the core or periinfarct zone remains unclear. The present study validates a method for continuous measurement of the local EP responses during focal cortical infarction induced via photothrombosis. Single microwire electrodes were acutely implanted into the primary auditory cortex of eight rats. Multi-unit neural activity, evoked via a continuous 2 Hz click stimulus, was recorded before, during and after infarction to assess neuronal function in response to local, permanent ischemia. During sham infarction, the average stimulus-evoked peak firing rate over 20 min remained stable at 495.5 ± 14.5 spikes s-1, indicating temporal stability of neural function under normal conditions. Stimulus-evoked peak firing was reliably reduced to background levels (firing frequency in the absence of stimulus) following initiation of photothrombosis over a period of 439 ± 92 s. The post-infarction firing patterns exhibited unique temporal degradation of the peak firing rate, suggesting a variable response to ischemic challenge. Despite the inherent complexity of cerebral ischemia secondary to microvascular occlusion, complete loss of EP function consistently occurred 300-600 s after photothrombosis. The results suggest that microwire recording during photothrombosis provides a simple and highly efficacious strategy for assessing the electrophysiological dynamics of cortical infarction.

EEG patterns from acute to chronic stroke phases in focal cerebral ischemic rats: correlations with functional recovery.

PubMed

Zhang, Shao-jie; Ke, Zheng; Li, Le; Yip, Shea-ping; Tong, Kai-yu

2013-04-01

Monitoring the neural activities from the ischemic penumbra provides critical information on neurological recovery after stroke. The purpose of this study is to evaluate the temporal alterations of neural activities using electroencephalography (EEG) from the acute phase to the chronic phase, and to compare EEG with the degree of post-stroke motor function recovery in a rat model of focal ischemic stroke. Male Sprague-Dawley rats were subjected to 90 min transient middle cerebral artery occlusion surgery followed by reperfusion for seven days (n = 58). The EEG signals were recorded at the pre-stroke phase (0 h), acute phase (3, 6 h), subacute phase (12, 24, 48, 72 h) and chronic phase (96, 120, 144, 168 h) (n = 8). This study analyzed post-stroke seizures and polymorphic delta activities (PDAs) and calculated quantitative EEG parameters such as the alpha-to-delta ratio (ADR). The ADR represented the ratio between alpha power and delta power, which indicated how fast the EEG activities were. Forelimb and hindlimb motor functions were measured by De Ryck's test and the beam walking test, respectively. In the acute phase, delta power increased fourfold with the occurrence of PDAs, and the histological staining showed that the infarct was limited to the striatum and secondary sensory cortex. In the subacute phase, the alpha power reduced to 50% of the baseline, and the infarct progressed to the forelimb cortical region. ADRs reduced from 0.23 ± 0.09 to 0.04 ± 0.01 at 3 h in the acute phase and gradually recovered to 0.22 ± 0.08 at 168 h in the chronic phase. In the comparison of correlations between the EEG parameters and the limb motor function from the acute phase to the chronic phase, ADRs were found to have the highest correlation coefficients with the beam walking test (r = 0.9524, p < 0.05) and De Ryck's test (r = 0.8077, p < 0.05). This study measured EEG activities after focal cerebral ischemia and showed that functional recovery was closely

Depletion of CD11c+ Cells Does Not Influence Outcomes in Mice Subjected to Transient Middle Cerebral Artery Occlusion.

PubMed

Kraft, Peter; Scholtyschik, Karolina; Schuhmann, Michael K; Kleinschnitz, Christoph

2017-01-01

While it has been shown that different T-cell subsets have a detrimental role in the acute phase of ischemic stroke, data on the impact of dendritic cells (DC) are missing. Classic DC can be characterized by the cluster of differentiation (CD)11c surface antigen. In this study, we depleted CD11c+ cells by using a CD11c-diphtheria toxin (DTX) receptor mouse strain that allows selective depletion of CD11c+ cells by DTX injection. For stroke induction, we used the model of transient middle cerebral artery occlusion (tMCAO) and analyzed stroke volume and functional outcome on days 1 and 3 as well as expression of prototypical pro- and anti-inflammatory cytokines on day 1 after tMCAO. Three different protocols for CD11c+ cell depletion, tMCAO duration, and readout time point were applied. Injection of DTX (5 or 100 ng/g) reliably depleted CD11c+ cells without influencing the fractions of other immune cell subsets. CD11c+ cell depletion had no impact on stroke volume, but mice with a longer DTX pretreatment performed worse than those with vehicle treatment. CD11c+ cell depletion led to a decrease in cortical interleukin (IL)-1β and IL-6 messenger ribonucleic acid levels. We show, for the first time, that CD11c+ cell depletion does not influence stroke volume in a mouse model of focal cerebral ischemia. Nevertheless, given the unspecificity of the CD11c surface antigen for DC, mouse models that allow a more selective depletion of DC are needed to investigate the role of DC in stroke pathophysiology. © 2017 S. Karger AG, Basel.

Non-invasive detection of matrix-metalloproteinase activity in a mouse model of cerebral ischemia using multispectral optoacoustic tomography

NASA Astrophysics Data System (ADS)

Ni, Ruiqing; Vaas, Markus; Ren, Wuwei; Klohs, Jan

2018-02-01

Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of cerebral ischemia. Here we visualized in vivo MMP activity in the transient middle cerebral artery occlusion (tMCAO) mouse model using multispectral optoacoustic imaging (MSOT) with a MMP-activatable probe. MSOT data was co-registered with structural magnetic resonance imaging (MRI) obtained at 7 T for localization of signal distribution. We demonstrated upregulated MMP signal within the focal ischemic lesion in the tMCAO mouse model using MSOT/MRI multimodal imaging. This convenient non-invasive method will allow repetitive measurement following the time course of MMP-lesion development in ischemic stroke animal model.

The Kringle-2 domain of tissue plasminogen activator significantly reduces mortality and brain infarction in middle cerebral artery occlusion rats.

PubMed

Zhang, Haitao; Bi, Feng; Xiao, Chunlan; Liu, Jianxia; Wang, Zhixia; Liu, Jian-Ning; Zhang, Jing

2010-08-01

Tissue plasminogen activator (TPA) showed brain-protective activity within the first 15 min after cerebral ischemia in rats. To understand its molecular mechanism, TPA derivates were intracerebroventricularly administered at 15 min before, and 15, 90, 120 min after middle cerebral artery occlusion (MCAO) in rats. The reduction in mortality and cerebral infarction at 24 h was seen only with TPA administered at 15 min after MCAO. The down-regulation of endogenous TPA by the intracerebroventricular injection of TPA was found to be responsible for the protective effect on the integrity of blood-brain barrier after MCAO, as well as for the reduction in mortality and cerebral infarction. Moreover, for the first time we have found that the Kringle-2 domain is essential for the brain-protective activity of TPA.

Exercise preconditioning improves behavioral functions following transient cerebral ischemia induced by 4-vessel occlusion (4-VO) in rats.

PubMed

Tahamtan, Mahshid; Allahtavakoli, Mohammad; Abbasnejad, Mehdi; Roohbakhsh, Ali; Taghipour, Zahra; Taghavi, Mohsen; Khodadadi, Hassan; Shamsizadeh, Ali

2013-12-01

There is evidence that exercise decreases ischemia/reperfusion injury in rats. Since behavioral deficits are the main outcome in patients after stroke, our study was designed to investigate whether exercise preconditioning improves the acute behavioral functions and also brain inflammatory injury following cerebral ischemia. Male rats weighing 250-300 g were randomly allocated into five experimental groups. Exercise was performed on a treadmill 30min/day for 3 weeks. Ischemia was induced by 4-vessel occlusion method. Recognition memory was assessed by novel object recognition task (NORT) and step-through passive avoidance task. Sensorimotor function and motor movements were evaluated by adhesive removal test and ledged beam-walking test, respectively. Brain inflammatory injury was evaluated by histological assessment. In NORT, the discrimination ratio was decreased after ischemia (P < 0.05) and exercise preconditioning improved it in ischemic animals. In the passive avoidance test, a significant reduction in response latency was observed in the ischemic group. Exercise preconditioning significantly decreased the response latency in the ischemic rats (P < 0.001). In the adhesive removal test, latency to touch and remove the sticky labels from forepaw was increased following induction of ischemia (all P < 0.001) and exercise preconditioning decreased these indices compared to the ischemic group (all P < 0.001). In the ledged beam-walking test, the slip ratio was increased following ischemia (P < 0.05).  In the ischemia group, marked neuronal injury in hippocampus was observed. These neuropathological changes were attenuated by exercise preconditioning (P < 0.001). Our results showed that exercise preconditioning improves behavioral functions and maintains more viable cells in the dorsal hippocampus of the ischemic brain.

T2’-Imaging to Assess Cerebral Oxygen Extraction Fraction in Carotid Occlusive Disease: Influence of Cerebral Autoregulation and Cerebral Blood Volume

PubMed Central

Deichmann, Ralf; Pfeilschifter, Waltraud; Hattingen, Elke; Singer, Oliver C.; Wagner, Marlies

2016-01-01

Purpose Quantitative T2'-mapping detects regional changes of the relation of oxygenated and deoxygenated hemoglobin (Hb) by using their different magnetic properties in gradient echo imaging and might therefore be a surrogate marker of increased oxygen extraction fraction (OEF) in cerebral hypoperfusion. Since elevations of cerebral blood volume (CBV) with consecutive accumulation of Hb might also increase the fraction of deoxygenated Hb and, through this, decrease the T2’-values in these patients we evaluated the relationship between T2’-values and CBV in patients with unilateral high-grade large-artery stenosis. Materials and Methods Data from 16 patients (13 male, 3 female; mean age 53 years) with unilateral symptomatic or asymptomatic high-grade internal carotid artery (ICA) or middle cerebral artery (MCA) stenosis/occlusion were analyzed. MRI included perfusion-weighted imaging and high-resolution T2’-mapping. Representative relative (r)CBV-values were analyzed in areas of decreased T2’ with different degrees of perfusion delay and compared to corresponding contralateral areas. Results No significant elevations in cerebral rCBV were detected within areas with significantly decreased T2’-values. In contrast, rCBV was significantly decreased (p<0.05) in regions with severe perfusion delay and decreased T2’. Furthermore, no significant correlation between T2’- and rCBV-values was found. Conclusions rCBV is not significantly increased in areas of decreased T2’ and in areas of restricted perfusion in patients with unilateral high-grade stenosis. Therefore, T2’ should only be influenced by changes of oxygen metabolism, regarding our patient collective especially by an increase of the OEF. T2’-mapping is suitable to detect altered oxygen consumption in chronic cerebrovascular disease. PMID:27560515

PPARδ regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury

PubMed Central

Yin, K.J.; Deng, Z.; Hamblin, M.; Xiang, Y.; Huang, H.R.; Zhang, J.; Jiang, X. D.; Wang, Y.; Chen, Y. E.

2010-01-01

Cerebral endothelial cell (CEC) degeneration significantly contributes to blood-brain barrier (BBB) breakdown and neuronal loss after cerebral ischemia. Recently, emerging data suggest that peroxisome proliferator-activated receptor δ (PPARδ) activation has a potential neuroprotective role in ischemic stroke. Here we report for the first time that PPARδ is significantly reduced in oxygen-glucose deprivation (OGD)-induced mouse CEC death. Interestingly, PPARδ overexpression can suppress OGD-induced caspase-3 activity, Golgi fragmentation, and CEC death through an increase of bcl-2 protein levels without change of bcl-2 mRNA levels. To explore the molecular mechanisms, we have identified that upregulation of PPARδ can alleviate ODG-activated microRNA-15a (miR-15a) expression in CECs. Moreover, we have demonstrated that bcl-2 is a translationally-repressed target of miR-15a. Intriguingly, gain- or loss-of-miR-15a function can significantly reduce or increase OGD-induced CEC death, respectively. Furthermore, we have identified that miR-15a is a transcriptional target of PPARδ. Consistent with the in vitro findings, we found that intracerebroventricular infusion of a specific PPARδ agonist, GW 501516, significantly reduced ischemia-induced miR-15a expression, increased bcl-2 protein levels, and attenuated caspase-3 activity and subsequent DNA fragmentation in isolated cerebral microvessels, leading to decreased BBB disruption and reduced cerebral infarction in mice after transient focal cerebral ischemia. Taken together, these results suggest that PPARδ plays a vascular-protective role in ischemia-like insults via transcriptional repression of miR-15a, resulting in subsequent release of its posttranscriptional inhibition of bcl-2. Thus, regulation of PPARδ-mediated miR-15a inhibition of bcl-2 could provide a novel therapeutic strategy for the treatment of stroke-related vascular dysfunction. PMID:20445066

Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia.

PubMed

Moraga, Ana; Pradillo, Jesús M; García-Culebras, Alicia; Palma-Tortosa, Sara; Ballesteros, Ivan; Hernández-Jiménez, Macarena; Moro, María A; Lizasoain, Ignacio

2015-05-10

Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals. Our objective is to determine the role of aging on the process of neurogenesis after stroke. We have studied neurogenesis by analyzing proliferation, migration, and formation of new neurons, as well as inflammatory parameters, in a model of cerebral ischemia induced by permanent occlusion of the middle cerebral artery in young- (2 to 3 months) and middle-aged mice (13 to 14 months). Aging increased both microglial proliferation, as shown by a higher number of BrdU(+) cells and BrdU/Iba1(+) cells in the ischemic boundary and neutrophil infiltration. Interestingly, aging increased the number of M1 monocytes and N1 neutrophils, consistent with pro-inflammatory phenotypes when compared with the alternative M2 and N2 phenotypes. Aging also inhibited (subventricular zone) SVZ cell proliferation by decreasing both the number of astrocyte-like type-B (prominin-1(+)/epidermal growth factor receptor (EGFR)(+)/nestin(+)/glial fibrillary acidic protein (GFAP)(+) cells) and type-C cells (prominin-1(+)/EGFR(+)/nestin(-)/Mash1(+) cells), and not affecting apoptosis, 1 day after stroke. Aging also inhibited migration of neuroblasts (DCX(+) cells), as indicated by an accumulation of neuroblasts at migratory zones 14 days after injury; consistently, aged mice presented a smaller number of differentiated interneurons (NeuN(+)/BrdU(+) and GAD67(+) cells) in the peri-infarct cortical area 14 days after stroke. Our data confirm that stroke-induced neurogenesis is maintained but reduced in aged animals. Importantly, we now demonstrate that aging not only inhibits proliferation of specific SVZ cell subtypes but also blocks migration of neuroblasts to the damaged area and decreases the number of new interneurons in

Cerebral blood flow reduction in Alzheimer's disease: impact of capillary occlusions on mice and humans

NASA Astrophysics Data System (ADS)

Berg, Maxime; Merlo, Adlan; Peyrounette, Myriam; Doyeux, Vincent; Smith, Amy; Cruz-Hernandez, Jean; Bracko, Oliver; Haft-Javaherian, Mohammad; Nishimura, Nozomi; Schaffer, Chris B.; Davit, Yohan; Quintard, Michel; Lorthois, Sylvie

2017-11-01

Alzheimer's disease may be the most common form of dementia, yet a satisfactory diagnosis procedure has still to be found. Recent studies suggest that a significant decrease of cerebral blood flow, probably caused by white blood cells stalling small vessels, may be among the earliest biological markers. To assess this hypothesis we derive a blood flow model, validate it against in vitro controlled experiments and in vivo measurements made on mice. We then investigate the influence of capillary occlusions on regional perfusion (sum of all arteriole flowrates feeding the network) of large mice and humans anatomical networks. Consistent with experiments, we observe no threshold effect, so that even a small percentage of occlusions (2-4%) leads to significant blood flow decrease (5-12%). We show that both species share the same linear dependance, suggesting possible translation from mice to human. ERC BrainMicroFlow GA61510, CALMIP HPC (Grant 2017-1541).

Cerebral Autoregulation in Hypertension and Ischemic Stroke: A Mini Review

PubMed Central

Shekhar, Shashank; Liu, Ruen; Travis, Olivia K; Roman, Richard J; Fan, Fan

2017-01-01

Aging and chronic hypertension are associated with dysfunction in vascular smooth muscle, endothelial cells, and neurovascular coupling. These dysfunctions induce impaired myogenic response and cerebral autoregulation, which diminish the protection of cerebral arterioles to the cerebral microcirculation from elevated pressure in hypertension. Chronic hypertension promotes cerebral focal ischemia in response to reductions in blood pressure that are often seen in sedentary elderly patients on antihypertensive therapy. Cerebral autoregulatory dysfunction evokes Blood-Brain Barrier (BBB) leakage, allowing the circulating inflammatory factors to infiltrate the brain to activate glia. The impaired cerebral autoregulation-induced inflammatory and ischemic injury could cause neuronal cell death and synaptic dysfunction which promote cognitive deficits. In this brief review, we summarize the pathogenesis and signaling mechanisms of cerebral autoregulation in hypertension and ischemic stroke-induced cognitive deficits, and discuss our new targets including 20-Hydroxyeicosatetraenoic acid (20-HETE), Gamma-Adducin (Add3) and Matrix Metalloproteinase-9 (MMP-9) that may contribute to the altered cerebral vascular function. PMID:29333537

Phosphorylation enhances recombinant HSP27 neuroprotection against focal cerebral ischemia in mice.

PubMed

Shimada, Y; Tanaka, R; Shimura, H; Yamashiro, K; Urabe, T; Hattori, N

2014-10-10

Heat shock protein 27 (HSP27) exerts cytoprotection against many cellular insults including cerebral ischemia. We previously indicated that intravenous injection of HSP27 purified from human lymphocytes (hHSP27) significantly reduced infarct volume following cerebral ischemia-reperfusion injury, while recombinant HSP27 (rHSP27) was less effective. Phosphorylation is important for HSP27 function, and hHSP27 was more highly phosphorylated than rHSP27. We hypothesized that MAPKAP kinase 2 in vitro-phosphorylated rHSP27 (prHSP27) might increase its brain protection. Mice underwent transient 1-h middle cerebral artery occlusion (MCAO), and then received tail-vein injections of one of the following 1h after reperfusion: hHSP27 as positive control, rHSP27, prHSP27, or bovine serum albumin (BSA) as control. We measured infarct volume, neurological deficits, neurological severity, physiological parameters, cell-death, oxidative stress, and inflammatory response. Compared with BSA controls (30.7±3.1mm(3), n=5), infarct volume was reduced by 67% in the hHSP27 positive-control group (10.1±4.6mm(3), P<0.001, n=5), 17% following rHSP27 (25.4±3.6mm(3), P<0.05, n=5), and 46% following prHSP27 (16.5±4.0mm(3), P<0.001, n=9). Compared to the rHSP27 and BSA-treated groups, prHSP27 also reduced functional deficits, and significantly suppressed apoptosis, oxidative stress, and inflammatory responses. Here, we showed the superior neuroprotective effects of phosphorylated HSP27 by administering prHSP27. prHSP27 may be a useful therapeutic agent to protect against acute cerebral ischemic stroke. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Focal mechanism determination for induced seismicity using the neighbourhood algorithm

NASA Astrophysics Data System (ADS)

Tan, Yuyang; Zhang, Haijiang; Li, Junlun; Yin, Chen; Wu, Furong

2018-06-01

Induced seismicity is widely detected during hydraulic fracture stimulation. To better understand the fracturing process, a thorough knowledge of the source mechanism is required. In this study, we develop a new method to determine the focal mechanism for induced seismicity. Three misfit functions are used in our method to measure the differences between observed and modeled data from different aspects, including the waveform, P wave polarity and S/P amplitude ratio. We minimize these misfit functions simultaneously using the neighbourhood algorithm. Through synthetic data tests, we show the ability of our method to yield reliable focal mechanism solutions and study the effect of velocity inaccuracy and location error on the solutions. To mitigate the impact of the uncertainties, we develop a joint inversion method to find the optimal source depth and focal mechanism simultaneously. Using the proposed method, we determine the focal mechanisms of 40 stimulation induced seismic events in an oil/gas field in Oman. By investigating the results, we find that the reactivation of pre-existing faults is the main cause of the induced seismicity in the monitored area. Other observations obtained from the focal mechanism solutions are also consistent with earlier studies in the same area.

Effect of electroacupuncture on the expression of interlukin-1beta mRNA after transient focal cerebral ischemia.

PubMed

Xu, Zhen-Feng; Wu, Gen-Cheng; Cao, Xiao-Ding

2002-01-01

It has been reported that interleukin-1beta (IL-1beta ) play a key role in the pathogenesis of cerebral ischemia. Acupuncture is an effective traditional medical therapy in China. The aim of present study was to evaluate the effect of electroacupuncture (EA) on IL-1beta mRNA expression after middle cerebral artery occlusion (MCAO) in rats. Using in situ hybridization technique, it was found that in the MCAO group the expression of IL-1beta mRNA was significantly increased at 2h, 6h, 12h after reperfusion in cerebral ischemic cortex compared with normal group. In EA+ MCAO group the expression of IL-1beta mRNA was significantly decreased at 2h, 6h and 12h in ischemic cortex compared with MCAO group. The results indicated that EA might decrease the IL-1beta protein expression by reducing the IL-beta mRNA expression in ischemic cortex.

Neuroprotective mechanism of BNG-1 against focal cerebral ischemia: a neuroimaging and neurotrophin study.

PubMed

Chi, Nai-Fang; Liu, Ho-Ling; Yang, Jen-Tsung; Lin, Jr-Rung; Liao, Shu-Li; Peng, Bo-Han; Lee, Yen-Tung; Lee, Tsong-Hai

2014-01-01

BNG-1 is a herb complex used in traditional Chinese medicine to treat stroke. In this study, we attempted to identify the neuroprotective mechanism of BNG-1 by using neuroimaging and neurotrophin analyses of a stroke animal model. Rats were treated with either saline or BNG-1 for 7 d after 60-min middle cerebral artery occlusion by filament model. The temporal change of magnetic resonance (MR) imaging of brain was studied using a 7 Tesla MR imaging (MRI) system and the temporal expressions of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in brain were analyzed before operation and at 4 h, 2 d, and 7 d after operation. Compared with the saline group, the BNG-1 group exhibited a smaller infarction volume in the cerebral cortex in T2 image from as early as 4 h to 7 d, less edema in the cortex in diffusion weighted image from 2 to 7 d, earlier reduction of postischemic hyperperfusion in both the cortex and striatum in perfusion image at 4 h, and earlier normalization of the ischemic pattern in the striatum in susceptibility weighted image at 2 d. NT-3 and BDNF levels were higher in the BNG-1 group than the saline group at 7 d. We concluded that the protective effect of BNG-1 against cerebral ischemic injury might act through improving cerebral hemodynamics and recovering neurotrophin generation.

Occlusal adjustment using the bite plate-induced occlusal position as a reference position for temporomandibular disorders: a pilot study

PubMed Central

2010-01-01

Background Many researchers have not accepted the use of occlusal treatments for temporomandibular disorders (TMDs). However, a recent report described a discrepancy between the habitual occlusal position (HOP) and the bite plate-induced occlusal position (BPOP) and discussed the relation of this discrepancy to TMD. Therefore, the treatment outcome of evidence-based occlusal adjustments using the bite plate-induced occlusal position (BPOP) as a muscular reference position should be evaluated in patients with TMD. Methods The BPOP was defined as the position at which a patient voluntarily closed his or her mouth while sitting in an upright posture after wearing an anterior flat bite plate for 5 minutes and then removing the plate. Twenty-one patients with TMDs underwent occlusal adjustment using the BPOP. The occlusal adjustments were continued until bilateral occlusal contacts were obtained in the BPOP. The treatment outcomes were evaluated using the subjective dysfunction index (SDI) and the Helkimo Clinical Dysfunction Index (CDI) before and after the occlusal adjustments; the changes in these two indices between the first examination and a one-year follow-up examination were then analyzed. In addition, the difference between the HOP and the BPOP was three-dimensionally measured before and after the treatment. Results The percentage of symptom-free patients after treatment was 86% according to the SDI and 76% according to the CDI. The changes in the two indices after treatment were significant (p < 0.001). The changes in the mean HOP-BPOP differences on the x-axis (mediolateral) and the y-axis (anteroposterior) were significant (p < 0.05), whereas the change on the z-axis (superoinferior) was not significant (p > 0.1). Conclusion Although the results of the present study should be confirmed in other studies, a randomized clinical trial examining occlusal adjustments using the BPOP as a reference position appears to be warranted. PMID:20346167

Intraoperative laser speckle contrast imaging improves the stability of rodent middle cerebral artery occlusion model

NASA Astrophysics Data System (ADS)

Yuan, Lu; Li, Yao; Li, Hangdao; Lu, Hongyang; Tong, Shanbao

2015-09-01

Rodent middle cerebral artery occlusion (MCAO) model is commonly used in stroke research. Creating a stable infarct volume has always been challenging for technicians due to the variances of animal anatomy and surgical operations. The depth of filament suture advancement strongly influences the infarct volume as well. We investigated the cerebral blood flow (CBF) changes in the affected cortex using laser speckle contrast imaging when advancing suture during MCAO surgery. The relative CBF drop area (CBF50, i.e., the percentage area with CBF less than 50% of the baseline) showed an increase from 20.9% to 69.1% when the insertion depth increased from 1.6 to 1.8 cm. Using the real-time CBF50 marker to guide suture insertion during the surgery, our animal experiments showed that intraoperative CBF-guided surgery could significantly improve the stability of MCAO with a more consistent infarct volume and less mortality.

Verapamil-induced breakdown of the blood-brain barrier presenting as a transient right middle cerebral artery syndrome.

PubMed

Pace, Jonathan; Nelson, Jeffrey; Ray, Abhishek; Hu, Yin

2017-12-01

A middle-aged patient presented for elective embolization of an incidentally found right internal carotid aneurysm. An angiogram was performed, during which the left internal carotid artery was visualized to evaluate a second, small aneurysm. During the embolization of the right internal carotid artery aneurysm, a catheter-induced vasospasm was identified that prompted treatment with intra-arterial verapamil. The procedure was uncomplicated; a postoperative rotational flat-panel computed tomography scan was performed on the angiography table that demonstrated right hemisphere contrast staining. The patient developed a right middle cerebral artery (MCA) syndrome after extubation with repeat cerebral angiography negative for occlusion and magnetic resonance imaging negative for stroke. The patient was observed for 48 hours, during which time the patient had slowly improved. At a six-week follow up visit, the patient had fully recovered. We present an interesting case of a verapamil-induced breakdown of the blood-brain barrier and self-limited right MCA syndrome.

A non-ionotropic activity of NMDA receptors contributes to glycine-induced neuroprotection in cerebral ischemia-reperfusion injury.

PubMed

Chen, Juan; Hu, Rong; Liao, Huabao; Zhang, Ya; Lei, Ruixue; Zhang, Zhifeng; Zhuang, Yang; Wan, Yu; Jin, Ping; Feng, Hua; Wan, Qi

2017-06-15

NMDA receptor (NMDAR) is known for its ionotropic function. But recent evidence suggests that NMDAR also has a non-ionotropic property. To determine the role of non-ionotropic activity of NMDARs in clinical relevant conditions, we tested the effect of glycine, a co-agonist of NMDARs, in rat middle cerebral artery occlusion (MCAO), an animal model of cerebral ischemia-reperfusion injury after the animals were injected with the NMDAR channel blocker MK-801 and the glycine receptor antagonist strychnine. We show that glycine reduces the infarct volume in the brain of ischemic stroke animals pre-injected with MK-801 and strychnine. The effect of glycine is sensitive to the antagonist of glycine-GluN1 binding site and blocked by Akt inhibition. In the neurobehavioral tests, glycine improves the functional recovery of stroke animals pre-injected with MK-801 and strychnine. This study suggests that glycine-induced neuroprotection is mediated in part by the non-ionotropic activity of NMDARs via Akt activation in cerebral ischemia-reperfusion injury.

Mechanical thrombectomy for acute ischemic stroke with occlusion of the M2 segment of the middle cerebral artery: a meta-analysis.

PubMed

Saber, Hamidreza; Narayanan, Sandra; Palla, Mohan; Saver, Jeffrey L; Nogueira, Raul G; Yoo, Albert J; Sheth, Sunil A

2017-11-10

Endovascular thrombectomy has demonstrated benefit for patients with acute ischemic stroke from proximal large vessel occlusion. However, limited evidence is available from recent randomized trials on the role of thrombectomy for M2 segment occlusions of the middle cerebral artery (MCA). We conducted a systematic review and meta-analysis to investigate clinical and radiographic outcomes, rates of hemorrhagic complications, and mortality after M2 occlusion thrombectomy using modern devices, and compared these outcomes against patients with M1 occlusions. Recanalization was defined as Thrombolysis in Cerebral Infarction (TICI) 2b/3 or modified TICI 2b/3. A total of 12 studies with 1080 patients with M2 thrombectomy were included in our analysis. Functional independence (modified Rankin Scale 0-2) rate was 59% (95% CI 54% to 64%). Mortality and symptomatic intracranial hemorrhage rates were 16% (95% CI 11% to 23%) and 10% (95% CI 6% to 16%), respectively. Recanalization rates were 81% (95% CI 79% to 84%), and were equally comparable for stent-retriever versus aspiration (OR 1.05; 95% CI 0.91 to 1.21). Successful M2 recanalization was associated with greater rates of favorable outcome (OR 4.22; 95% CI 1.96 to 9.1) compared with poor M2 recanalization (TICI 0-2a). There was no significant difference in recanalization rates for M2 versus M1 thrombectomy (OR 1.05; 95% CI 0.77 to 1.42). This meta-analysis suggests that mechanical thrombectomy for M2 occlusions that can be safely accessed is associated with high functional independence and recanalization rates, but may be associated with an increased risk of hemorrhage. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Effect of dehydration on the development of collaterals in acute middle cerebral artery occlusion.

PubMed

Chang, S-W; Huang, Y-C; Lin, L-C; Yang, J-T; Weng, H-H; Tsai, Y-H; Lee, T-H

2016-03-01

Recent large series studies have demonstrated that dehydration is common amongst stroke subjects and is associated with poor outcome. However, the effects of hydration status on the development of collaterals have never been discussed. In this study, the hypothesis that hydration status is an important factor for developing collaterals after acute middle cerebral artery (MCA) infarction was tested. Eighty-seven patients with acute infarction due to occlusion of the MCA were enrolled. Two collateral markers, posterior cerebral artery (PCA) laterality and fluid-attenuated inversion recovery hyperintense vessels (HVs) were assessed from magnetic resonance imaging. Dehydration status was defined by a nitrogen to creatinine ratio ≧ of 15. The associations between dehydration status and the development of collaterals were estimated. Sixty-one of 87 patients (70.1%) were identified as dehydrated. The development of PCA laterality and HVs shows a significant difference between dehydrated and euhydrated patients. A serum nitrogen to creatinine ratio <15, diastolic blood pressure and the presence of a dense MCA on computed tomography were significantly associated with the development of PCA laterality. A serum nitrogen to creatinine ratio <15, the initial National Institutes of Health Stroke Scale score, the presence of a dense MCA and calcifications of the internal carotid artery on computed tomography were significantly associated with the development of HVs. Dehydration remained an independent negative predictor for the development of PCA laterality and HVs in the multivariate analysis. Hydration status is associated with the development of collateral flow after acute MCA occlusion. This preliminary study provides an imaging clue that hydration status and early hydration therapy could be important for acute stroke management. © 2016 EAN.

Digital map of posterior cerebral artery infarcts associated with posterior cerebral artery trunk and branch occlusion.

PubMed

Phan, Thanh G; Fong, Ashley C; Donnan, Geoffrey; Reutens, David C

2007-06-01

Knowledge of the extent and distribution of infarcts of the posterior cerebral artery (PCA) may give insight into the limits of the arterial territory and infarct mechanism. We describe the creation of a digital atlas of PCA infarcts associated with PCA branch and trunk occlusion by magnetic resonance imaging techniques. Infarcts were manually segmented on T(2)-weighted magnetic resonance images obtained >24 hours after stroke onset. The images were linearly registered into a common stereotaxic coordinate space. The segmented images were averaged to yield the probability of involvement by infarction at each voxel. Comparisons were made with existing maps of the PCA territory. Thirty patients with a median age of 61 years (range, 22 to 86 years) were studied. In the digital atlas of the PCA, the highest frequency of infarction was within the medial temporal lobe and lingual gyrus (probability=0.60 to 0.70). The mean and maximal PCA infarct volumes were 55.1 and 128.9 cm(3), respectively. Comparison with published maps showed greater agreement in the anterior and medial boundaries of the PCA territory compared with its posterior and lateral boundaries. We have created a probabilistic digital atlas of the PCA based on subacute magnetic resonance scans. This approach is useful for establishing the spatial distribution of strokes in a given cerebral arterial territory and determining the regions within the arterial territory that are at greatest risk of infarction.

Losartan protects against cerebral ischemia/reperfusion-induced apoptosis through β-arrestin1-mediated phosphorylation of Akt.

PubMed

Chen, Lin; Ren, Zhiping; Wei, Xinbing; Wang, Shuaishuai; Wang, Yimeng; Cheng, Yanyan; Gao, Hua; Liu, Huiqing

2017-11-15

Losartan, an angiotensin (Ang) II type 1 receptor blocker (ARB), has been revealed to protect against cerebral ischemia/reperfusion (I/R) injury. However, the mechanism by which losartan protect brain ischemia injury is still obscure. In this study, we investigated whether losartan protected against cerebral I/R injury by reducing apoptosis and the possible signaling pathways. Wistar rats were pretreated for 14 days with 5mg/kg losartan, and then subjected to middle cerebral artery occlusion (MCAO) for 2h followed by reperfusion. Meanwhile, PC12 cells pretreated with losartan were exposed to oxygen-glucose deprivation-reoxygenation (OGD/R), an in vitro model of cerebral ischemia. Our results showed that administration of losartan significantly inhibited the apoptosis by decreasing the number of apoptotic cells, decreasing the protein level of cleaved caspase-3, cytochrom C and Bax, and increasing the level of Bcl-2 both in vivo and in vitro. Moreover, losartan treatment markedly enhanced the phosphorylation of Akt and blockade of PI3K activity by wortmannin dramatically inhibited Akt phosphorylation and attenuated the anti-apoptotic effect of losartan. Furthermore, pretreatment with losartan significantly increased the protein level of β-arrestin1 and silence of β-arrestin1 by siRNA partly attenuated losartan-induced anti-apoptotic effect and the phosphorylation of Akt. These results suggested that β-arrestin1 modulated the activation of Akt in losartan-induced anti-apoptotic effect in cerebral I/R. Our data would provide a new molecular basis for further understanding of protective effect of losartan in cerebral I/R injury and may provide benefits of using losartan in the treatment of cerebrovascular disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Nrf2 activator ameliorates hemorrhagic transformation in focal cerebral ischemia under warfarin anticoagulation.

PubMed

Imai, Takahiko; Takagi, Toshinori; Kitashoji, Akira; Yamauchi, Keita; Shimazawa, Masamitsu; Hara, Hideaki

2016-05-01

Oxidative stress has been reported to be a main cause of neuronal cell death in ischemia reperfusion injury (IRI). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important factor involved in anti-oxidative responses. We previously reported that bardoxolone methyl (BARD), an Nrf2 activator, prevented damage induced by IRI. In this study, we investigated the effect of BARD on hemorrhagic transformation in the context of blood brain barrier (BBB) protection. Mice received pre-treatment with warfarin (4.0 mg/kg, p.o.). IRI was subsequently induced 18 h after the warfarin administration by transient middle cerebral artery occlusion (MCAO) for 6 h. BARD (0.06, 0.2, 0.6 or 2.0 mg/kg) or saline was injected intravenously immediately after reperfusion. The infarct volume, neurological score, intracranial hemorrhage volume, and BBB permeability were evaluated 24 h after MCAO. The survival rate and behavioral functional recovery were evaluated for 7 days following IRI. Furthermore, the effects of BARD on BBB components were investigated by western blotting and immunostaining analysis. BARD suppressed warfarin-mediated increases in the intracranial hemorrhage volume without affecting the infarct volume. BBB permeability was also suppressed by administration of BARD. Western blotting showed that BARD increased expression of BBB components such as endothelial cells, pericytes, and tight junction proteins. Furthermore, immunostaining showed that BARD induced localization of Nrf2 to endothelial cells and pericytes. BARD suppressed the exacerbation hemorrhage caused by warfarin pretreatment and ameliorated BBB disruption by protecting endothelial cells, pericytes, and tight junction protein expressions. These results indicate that Nrf2 activators may be an effective therapy against hemorrhagic transformation caused by anticoagulant drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

Facilitated beam-walking recovery during acute phase by kynurenic acid treatment in a rat model of photochemically induced thrombosis causing focal cerebral ischemia.

PubMed

Abo, Masahiro; Yamauchi, Hideki; Suzuki, Masahiko; Sakuma, Mio; Urashima, Mitsuyoshi

We previously demonstrated the presence of activated areas in the non-injured contralateral sensorimotor cortex in addition to the ipsilateral sensorimotor cortex of the area surrounding a brain infarction, using a rat model of focal photochemically induced thrombosis (PIT) and functional magnetic resonance imaging. Using this model, we next applied gene expression profiling to screen key molecules upregulated in the activated area. RNA was extracted from the ipsilateral and contralateral sensorimotor cortex to the focal brain infarction and from the sham controlled cortex, and hybridized to gene-expression profiling arrays containing 1,322 neurology-related genes. Results showed that glycine receptors were upregulated in both the ipsilateral and contralateral cortex to the focal ischemic lesion. To prove the preclinical significance of upregulated glycine receptors, kynurenic acid, an endogenous antagonist to glycine receptors on neuronal cells, was administered intrathecally. As a result, the kynurenic acid significantly improved behavioral recovery within 10 days from paralysis induced by the focal PIT (p < 0.0001), as evaluated with beam walking. These results suggest that intrathecal administration of a glycine receptor antagonist may facilitate behavioral recovery during the acute phase after brain infarction. Copyright (c) 2006 S. Karger AG, Basel.

Assessment transcallosal Diaschisis in a model of focal cerebral ischemia in rats

PubMed Central

Muñoz Ospina, Beatriz Elena; Castaño, Daniel Manrique; Potes, Laura; Umbarila Prieto, John

2016-01-01

Objective: To evaluate transcallosal changes after a local ischemic injury in rats by using the monoclonal marker anti-NeuN (Mouse anti-neuronal nuclei). Methods: Twenty-eight adult, male, Wistar rats were subjected to focal injury in the right hemisphere. The technique used was the experimental model of focal ischemic injury through intraluminal suture of the middle cerebral artery. Analyses were made for the five groups: after the lesion (control), at 24 h, 96 h, 10 days and 20 days. Exofocal neuronal damage was inferred from neuronal immunoreactivity changes to NeuN. Results: In the cortex contralateral to the lesion, immunoreactivity was diminished. This finding was most notable in the supra-granular sheets 24 h post ischemia. After 96 h, there was a generalized diminishment of the inmmunoreactivity in the supra and infra-granular sheets. At 10 and 20 days, the tissue recovered some immunoreactivity to NeuN, but there were some changes in the VI layer. Conclusion: The immunoreactive changes to NeuN support the process of inter-hemispheric diaschisis. Changes in immunoreactivity could indicate metabolic stress secondary to the disruption in connectivity to the site of lesion. PMID:27546930

Assessment transcallosal Diaschisis in a model of focal cerebral ischemia in rats.

PubMed

Arango-Dávila, César Augusto; Muñoz Ospina, Beatriz Elena; Castaño, Daniel Manrique; Potes, Laura; Umbarila Prieto, John

2016-06-30

To evaluate transcallosal changes after a local ischemic injury in rats by using the monoclonal marker anti-NeuN (Mouse anti-neuronal nuclei). Twenty-eight adult, male, Wistar rats were subjected to focal injury in the right hemisphere. The technique used was the experimental model of focal ischemic injury through intraluminal suture of the middle cerebral artery. Analyses were made for the five groups: after the lesion (control), at 24 h, 96 h, 10 days and 20 days. Exofocal neuronal damage was inferred from neuronal immunoreactivity changes to NeuN. In the cortex contralateral to the lesion, immunoreactivity was diminished. This finding was most notable in the supra-granular sheets 24 h post ischemia. After 96 h, there was a generalized diminishment of the inmmunoreactivity in the supra and infra-granular sheets. At 10 and 20 days, the tissue recovered some immunoreactivity to NeuN, but there were some changes in the VI layer. The immunoreactive changes to NeuN support the process of inter-hemispheric diaschisis. Changes in immunoreactivity could indicate metabolic stress secondary to the disruption in connectivity to the site of lesion.

Effects of dexmedetomidine on microregional O2 balance during reperfusion after focal cerebral ischemia.

PubMed

Chi, Oak Z; Grayson, Jeremy; Barsoum, Sylviana; Liu, Xia; Dinani, Aliraza; Weiss, Harvey R

2015-01-01

This study was performed to determine whether there is an association between microregional O2 balance and neuronal survival in cerebral ischemia-reperfusion using dexmedetomidine, an α2-adrenoreceptor agonist and a sedative. Rats were subjected to 1 hour middle cerebral artery occlusion and a 2-hour reperfusion. During reperfusion, normal saline (n = 14) or dexmedetomidine 1 μg/kg/minute (n = 14) was infused intravenously. At 2 hours of reperfusion, regional cerebral blood flow using (14)C-iodoantipyrine autoradiography, microregional arterial and venous (20-60 μm in diameter) O2 saturation (SvO2) using cryomicrospectrophotometry, and the size of cortical infarction were determined. Ischemia-reperfusion decreased microregional SvO2 (52.9 ± 3.7% vs. 61.1 ± .6%, P < .005) with increased variation or heterogeneity (P < .0001) with similar regional cerebral blood flow and O2 consumption. Dexmedetomidine during reperfusion decreased the heterogeneity of SvO2 that was analyzed with an analysis of variance (P < .01) and reported as coefficient of variation (100 × standard deviation/Mean) (11.8 vs. 16.4). The number of veins with O2 saturation less than 50% decreased with dexmedetomidine (13/80 vs. 27/81, P < .01). The percentage of cortical infarct in total cortex was smaller with dexmedetomidine (8.3 ± 2.2% vs. 12.6 ± 1.5%, P < .005). In the cerebral ischemic reperfused cortex, dexmedetomidine decreased the heterogeneity of SvO2 and the number of small veins with low O2 saturation suggesting improved microregional O2 supply/consumption balance. The improvement was accompanied by the reduced size of cortical infarction. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Neuroprotective effect of mesenchymal stem cell through complement component 3 downregulation after transient focal cerebral ischemia in mice.

PubMed

Jung, Hye-Seon; Jeong, Si-Yeon; Yang, Jiwon; Kim, So-Dam; Zhang, Baojin; Yoo, Hyun Seung; Song, Sun U; Jeon, Myung-Shin; Song, Yun Seon

2016-10-28

Bone marrow-derived mesenchymal stem cells (MSCs) are used in stroke treatment despite the poor understanding of its mode of action. The immune suppressive and anti-inflammatory properties of MSCs possibly play important roles in regulating neuroinflammation after stroke. We investigated whether MSCs reduce the inflammatory complement component 3 (C3) levels, thus, providing neuroprotection during stroke. Mice were subjected to transient focal cerebral ischemia (tFCI), after which MSCs were intravenously injected. The infarct volume of the brain was reduced in MSC-injected tFCI mice, and C3 expression was significantly reduced in both the brain and the blood. Additionally, the profiles of other inflammatory mediators demonstrated neuroprotective changes in the MSCs-treated group. In order to analyze the effect of MSCs on neurons during cerebral ischemia, primary cortical neurons were co-cultured with MSCs under oxygen-glucose deprivation (OGD). Primary neurons co-cultured with MSCs exhibited reduced levels of C3 expression and increased protection against OGD, indicating that treatment with MSCs reduces excessive C3 expression and rescues ischemia-induced neuronal damage. Our finding suggests that reduction of C3 expression by MSCs can help to ameliorate ischemic brain damage, offering a new neuroprotective strategy in stroke therapy. Copyright © 2016. Published by Elsevier Ireland Ltd.

Apparent diffusion coefficient evaluation for secondary changes in the cerebellum of rats after middle cerebral artery occlusion

PubMed Central

Yang, Yunjun; Gao, Lingyun; Fu, Jun; Zhang, Jun; Li, Yuxin; Yin, Bo; Chen, Weijian; Geng, Daoying

2013-01-01

Supratentorial cerebral infarction can cause functional inhibition of remote regions such as the cerebellum, which may be relevant to diaschisis. This phenomenon is often analyzed using positron emission tomography and single photon emission CT. However, these methods are expensive and radioactive. Thus, the present study quantified the changes of infarction core and remote regions after unilateral middle cerebral artery occlusion using apparent diffusion coefficient values. Diffusion-weighted imaging showed that the area of infarction core gradually increased to involve the cerebral cortex with increasing infarction time. Diffusion weighted imaging signals were initially increased and then stabilized by 24 hours. With increasing infarction time, the apparent diffusion coefficient value in the infarction core and remote bilateral cerebellum both gradually decreased, and then slightly increased 3–24 hours after infarction. Apparent diffusion coefficient values at remote regions (cerebellum) varied along with the change of supratentorial infarction core, suggesting that the phenomenon of diaschisis existed at the remote regions. Thus, apparent diffusion coefficient values and diffusion weighted imaging can be used to detect early diaschisis. PMID:25206615

Optically measured NADH concentrations are unaffected by propofol induced EEG silence during transient cerebral hypoperfusion in anesthetized rabbits☆

PubMed Central

Wang, Mei; Agarwal, Sachin; Mayevsky, Avraham; Joshi, Shailendra

2014-01-01

The neuroprotective benefit of intra-operative anesthetics is widely described and routinely aimed to invoke electroencephalographic (EEG) silence in anticipation of transient cerebral ischemia. Previous rat survival studies have questioned an additional benefit from achieving EEG silence during transient global cerebral hypoperfusion. Surgical preparation on twelve New Zealand white rabbits under ketamine–propofol anesthesia, included placement of skull screws for bilateral EEG monitoring, skull shaving for laser Doppler probes, and a 5 mm diameter right temporal craniotomy for the NADH probe. Transient global cerebral hypoperfusion was achieved with bilateral internal carotid artery occlusion and pharmacologically induced systemic hypotension. All animals acted as controls, and had cerebral hypoperfusion under baseline propofol anesthesia with an active EEG. Thereafter, animals were randomized to receive bolus injection of intracarotid (3–5 mg) or intravenous (10–20 mg) 1% propofol to create EEG silence for 1–2 min. The data collected at baseline, peak hypoperfusion, and 5 and 10 min post hypoperfusion was analyzed by repeated measures ANOVA with post hoc Bonferroni–Dunn test. Eleven of the twelve rabbits completed the protocol. Hemodynamics and cerebral blood flow changes were comparable in all the animals. Compared to controls, the increase in NADH during ischemia was unaffected by EEG silence with either intravenous or intraarterial propofol. We failed to observe any significant additional attenuation of the elevation in NADH levels with propofol induced EEG silence during transient global cerebral hypoperfusion. This is consistent with previous rat survival studies showing that EEG silence was not required for full neuroprotective effects of pentothal anesthesia. PMID:21570061

Bepridil decreases Aβ and calcium levels in the thalamus after middle cerebral artery occlusion in rats

PubMed Central

Sarajärvi, Timo; Lipsanen, Anu; Mäkinen, Petra; Peräniemi, Sirpa; Soininen, Hilkka; Haapasalo, Annakaisa; Jolkkonen, Jukka; Hiltunen, Mikko

2012-01-01

Alzheimer's disease (AD) and cerebral ischaemia share similar features in terms of altered amyloid precursor protein (APP) processing and β-amyloid (Aβ) accumulation. We have previously shown that Aβ and calcium deposition, and β-secretase activity, are robustly increased in the ipsilateral thalamus after transient middle cerebral artery occlusion (MCAO) in rats. Here, we investigated whether the non-selective calcium channel blocker bepridil, which also inhibits β-secretase cleavage of APP, affects thalamic accumulation of Aβ and calcium and in turn influences functional recovery in rats subjected to MCAO. A 27-day bepridil treatment (50 mg/kg, p.o.) initiated 2 days after MCAO significantly decreased the levels of soluble Aβ40, Aβ42 and calcium in the ipsilateral thalamus, as compared with vehicle-treated MCAO rats. Expression of seladin-1/DHCR24 protein, which is a potential protective factor against neuronal damage, was decreased at both mRNA and protein levels in the ipsilateral thalamus of MCAO rats. Conversely, bepridil treatment restored seladin-1/DHCR24 expression in the ipsilateral thalamus. Bepridil treatment did not significantly affect heme oxygenase-1- or NAD(P)H quinone oxidoreductase-1-mediated oxidative stress or inflammatory responses in the ipsilateral thalamus of MCAO rats. Finally, bepridil treatment mitigated MCAO-induced alterations in APP processing in the ipsilateral thalamus and improved contralateral forelimb use in MCAO rats. These findings suggest that bepridil is a plausible therapeutic candidate in AD or stroke owing to its multifunctional role in key cellular events that are relevant for the pathogenesis of these diseases. PMID:22805236

The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice

PubMed Central

Gelderblom, Mathias; Leypoldt, Frank; Lewerenz, Jan; Birkenmayer, Gabriel; Orozco, Denise; Ludewig, Peter; Thundyil, John; Arumugam, Thiruma V; Gerloff, Christian; Tolosa, Eva; Maher, Pamela; Magnus, Tim

2012-01-01

The development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, a flavonoid, has multiple biological effects, including neuroprotective and antiinflammatory properties. We analyzed the effects of fisetin on infarct size and the inflammatory response in a mouse model of stroke, temporary middle cerebral artery occlusion, and on the activation of immune cells, murine primary and N9 microglial and Raw264.7 macrophage cells and human macrophages, in an in vitro model of inflammatory immune cell activation by lipopolysaccharide (LPS). Fisetin not only protected brain tissue against ischemic reperfusion injury when given before ischemia but also when applied 3 hours after ischemia. Fisetin also prominently inhibited the infiltration of macrophages and dendritic cells into the ischemic hemisphere and suppressed the intracerebral immune cell activation as measured by intracellular tumor necrosis factor α (TNFα) production. Fisetin also inhibited LPS-induced TNFα production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor κB activation and JNK/Jun phosphorylation. Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia. PMID:22234339

Oleuropein, a natural extract from plants, offers neuroprotection in focal cerebral ischemia/reperfusion injury in mice.

PubMed

Yu, Hailong; Liu, Peipei; Tang, Hui; Jing, Jian; Lv, Xiang; Chen, Lanlan; Jiang, Li; Xu, Jun; Li, Jun

2016-03-15

Oleuropein (OLE) was found to have anti-inflammatory and anti-oxidant effects. The latest study has shown that it can resist myocardial injury that follows an acute myocardial infarction and can rescue impaired spinal nerve cells. In this study, we investigated the neuroprotective effects of OLE on cerebral ischemia and reperfusion injury in a middle cerebral artery occlusion model in mice.OLE (100 mg/kg) was injected intraperitoneally 1h before ischemia. We found that the volume of cerebral infarction was significantly reduced after 75 min of ischemia and 24 h of reperfusion compared with the I/R (ischemia/reperfusion) group. This protective function occurred in a dose-dependent manner. We also found that treatment with OLE could reduce the cerebral infarct volume. The neuroprotective effect was prolonged from 2 h to 4 h when we injected OLE intracerebroventricularly after reperfusion. We then found that OLE can decrease the level of cleavedcaspase-3, an important marker of apoptosis, in the ischemic mouse brain. Finally, we explored the role of OLE in providing anti-apoptotic effects through the increased expression of Bcl-2 and the decreased expression of Bax, which are important markers in apoptosis. As shown above, the function and safety of OLE in cardiovascular disease may indicate that it is a potential therapeutic for stroke. Copyright © 2016 Elsevier B.V. All rights reserved.

Unique action mechanisms of tramadol in global cerebral ischemia-induced mechanical allodynia.

PubMed

Matsuura, Wataru; Kageyama, Erika; Harada, Shinichi; Tokuyama, Shogo

2016-06-15

Central poststroke pain is associated with specific somatosensory abnormalities, such as neuropathic pain syndrome. Although central poststroke pain is a serious condition, details pertaining to underlying mechanisms are not well established, making current standard treatments only partially effective. Here, we assessed the effects of tramadol, an analgesic drug mediated by opioid receptors, using a mouse model of global cerebral ischemia. Ischemia was induced by bilateral carotid artery occlusion (30 min) in male ddY mice. Development of hind-paw mechanical allodynia was measured 3 days after bilateral carotid artery occlusion using the von Frey test. Mechanical allodynia was significantly and dose dependently suppressed by intraperitoneal tramadol (10 or 20 mg/kg). These effects, which peaked at 10 min and continued for at least 60 min, were inhibited by naloxone (nonselective opioid receptor antagonist, 1 mg/kg, intraperitoneal). Tramadol antinociception was significantly negated by β-funaltrexamine (selective μ-opioid receptor antagonist, 20 mg/kg, intraperitoneal), but not naltrindole (selective δ-opioid receptor antagonist, 5 mg/kg, intraperitoneal) or nor-binaltorphimine (selective κ-opioid receptor antagonist, 10 mg/kg, intraperitoneal) after 5 min, by β-funaltrexamine and nor-binaltorphimine but not naltrindole after 10 min, and by all selective opioid receptor antagonists at 15 and 30 min after tramadol treatment. These results suggested that antinociception induced by tramadol through various opioid receptors was time dependent. Furthermore, it is possible that the opioid receptors involved in tramadol-induced antinociception change over time with the metabolism of this drug.

Proteomic analysis of cPKCβII-interacting proteins involved in HPC-induced neuroprotection against cerebral ischemia of mice.

PubMed

Bu, Xiangning; Zhang, Nan; Yang, Xuan; Liu, Yanyan; Du, Jianli; Liang, Jing; Xu, Qunyuan; Li, Junfa

2011-04-01

Hypoxic preconditioning (HPC) initiates intracellular signaling pathway to provide protection against subsequent cerebral ischemic injuries, and its mechanism may provide molecular targets for therapy in stroke. According to our study of conventional protein kinase C βII (cPKCβII) activation in HPC, the role of cPKCβII in HPC-induced neuroprotection and its interacting proteins were determined in this study. The autohypoxia-induced HPC and middle cerebral artery occlusion (MCAO)-induced cerebral ischemia mouse models were prepared as reported. We found that HPC reduced 6 h MCAO-induced neurological deficits, infarct volume, edema ratio and cell apoptosis in peri-infarct region (penumbra), but cPKCβII inhibitors Go6983 and LY333531 blocked HPC-induced neuroprotection. Proteomic analysis revealed that the expression of four proteins in cytosol and eight proteins in particulate fraction changed significantly among 49 identified cPKCβII-interacting proteins in cortex of HPC mice. In addition, HPC could inhibit the decrease of phosphorylated collapsin response mediator protein-2 (CRMP-2) level and increase of CRMP-2 breakdown product. TAT-CRMP-2 peptide, which prevents the cleavage of endogenous CRMP-2, could inhibit CRMP-2 dephosphorylation and proteolysis as well as the infarct volume of 6 h MCAO mice. This study is the first to report multiple cPKCβII-interacting proteins in HPC mouse brain and the role of cPKCβII-CRMP-2 in HPC-induced neuroprotection against early stages of ischemic injuries in mice. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Neuroprotective effect of cathodal transcranial direct current stimulation in a rat stroke model.

PubMed

Notturno, Francesca; Pace, Marta; Zappasodi, Filippo; Cam, Etrugul; Bassetti, Claudio L; Uncini, Antonino

2014-07-15

Experimental focal brain ischemia generates in the penumbra recurrent depolarizations which spread across the injured cortex inducing infarct growth. Transcranial direct current stimulation can induce a lasting, polarity-specific, modulation of cortical excitability. To verify whether cathodal transcranial direct current stimulation could reduce the infarct size and the number of depolarizations, focal ischemia was induced in the rat by the 3 vessels occlusion technique. In the first experiment 12 ischemic rats received cathodal stimulation (alternating 15 min on and 15 min off) starting 45 min after middle cerebral artery occlusion and lasting 4 h. In the second experiment 12 ischemic rats received cathodal transcranial direct current stimulation with the same protocol but starting soon after middle cerebral artery occlusion and lasting 6 h. In both experiments controls were 12 ischemic rats not receiving stimulation. Cathodal stimulation reduced the infarct volume in the first experiment by 20% (p=0.002) and in the second by 30% (p=0.003). The area of cerebral infarction was smaller in animals receiving cathodal stimulation in both experiments (p=0.005). Cathodal stimulation reduced the number of depolarizations (p=0.023) and infarct volume correlated with the number of depolarizations (p=0.048). Our findings indicate that cathodal transcranial direct current stimulation exert a neuroprotective effect in the acute phase of stroke possibly decreasing the number of spreading depolarizations. These findings may have translational relevance and open a new avenue in neuroprotection of stroke in humans. Copyright © 2014. Published by Elsevier B.V.

Platelet adhesion via glycoprotein IIb integrin is critical for atheroprogression and focal cerebral ischemia: an in vivo study in mice lacking glycoprotein IIb.

PubMed

Massberg, Steffen; Schürzinger, Katrin; Lorenz, Michael; Konrad, Ildiko; Schulz, Christian; Plesnila, Nikolaus; Kennerknecht, Elisabeth; Rudelius, Martina; Sauer, Susanne; Braun, Siegmund; Kremmer, Elisabeth; Emambokus, Nikla R; Frampton, Jon; Gawaz, Meinrad

2005-08-23

The platelet glycoprotein (GP) IIb/IIIa integrin binds to fibrinogen and thereby mediates platelet aggregation. Here, we addressed the role of GP IIb for platelet adhesion and determined the relevance of platelet GP IIb for the processes of atherosclerosis and cerebral ischemia-reperfusion (I/R) injury. GP IIb(-/-) mice were generated and bred with ApoE(-/-) animals to create GP IIb(-/-)ApoE(-/-) mice. Platelet adhesion to the mechanically injured or atherosclerotic vessel wall was monitored by in vivo video fluorescence microscopy. In the presence of GP IIb, vascular injury and early atherosclerosis induced platelet adhesion in the carotid artery (CA). In contrast, platelet adhesion was significantly reduced in the absence of GP IIb integrin (P<0.05). To address the contribution of platelet GP IIb to atheroprogression, we determined atherosclerotic lesion formation in the CA and aortic arch (AA) of GP IIb(+/+)ApoE(-/-) or GP IIb(-/-)ApoE(-/-) mice. Interestingly, the absence of GP IIb attenuated lesion formation in CA and AA, indicating that platelets, via GP IIb, contribute substantially to atherosclerosis. Next, we assessed the implication of GP IIb for cerebral I/R injury. We observed that after occlusion of the middle cerebral artery, the cerebral infarct size was drastically reduced in mice lacking GP IIb compared with wild-types. These findings show for the first time in vivo that GP IIb not only mediates platelet aggregation but also triggers platelet adhesion to exposed extracellular matrices and dysfunctional endothelial cells. In a process strictly involving GP IIb, platelets, which are among the first blood cells to arrive at the scene of endothelial dysfunction, contribute essentially to atherosclerosis and cerebral I/R injury.

Ameliorating effects of dexpanthenol in cerebral ischaemia reperfusion induced injury in rat brain.

PubMed

Zakaria, Mohammad Mehdi Hosseinian; Hajipour, Babak; Khodadadi, Ali; Afshari, Fatemeh

2011-09-01

To study the attenuating effect of Dexpanthenol (Dxp) provitamin B5 on neuronal damage after cerebral ischaemia/reperfusion. This was a randomized, controlled experimental study conducted at the Islamic Azad University, Tabriz, Iran, from April to September 2008. Male wistar rats were divided into 4 groups randomly (n=13): 1- sham group, Group 2 :two hours occlusion of middle cerebral artery (MCA) and 24 hours reperfusion. Group 3: two hours occlusion of MCA and 24 hours reperfusion + Dxp (250mg/kg) since 3 days before ischaemia. Group 4: two hours occlusion of MCA and 24 hours reperfusion which had received Dxp (500mg/kg) since 3 days before ischaemia. Glutathione (GSH) and malondialdehyde (MDA) levels were studied in brain tissue and numbers of cornu ammonis (CA1 and CA3) pyramidal neurons were studied with light microscopy. The GSH levels were significantly higher in groups 3 and 4 as compared with group 2. In group 3 and group 4 animals, the MDA levels were significantly lower than in group 2 (P < 0.05). Numbers of CA1 and CA3 neurons were completely normal in appearance in the group 1. The surviving neurons in the CA1 and CA3 subfield were markedly decreased in number, in group 2 (P < 0.05). Our pathologic and biochemical study has proven positive effect of Dxp on protection of cerebral tissue after I/R. The present findings correlate with previous studies on the protective effects of Dxp against cell and tissue injury by I/R.

Vascular growth responses to chronic arterial occlusion are unaffected by myeloid specific focal adhesion kinase (FAK) deletion

NASA Astrophysics Data System (ADS)

Heuslein, Joshua L.; Murrell, Kelsey P.; Leiphart, Ryan J.; Llewellyn, Ryan A.; Meisner, Joshua K.; Price, Richard J.

2016-05-01

Arteriogenesis, or the lumenal expansion of pre-existing arterioles in the presence of an upstream occlusion, is a fundamental vascular growth response. Though alterations in shear stress stimulate arteriogenesis, the migration of monocytes into the perivascular space surrounding collateral arteries and their differentiation into macrophages is critical for this vascular growth response to occur. Focal adhesion kinase’s (FAK) role in regulating cell migration has recently been expanded to primary macrophages. We therefore investigated the effect of the myeloid-specific conditional deletion of FAK on vascular remodeling in the mouse femoral arterial ligation (FAL) model. Using laser Doppler perfusion imaging, whole mount imaging of vascular casted gracilis muscles, and immunostaining for CD31 in gastrocnemius muscles cross-sections, we found that there were no statistical differences in perfusion recovery, arteriogenesis, or angiogenesis 28 days after FAL. We therefore sought to determine FAK expression in different myeloid cell populations. We found that FAK is expressed at equally low levels in Ly6Chi and Ly6Clo blood monocytes, however expression is increased over 2-fold in bone marrow derived macrophages. Ultimately, these results suggest that FAK is not required for monocyte migration to the perivascular space and that vascular remodeling following arterial occlusion occurs independently of myeloid specific FAK.

[Cerebral protection].

PubMed

Cattaneo, A D

1993-09-01

Cerebral protection means prevention of cerebral neuronal damage. Severe brain damage extinguishes the very "human" functions such as speech, consciousness, intellectual capacity, and emotional integrity. Many pathologic conditions may inflict injuries to the brain, therefore the protection and salvage of cerebral neuronal function must be the top priorities in the care of critically ill patients. Brain tissue has unusually high energy requirements, its stores of energy metabolites are small and, as a result, the brain is totally dependent on a continuous supply of substrates and oxygen, via the circulation. In complete global ischemia (cardiac arrest) reperfusion is characterized by an immediate reactive hyperemia followed within 20-30 min by a delayed hypoperfusion state. It has been postulated that the latter contributes to the ultimate neurologic outcome. In focal ischemia (stroke) the primary focus of necrosis is encircled by an area (ischemic penumbra) that is underperfused and contains neurotoxic substances such as free radicals, prostaglandins, calcium, and excitatory neurotransmitters. The variety of therapeutic effort that have addressed the question of protecting the brain reflects their limited success. 1) Barbiturates. After an initial enthusiastic endorsement by many clinicians and years of vigorous controversy, it can now be unequivocally stated that there is no place for barbiturate therapy following resuscitation from cardiac arrest. One presumed explanation for this negative statement is that cerebral metabolic suppression by barbiturates (and other anesthetics) is impossible in the absence of an active EEG. Conversely, in the event of incomplete ischemia EEG activity in usually present (albeit altered) and metabolic suppression and hence possibly protection can be induced with barbiturates. Indeed, most of the animal studies led to a number of recommendations for barbiturate therapy in man for incomplete ischemia. 2) Isoflurane. From a cerebral

Electro-acupuncture up-regulates astrocytic MCT1 expression to improve neurological deficit in middle cerebral artery occlusion rats.

PubMed

Lu, Yan; Zhao, Haijun; Wang, Yuan; Han, Bingbing; Wang, Tong; Zhao, Hong; Cui, Kemi; Wang, Shijun

2015-08-01

Cerebral ischemia is one of the common diseases treated by electro-acupuncture (EA). Although the clinical efficacy has been widely affirmed, the mechanisms of action leading to the health benefits are not understood. In this study, the role of EA in modulating the lactate energy metabolism and lactate transportation was explored on the middle cerebral artery occlusion (MCAO) ischemic rat model. Repeated EA treatments once daily for 7 days were applied to the MCAO rats and neurological function evaluation was performed. Brain tissues were harvested for lactate concentration examination, immunohistochemical staining, Western blot and qRT-PCR analyses for the expressions of lactate transporter (monocarboxylate transporter 1, MCT1) and glial fibrillary acidic protein (GFAP). The animal behavioral tests showed that the 7-day EA treatments significantly promoted the recovery of neurological deficits in the MCAO rats, which correlated with the enhanced lactate energy metabolism in the ischemic brain. In the cortical ischemic area of the MCAO rats, EA treatments led to the activation of astrocytes, and induced a further increase of lactate transporter (monocarboxylate transporter 1, MCT1) expression in astrocytes at both protein and mRNA levels. Our results suggest that the EA treatments activated lactate metabolism in the resident astrocytes around the ischemic area and up-regulated the expression of MCT1 in these astrocytes which facilitated the transfer of intracellular lactate to extracellular domain to be utilized by injured neurons to improve the neurological deficit. Copyright © 2015 Elsevier Inc. All rights reserved.

Detection of Anterior Circulation Large Artery Occlusion in Ischemic Stroke Using Noninvasive Cerebral Oximetry.

PubMed

Flint, Alexander C; Bhandari, Shiv G; Cullen, Sean P; Reddy, Adhikari V; Hsu, Daniel P; Rao, Vivek A; Patel, Minal; Pombra, Jasmeen; Edwards, Nancy J; Chan, Sheila L

2018-02-01

Large artery occlusion (LAO) in ischemic stroke requires recognition and triage to an endovascular stroke treatment center. Noninvasive LAO detection is needed to improve triage. Prospective study to test whether noninvasive cerebral oximetry can detect anterior circulation LAO in acute stroke. Interhemispheric ΔBrSO 2 in LAO was compared with controls. In LAO stroke, mean interhemispheric ΔBrSO 2 was -8.3±5.8% (n=19), compared with 0.4±5.8% in small artery stroke (n=17), 0.4±6.0% in hemorrhagic stroke (n=14), and 0.2±7.5% in subjects without stroke (n=19) ( P <0.001). Endovascular stroke treatment reduced the ΔBrSO 2 in most LAO subjects (16/19). Discrimination of LAO at a -3% ΔBrSO 2 cut had 84% sensitivity and 70% specificity. Addition of the G-FAST clinical score (gaze-face-arm-speech- time) to the BrSO 2 measure had 84% sensitivity and 90% specificity. Noninvasive cerebral oximetry may help detect LAO in ischemic stroke, particularly when combined with a simple clinical scoring system. © 2018 American Heart Association, Inc.

Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia.

PubMed

Liu, Yu-Cheng; Lee, Yu-Da; Wang, Hwai-Lee; Liao, Kate Hsiurong; Chen, Kuen-Bao; Poon, Kin-Shing; Pan, Yu-Ling; Lai, Ted Weita

2017-01-01

Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8-24 h, whereas the late phase of BBB disruption begins 48-58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison

The Antiepileptic Drug Levetiracetam Suppresses Non-Convulsive Seizure Activity and Reduces Ischemic Brain Damage in Rats Subjected to Permanent Middle Cerebral Artery Occlusion

PubMed Central

Cuomo, Ornella; Rispoli, Vincenzo; Leo, Antonio; Politi, Giovanni Bosco; Vinciguerra, Antonio; di Renzo, Gianfranco; Cataldi, Mauro

2013-01-01

The antiepileptic drug Levetiracetam (Lev) has neuroprotective properties in experimental stroke, cerebral hemorrhage and neurotrauma. In these conditions, non-convulsive seizures (NCSs) propagate from the core of the focal lesion into perilesional tissue, enlarging the damaged area and promoting epileptogenesis. Here, we explore whether Lev neuroprotective effect is accompanied by changes in NCS generation or propagation. In particular, we performed continuous EEG recordings before and after the permanent occlusion of the middle cerebral artery (pMCAO) in rats that received Lev (100 mg/kg) or its vehicle immediately before surgery. Both in Lev-treated and in control rats, EEG activity was suppressed after pMCAO. In control but not in Lev-treated rats, EEG activity reappeared approximately 30-45 min after pMCAO. It initially consisted in single spikes and, then, evolved into spike-and-wave and polyspike-and-wave discharges. In Lev-treated rats, only rare spike events were observed and the EEG power was significantly smaller than in controls. Approximately 24 hours after pMCAO, EEG activity increased in Lev-treated rats because of the appearance of polyspike events whose power was, however, significantly smaller than in controls. In rats sacrificed 24 hours after pMCAO, the ischemic lesion was approximately 50% smaller in Lev-treated than in control rats. A similar neuroprotection was observed in rats sacrificed 72 hours after pMCAO. In conclusion, in rats subjected to pMCAO, a single Lev injection suppresses NCS occurrence for at least 24 hours. This electrophysiological effect could explain the long lasting reduction of ischemic brain damage caused by this drug. PMID:24236205

Caffeine induced changes in cerebral circulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mathew, R.J.; Wilson, W.H.

1985-09-01

While the caffeine induced cerebral vasoconstriction is well documented, the effects of oral ingestion of the drug in a dose range comparable to the quantities in which it is usually consumed and the intensity and duration of the associated reduction in cerebral circulation are unknown. Cerebral blood flow was measured via the TTXenon inhalation technique before and thirty and ninety minutes after the oral administration of 250 mg of caffeine or a placebo, under double-blind conditions. Caffeine ingestion was found to be associated with significant reductions in cerebral perfusion thirty and ninety minutes later. The placebo group showed no differencesmore » between the three sets of cerebral blood flow values.« less

Britanin Ameliorates Cerebral Ischemia-Reperfusion Injury by Inducing the Nrf2 Protective Pathway.

PubMed

Wu, Guozhen; Zhu, Lili; Yuan, Xing; Chen, Hao; Xiong, Rui; Zhang, Shoude; Cheng, Hao; Shen, Yunheng; An, Huazhang; Li, Tiejun; Li, Honglin; Zhang, Weidong

2017-10-10

Oxidative stress is considered the major cause of tissue injury after cerebral ischemia. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important defensive mechanisms against oxidative stresses and has been confirmed as a target for stroke treatment. Thus, we desired to find new Nrf2 activators and test their neuronal protective activity both in vivo and in vitro. The herb-derived compound, Britanin, is a potent inducer of the Nrf2 system. Britanin can induce the expression of protective enzymes and reverse oxygen-glucose deprivation, followed by reperfusion (OGD-R)-induced neuronal injury in primary cortical neurons in vitro. Furthermore, the administration of Britanin significantly ameliorated middle cerebral artery occlusion-reperfusion (MCAO-R) insult in vivo. We report here the crystal structure of the complex of Britanin and the BTB domain of Keap1. Britanin selectively binds to a conserved cysteine residue, cysteine 151, of Keap1 and inhibits Keap1-mediated ubiquitination of Nrf2, leading to induction of the Nrf2 pathway. Britanin is a potent inducer of Nrf2. The complex crystal structure of Britanin and the BTB domain of Keap1 help clarify the mechanism of Nrf2 induction. Britanin was proven to protect primary cortical neurons against OGD-R-induced injury in an Nrf2-dependant way. Additionally, Britanin had excellent cerebroprotective effect in an MCAO-R model. Our results demonstrate that the natural product Britanin with potent Nrf2-activating and neural protective activities both in vitro and in vivo could be developed into a cerebroprotective therapeutic agent. Antioxid. Redox Signal. 27, 754-768.

Risk of bias reporting in the recent animal focal cerebral ischaemia literature.

PubMed

Bahor, Zsanett; Liao, Jing; Macleod, Malcolm R; Bannach-Brown, Alexandra; McCann, Sarah K; Wever, Kimberley E; Thomas, James; Ottavi, Thomas; Howells, David W; Rice, Andrew; Ananiadou, Sophia; Sena, Emily

2017-10-15

Findings from in vivo research may be less reliable where studies do not report measures to reduce risks of bias. The experimental stroke community has been at the forefront of implementing changes to improve reporting, but it is not known whether these efforts are associated with continuous improvements. Our aims here were firstly to validate an automated tool to assess risks of bias in published works, and secondly to assess the reporting of measures taken to reduce the risk of bias within recent literature for two experimental models of stroke. We developed and used text analytic approaches to automatically ascertain reporting of measures to reduce risk of bias from full-text articles describing animal experiments inducing middle cerebral artery occlusion (MCAO) or modelling lacunar stroke. Compared with previous assessments, there were improvements in the reporting of measures taken to reduce risks of bias in the MCAO literature but not in the lacunar stroke literature. Accuracy of automated annotation of risk of bias in the MCAO literature was 86% (randomization), 94% (blinding) and 100% (sample size calculation); and in the lacunar stroke literature accuracy was 67% (randomization), 91% (blinding) and 96% (sample size calculation). There remains substantial opportunity for improvement in the reporting of animal research modelling stroke, particularly in the lacunar stroke literature. Further, automated tools perform sufficiently well to identify whether studies report blinded assessment of outcome, but improvements are required in the tools to ascertain whether randomization and a sample size calculation were reported. © 2017 The Author(s).

Effect of combination therapy with the angiotensin receptor blocker losartan plus hydrochlorothiazide on brain perfusion in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic major cerebral artery steno-occlusive disease: a SPECT study.

PubMed

Saura, Hiroaki; Ogasawara, Kuniaki; Suzuki, Taro; Kuroda, Hiroki; Yamashita, Takeshi; Kobayashi, Masakazu; Terasaki, Kazunori; Ogawa, Akira

2012-01-01

While the combination of an angiotensin receptor blocker with thiazide diuretics produces a clinically beneficial reduction in blood pressure in patients who otherwise only partially respond to monotherapy with an angiotensin receptor blocker, blood pressure-lowering therapy with combination antihypertensive drug regimens in patients with cerebral hemodynamic impairment may adversely affect cerebral hemodynamics. The purpose of the present exploratory study was to determine whether blood pressure-lowering therapy with the combination of the angiotensin receptor blocker losartan plus hydrochlorothiazide (LPH) worsens brain perfusion in patients with both hypertension and cerebral hemodynamic impairment due to symptomatic chronic major cerebral artery steno-occlusive disease. Patients with losartan-resistant hypertension and reduced cerebrovascular reactivity (CVR) to acetazolamide due to symptomatic chronic internal carotid artery (ICA) or middle cerebral artery (MCA) steno-occlusive disease were prospectively entered into the present study and received 50 mg/day of losartan plus 12.5 mg/day of hydrochlorothiazideat 14 weeks after the last ischemic event. Cerebral blood flow (CBF) and CVR were measured before and 12 weeks after initiating LPH using N-isopropyl-p-[(123)I]-iodoamphetamine single-photon emission computed tomography (SPECT). A region of interest (ROI) was automatically placed in the MCA territory on each SPECT image using a three-dimensional stereotactic ROI template. None of the 18 patients who participated in the study experienced any new neurological symptoms or adverse effects related to antihypertensive drugs. Systolic (p < 0.001) and diastolic (p < 0.001) blood pressures were significantly reduced after the administration of LPH, with average reductions of 11 mm Hg in systolic blood pressure and 10 mm Hg in diastolic blood pressure. While in the affected hemisphere CBF did not differ between measurements taken before and after the administration

Visualization of cell death in mice with focal cerebral ischemia using fluorescent annexin A5, propidium iodide, and TUNEL staining.

PubMed

Bahmani, Peyman; Schellenberger, Eyk; Klohs, Jan; Steinbrink, Jens; Cordell, Ryan; Zille, Marietta; Müller, Jochen; Harhausen, Denise; Hofstra, Leo; Reutelingsperger, Chris; Farr, Tracy Deanne; Dirnagl, Ulrich; Wunder, Andreas

2011-05-01

To monitor stroke-induced brain damage and assess neuroprotective therapies, specific imaging of cell death after cerebral ischemia in a noninvasive manner is highly desirable. Annexin A5 has been suggested as a marker for imaging cell death under various disease conditions including stroke. In this study, C57BL6/N mice received middle cerebral artery occlusion (MCAO) and were injected intravenously with either active or inactive Cy5.5-annexin A5 48 hours after reperfusion. Some mice also received propidium iodide (PI), a cell integrity marker. Only in mice receiving active Cy5.5-annexin A5 were fluorescence intensities significantly higher over the hemisphere ipsilateral to MCAO than on the contralateral side. This was detected noninvasively and ex vivo 4 and 8 hours after injection. The majority of cells positive for fluorescent annexin A5 were also positive for PI and fragmented DNA as detected by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining. This study demonstrates the high specificity of annexin A5 for visualization of cell death in a mouse model of stroke. To our knowledge, this is the first study to compare the distribution of injected active and inactive annexin A5, PI, and TUNEL staining. It provides important information on the experimental and potential clinical applications of annexin A5-based imaging agents in stroke.

Delayed neuroprotection against cerebral ischemia reperfusion injury: putative role of BDNF and GSK-3β.

PubMed

Taliyan, Rajeev; Ramagiri, Sruthi

2016-08-01

Numerous studies have demonstrated the possible neuroprotective role of lithium treatment against neurological disorders. However, the role of lithium in delayed phase of neuronal death against focal ischemia has not been explored. Therefore, the present study was designed to investigate the effect and molecular mechanisms of post-lithium treatment against cerebral ischemic reperfusion (I/R) injury and associated cognitive deficits in rats. I/R injury was induced by right middle cerebral artery occlusion and lithium (40 and 60 mg/kg) were given intraperitoneally, 24 h after the insult and continued for 1 week with 24-h interval. Using Lasser Doppler, cerebral blood flow was monitored before, during and after MCAO induction. Besides behavioral, biochemical, and histological evaluation, levels of tumor necrosis factor alpha (TNF-α) and brain-derived neurotrophic factor (BDNF) were also estimated. I/R injury resulted in significant elevation of neurological deficits, oxidative stress, neuroinflammation, and cognitive impairments. We found that lithium injection, 24 h after I/R-injury continued for 1 week, dose dependently prevented behavioral abnormality and cognitive impairments. Moreover, lithium attenuated the levels of oxidative stress and pro-inflammatory-cytokines TNF-α level. Further, lithium treatments significantly reduced neuronal damage and augmented healthy neuronal count and improved neuronal density in hippocampus. These neuroprotective effects of delayed lithium treatment were associated with upregulation of neurotrophic factor BDNF levels. Delayed lithium treatment provides neuroprotection against cerebral I/R injury and associated cognitive deficits by upregulating BDNF expression that opens a new avenue to treat I/R injury even after active cell death.

Norethisterone enanthate-induced cerebral venous sinus thrombosis (CVST)

PubMed Central

Bahall, Mandreker; Santlal, Manisha

2017-01-01

A 23-year-old East Indian woman with no significant medical history, except a depot-norethisterone enanthate injection taken 3 weeks prior to admission, presented with a gradually worsening headache for the past 5 days. She had no fever, vomiting, neck stiffness, focal weakness or rash, and examination was unremarkable with no focal neurological deficits. Vasculitic, thrombophilia and sepsis screens were normal. A brain CT scan showed a left parietal lobe venous infarct, secondary to a venous dural sinus thrombosis, with MRI and Magnetic Resonance Venogram (MRV) confirming a signal void. She was diagnosed to have multiple cerebral venous sinus thrombosis due to norethisterone enanthate. She made a complete recovery following treatment with mannitol, dexamethasone and anticoagulants. A follow-up brain MRI done at 6 months was normal. PMID:29141931

Quantitative electroencephalographic changes due to middle cerebral artery occlusion by endothelin 1 in conscious rats.

PubMed

Moyanova, S; Kortenska, L; Kirov, R; Iliev, I

1998-12-01

The powerful vasoconstrictor peptide endothelin-1 (ET1) has been shown to reduce local cerebral blood flow in brain areas supplied by the middle cerebral artery (MCA) to a pathologically low level upon intracerebral injection adjacent to the MCA. This reduction manifests itself as an ischemic infarct, that is fully developed within 3 days after ET1 injection. The aim of the present study is to examine the effect of ET1 on electroencephalographic (EEG) activity. ET1 was microinjected unilaterally at a dose of 60 pmol in 3 microl of saline to the MCA in conscious rats. EEG signals were recorded from the frontoparietal cortical area, supplied by MCA, from the first up to the fourteenth day after ET1 injection. EEG activity was analyzed by the fast Fourier transformation. A significant shift to a lower EEG frequency, i.e., augmentation of slow waves and a reduction of alpha-like and faster EEG waves was found post-ET1. This effect was maximal after 3-7 days when the most severe destruction of neurons in this cortical area occurs, as has been previously demonstrated. The results suggest that the quantitative EEG analysis may provide useful additional information about the functional disturbances associated with focal cerebral ischemia.

Radon inhalation protects against transient global cerebral ischemic injury in gerbils.

PubMed

Kataoka, Takahiro; Etani, Reo; Takata, Yuji; Nishiyama, Yuichi; Kawabe, Atsushi; Kumashiro, Masayuki; Taguchi, Takehito; Yamaoka, Kiyonori

2014-10-01

Although brain disorders are not the main indication for radon therapy, our previous study suggested that radon inhalation therapy might mitigate brain disorders. In this study, we assessed whether radon inhalation protects against transient global cerebral ischemic injury in gerbils. Gerbils were treated with inhaled radon at a concentration of 2,000 Bq/m(3) for 24 h. After radon inhalation, transient global cerebral ischemia was induced by bilateral occlusion of the common carotid artery. Results showed that transient global cerebral ischemia induced neuronal damage in hippocampal CA1, and the number of damaged neurons was significantly increased compared with control. However, radon treatment inhibited ischemic damage. Superoxide dismutase (SOD) activity in the radon-treated gerbil brain was significantly higher than that in sham-operated gerbils. These findings suggested that radon inhalation activates antioxidative function, especially SOD, thereby inhibiting transient global cerebral ischemic injury in gerbils.

Hawthorn extract reduces infarct volume and improves neurological score by reducing oxidative stress in rat brain following middle cerebral artery occlusion.

PubMed

Elango, Chinnasamy; Jayachandaran, Kasevan Sawaminathan; Niranjali Devaraj, S

2009-12-01

In our present investigation the neuroprotective effect of alcoholic extract of Hawthorn (Crataegus oxycantha) was evaluated against middle cerebral artery occlusion induced ischemia/reperfusion injury in rats. Male Sprague-Dawley rats were pretreated with 100 mg/kg body weight of the extract by oral gavage for 15 days. The middle cerebral artery was then occluded for 75 min followed by 24 h of reperfusion. The pretreated rats showed significantly improved neurological behavior with reduced brain infarct when compared to vehicle control rats. The glutathione level in brain was found to be significantly (p<0.05) low in vehicle control rats after 24 h of reperfusion when compared to sham operated animals. However, in Hawthorn extract pretreated rats the levels were found to be close to that of sham. Malondialdehyde levels in brain of sham and pretreated group were found to be significantly lower than the non-treated vehicle group (p<0.05). The nitric oxide levels in brain were measured and found to be significantly (p<0.05) higher in vehicle than in sham or extract treated rats. Our results suggest that Hawthorn extract which is a well known prophylactic for cardiac conditions may very well protect the brain against ischemia-reperfusion. The reduced brain damage and improved neurological behavior after 24 h of reperfusion in Hawthorn extract pretreated group may be attributed to its antioxidant property which restores glutathione levels, circumvents the increase in lipid peroxidation and nitric oxide levels thereby reducing peroxynitrite formation and free radical induced brain damage.

Sevoflurane postconditioning against cerebral ischemic neuronal injury is abolished in diet-induced obesity: role of brain mitochondrial KATP channels.

PubMed

Yang, Zecheng; Chen, Yunbo; Zhang, Yan; Jiang, Yi; Fang, Xuedong; Xu, Jingwei

2014-03-01

Obesity is associated with increased infarct volumes and adverse outcomes following ischemic stroke. However, its effect on anesthetic postconditioning‑induced neuroprotection has not been investigated. The present study examined the effect of sevoflurane postconditioning on focal ischemic brain injury in diet‑induced obesity. Sprague‑Dawley rats were fed a high‑fat diet (HF; 45% kcal as fat) for 12 weeks to develop obesity syndrome. Rats fed a low‑fat diet (LF; 10% kcal as fat) served as controls. The HF or LF‑fed rats were subjected to focal cerebral ischemia for 60 min, followed by 24 h of reperfusion. Postconditioning was performed by exposure to sevoflurane for 15 min immediately at the onset of reperfusion. The involvement of the mitochondrial KATP (mitoKATP) channel was analyzed by the administration of a selective inhibitor of 5‑hydroxydecanoate (5‑HD) prior to sevoflurane postconditioning or by administration of diazoxide (DZX), a mitoKATP channel opener, instead of sevoflurane. The cerebral infarct volume, neurological score and motor coordination were evaluated 24 h after reperfusion. The HF‑fed rats had larger infarct volumes, and lower neurological scores than the LF‑fed rats and also failed to respond to neuroprotection by sevoflurane or DZX. By contrast, sevoflurane and DZX reduced the infarct volumes and improved the neurological scores and motor coordination in the LF‑fed rats. Pretreatment with 5‑HD inhibited sevoflurane‑induced neuroprotection in the LF‑fed rats, whereas it had no effect in the HF‑fed rats. Molecular studies demonstrated that the expression of Kir6.2, a significant mitoKATP channel component, was reduced in the brains of the HF‑fed rats compared with the LF‑fed rats. The results of this study indicate that diet‑induced obesity eliminates the ability of anesthetic sevoflurane postconditioning to protect the brain against cerebral ischemic neuronal injury, most likely due to an impaired brain

Beneficial effect of agmatine on brain apoptosis, astrogliosis, and edema after rat transient cerebral ischemia

PubMed Central

2010-01-01

Background Although agmatine therapy in a mouse model of transient focal cerebral ischemia is highly protective against neurological injury, the mechanisms underlying the protective effects of agmatine are not fully elucidated. This study aimed to investigate the effects of agmatine on brain apoptosis, astrogliosis and edema in the rats with transient cerebral ischemia. Methods Following surgical induction of middle cerebral artery occlusion (MCAO) for 90 min, agmatine (100 mg/kg, i.p.) was injected 5 min after beginning of reperfusion and again once daily for the next 3 post-operative days. Four days after reperfusion, both motor and proprioception functions were assessed and then all rats were sacrificed for determination of brain infarct volume (2, 3, 5-triphenyltetrazolium chloride staining), apoptosis (TUNEL staining), edema (both cerebral water content and amounts of aquaporin-4 positive cells), gliosis (glial fibrillary acidic protein [GFAP]-positive cells), and neurotoxicity (inducible nitric oxide synthase [iNOS] expression). Results The results showed that agmatine treatment was found to accelerate recovery of motor (from 55 degrees to 62 degrees) and proprioception (from 54% maximal possible effect to 10% maximal possible effect) deficits and to prevent brain infarction (from 370 mm3 to 50 mm3), gliosis (from 80 GFAP-positive cells to 30 GFAP-positive cells), edema (cerebral water contents decreased from 82.5% to 79.4%; AQP4 positive cells decreased from 140 to 84 per section), apoptosis (neuronal apoptotic cells decreased from 100 to 20 per section), and neurotoxicity (iNOS expression cells decreased from 64 to 7 per section) during MCAO ischemic injury in rats. Conclusions The data suggest that agmatine may improve outcomes of transient cerebral ischemia in rats by reducing brain apoptosis, astrogliosis and edema. PMID:20815926

Acute Hyperglycemia Does Not Affect Brain Swelling or Infarction Volume After Middle Cerebral Artery Occlusion in Rats.

PubMed

McBride, Devin W; Matei, Nathanael; Câmara, Justin R; Louis, Jean-Sébastien; Oudin, Guillaume; Walker, Corentin; Adam, Loic; Liang, Xiping; Hu, Qin; Tang, Jiping; Zhang, John H

2016-01-01

Stroke disproportionally affects diabetic and hyperglycemic patients with increased incidence and is associated with higher morbidity and mortality due to brain swelling. In this study, the intraluminal suture middle cerebral artery occlusion (MCAO) model was used to examine the effects of blood glucose on brain swelling and infarct volume in acutely hyperglycemic rats and normo-glycemic controls. Fifty-four rats were distributed into normo-glycemic sham surgery, hyperglycemic sham surgery, normo-glycemic MCAO, and hyperglycemic MCAO. To induce hyperglycemia, 15 min before MCAO surgery, animals were injected with 50 % dextrose. Animals were subjected to 90 min of MCAO and sacrificed 24 h after reperfusion for hemispheric brain swelling and infarct volume calculations using standard equations. While normo-glycemic and hyperglycemic animals after MCAO presented with significantly higher brain swelling and larger infarcts than their respective controls, no statistical difference was observed for either brain swelling or infarct volume between normo-glycemic shams and hyperglycemic shams or normo-glycemic MCAO animals and hyperglycemic MCAO animals. The findings of this study suggest that blood glucose does not have any significant effect on hemispheric brain swelling or infarct volume after MCAO in rats.

No effect of ablation of surfactant protein-D on acute cerebral infarction in mice.

PubMed

Lambertsen, Kate L; Østergaard, Kamilla; Clausen, Bettina H; Hansen, Søren; Stenvang, Jan; Thorsen, Stine B; Meldgaard, Michael; Kristensen, Bjarne W; Hansen, Pernille B; Sorensen, Grith L; Finsen, Bente

2014-07-19

Crosstalk between the immune system in the brain and the periphery may contribute to the long-term outcome both in experimental and clinical stroke. Although, the immune defense collectin surfactant protein-D (SP-D) is best known for its role in pulmonary innate immunity, SP-D is also known to be involved in extrapulmonary modulation of inflammation in mice. We investigated whether SP-D affected cerebral ischemic infarction and ischemia-induced inflammatory responses in mice. The effect of SP-D was studied by comparing the size of ischemic infarction and the inflammatory and astroglial responses in SP-D knock out (KO) and wild type (WT) mice subjected to permanent middle cerebral artery occlusion. SP-D mRNA production was assessed in isolated cerebral arteries and in the whole brain by PCR, and SP-D protein in normal appearing and ischemic human brain by immunohistochemistry. Changes in plasma SP-D and TNF were assessed by ELISA and proximity ligation assay, respectively. Infarct volumetric analysis showed that ablation of SP-D had no effect on ischemic infarction one and five days after induction of ischemia. Further, ablation of SP-D had no effect on the ischemia-induced increase in TNF mRNA production one day after induction of ischemia; however the TNF response to the ischemic insult was affected at five days. SP-D mRNA was not detected in parenchymal brain cells in either naïve mice or in mice subjected to focal cerebral ischemia. However, SP-D mRNA was detected in middle cerebral artery cells in WT mice and SP-D protein in vascular cells both in normal appearing and ischemic human brain tissue. Measurements of the levels of SP-D and TNF in plasma in mice suggested that levels were unaffected by the ischemic insult. Microglial-leukocyte and astroglial responses were comparable in SP-D KO and WT mice. SP-D synthesis in middle cerebral artery cells is consistent with SP-D conceivably leaking into the infarcted area and affecting local cytokine production

Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia.

PubMed

Pérez-Mato, M; Ramos-Cabrer, P; Sobrino, T; Blanco, M; Ruban, A; Mirelman, D; Menendez, P; Castillo, J; Campos, F

2014-01-09

Blood glutamate scavenging is a novel and attractive protecting strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. Glutamate oxaloacetate transaminase 1 (GOT1) activation by means of oxaloacetate administration has been used to reduce the glutamate concentration in the blood. However, the protective effect of the administration of the recombinant GOT1 (rGOT1) enzyme has not been yet addressed in cerebral ischemia. The aim of this study was to analyze the protective effect of an effective dose of oxaloacetate and the human rGOT1 alone and in combination with a non-effective dose of oxaloacetate in an animal model of ischemic stroke. Sixty rats were subjected to a transient middle cerebral artery occlusion (MCAO). Infarct volumes were assessed by magnetic resonance imaging (MRI) before treatment administration, and 24 h and 7 days after MCAO. Brain glutamate levels were determined by in vivo MR spectroscopy (MRS) during artery occlusion (80 min) and reperfusion (180 min). GOT activity and serum glutamate concentration were analyzed during the occlusion and reperfusion period. Somatosensory test was performed at baseline and 7 days after MCAO. The three treatments tested induced a reduction in serum and brain glutamate levels, resulting in a reduction in infarct volume and sensorimotor deficit. Protective effect of rGOT1 supplemented with oxaloacetate at 7 days persists even when treatment was delayed until at least 2 h after onset of ischemia. In conclusion, our findings indicate that the combination of human rGOT1 with low doses of oxaloacetate seems to be a successful approach for stroke treatment.

Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia

PubMed Central

Pérez-Mato, M; Ramos-Cabrer, P; Sobrino, T; Blanco, M; Ruban, A; Mirelman, D; Menendez, P; Castillo, J; Campos, F

2014-01-01

Blood glutamate scavenging is a novel and attractive protecting strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. Glutamate oxaloacetate transaminase 1 (GOT1) activation by means of oxaloacetate administration has been used to reduce the glutamate concentration in the blood. However, the protective effect of the administration of the recombinant GOT1 (rGOT1) enzyme has not been yet addressed in cerebral ischemia. The aim of this study was to analyze the protective effect of an effective dose of oxaloacetate and the human rGOT1 alone and in combination with a non-effective dose of oxaloacetate in an animal model of ischemic stroke. Sixty rats were subjected to a transient middle cerebral artery occlusion (MCAO). Infarct volumes were assessed by magnetic resonance imaging (MRI) before treatment administration, and 24 h and 7 days after MCAO. Brain glutamate levels were determined by in vivo MR spectroscopy (MRS) during artery occlusion (80 min) and reperfusion (180 min). GOT activity and serum glutamate concentration were analyzed during the occlusion and reperfusion period. Somatosensory test was performed at baseline and 7 days after MCAO. The three treatments tested induced a reduction in serum and brain glutamate levels, resulting in a reduction in infarct volume and sensorimotor deficit. Protective effect of rGOT1 supplemented with oxaloacetate at 7 days persists even when treatment was delayed until at least 2 h after onset of ischemia. In conclusion, our findings indicate that the combination of human rGOT1 with low doses of oxaloacetate seems to be a successful approach for stroke treatment PMID:24407245

Magnetic resonance lactate and lipid signals in rat brain after middle cerebral artery occlusion model

PubMed Central

Harada, Kuniaki; Honmou, Osamu; Liu, He; Bando, Michio; Houkin, Kiyohiro; Kocsis, Jeffery D.

2008-01-01

Proton magnetic resonance spectroscopy (1-H MRS) has revealed changes of metabolites in acute cerebral infarction. Although the drastic changes of lactate and N-acetyl-aspartate have been reported to be useful indicators of the ischemic damage in both humans and experimental animals, lipid signals are also detected by the short echo time sequence 1–5 days after ischemia. The objective of this study was to find a novel technique to isolate lactate signals from lipid signals in the ischemic brain. First, MRS was used to study the lipid and lactate components of a spherical phantom in vitro, and parameters were established to separate these components in vitro. Then, MR measurements were obtained from the brains of middle cerebral artery occlusion rats. All MR measurements were performed using a 7-T (300 MHz), 18.3-cm-bore superconducting magnet (Oxford Magnet Technologies) interfaced to a Unity INOVA Imaging System (Varian Technologies). T2-weighted images were obtained from a 1.0-mm-thick coronal section using a 3-cm field of view. It is well known that lipid has a shorter and lactate a longer T2 relaxation time. These distinct magnetic characteristics allowed us to separate the lactate signal from the lipid signal. Thus, adjustment of the echo time is essential to analyze the metabolites in acute cerebral infarction, which may be useful in both the clinic and laboratory. PMID:17196558

Upregulation of Fibronectin and the α5β1 and αvβ3 Integrins on Blood Vessels within the Cerebral Ischemic Penumbra

PubMed Central

Li, Longxuan; Liu, Fudong; Welser-Alves, Jennifer V.; McCullough, Louise D.; Milner, Richard

2012-01-01

Following focal cerebral ischemia, blood vessels in the ischemic border, or penumbra, launch an angiogenic response. In light of the critical role for fibronectin in angiogenesis, and the observation that fibronectin and its integrin receptors are strongly upregulated on angiogenic vessels in the hypoxic CNS, the aim of this study was to establish whether angiogenic vessels in the ischemic CNS also show this response. Focal cerebral ischemia was established in C57/Bl6 mice by middle cerebral artery occlusion (MCA:O), and brain tissue analyzed seven days following re-perfusion, a time at which angiogenesis is ongoing. Within the ischemic core, immunofluorescent (IF) studies demonstrated vascular expression of MECA-32, a marker of leaky cerebral vessels, and vascular breakdown, defined by loss of staining for the endothelial marker, CD31, and the vascular adhesion molecules, laminin, dystroglycan and α6 integrin. Within the ischemic penumbra, dual-IF with CD31 and Ki67 revealed the presence of proliferating endothelial cells, indicating ongoing angiogenesis. Significantly, vessels in the ischemic penumbra showed strong upregulation of fibronectin and the fibronectin receptors, α5β1 and αvβ3 integrins. Taken together with our recent finding that the α5β1 integrin plays an important role in promoting cerebral angiogenesis in response to hypoxia, these results suggest that stimulation of the fibronectin-α5β1 integrin signalling pathway may provide a novel approach to amplifying the intrinsic angiogenic response to cerebral ischemia. PMID:22056225

A novel atherothrombotic model of ischemic stroke induced by injection of collagen into the cerebral vasculature

PubMed Central

Schunke, Kathryn J.; Toung, Thomas K.; Zhang, Jian; Pathak, Arvind P.; Xu, Jiadi; Zhang, Jiangyang; Koehler, Raymond C.; Faraday, Nauder

2017-01-01

Background Most ischemic strokes in humans are caused by ruptured arterial atheroma, which activate platelets and produce thrombi that occlude cerebral vessels. Methods To simulate these events, we threaded a catheter through the internal carotid artery toward the middle cerebral artery (MCA) orifice and injected collagen directly into the cerebral circulation of male C57Bl/6 mice and Wistar rats. Results Laser-Doppler flowmetry demonstrated reductions in cerebral blood flow (CBF) of ~80% in mice and ~60% in rats. CBF spontaneously increased but remained depressed after catheter withdrawal. Magnetic resonance imaging showed that ipsilateral CBF was reduced at 3 h after collagen injection and markedly improved at 48 h. Micro-computed tomography revealed reduced blood vessel density in the ipsilateral MCA territory at 3 h. Gross examination of excised brains revealed thrombi within ipsilateral cerebral arteries at 3 h, but not 24 h, after collagen injection. Immunofluorescence microscopy confirmed that platelets and fibrinogen/fibrin were major components of these thrombi at both macrovascular and microvascular levels. Cerebral infarcts comprising ~30% of hemispheric volume and neurobehavioral deficits were observed 48 h after ischemic injury in both mice and rats. Comparison with existing methods Collagen injection caused brain injury that was similar in magnitude and variability to mechanical MCA occlusion or injection of a pre-formed clot; however, alterations in CBF and the mechanism of vascular occlusion were more consistent with clinical ischemic stroke. Conclusion This novel rodent model of ischemic stroke has pathophysiologic characteristics consistent with clinical atherothrombotic stroke, is technically feasible, and creates reproducible brain injury. PMID:25314906

Sodium phenylbutyrate ameliorates focal cerebral ischemic/reperfusion injury associated with comorbid type 2 diabetes by reducing endoplasmic reticulum stress and DNA fragmentation.

PubMed

Srinivasan, Krishnamoorthy; Sharma, Shyam S

2011-11-20

Endoplasmic reticulum (ER) stress has been postulated to play a crucial role in the pathophysiology of cerebral ischemic/reperfusion (I/R) injury and diabetes. Diabetes is a major risk factor and also common amongst the people who suffer from stroke. In this study, we have investigated the neuroprotective potential of sodium 4-phenylbutyrate (SPB; 30-300mg/kg), a chemical chaperone by targeting ER stress in a rat model of transient focal cerebral ischemia associated with comorbid type 2 diabetes. Intraperitoneal treatment with SPB (100 and 300mg/kg) significantly ameliorated brain I/R damage as evidenced by reduction in cerebral infarct and edema volume. It also significantly improved the functional recovery of various neurobehavioral impairments (neurological deficit score, grip strength and rota rod) evoked by I/R compared with vehicle-treatment. Further, SPB (100mg/kg) significantly reduced the DNA fragmentation as shown by prominent reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells. This effect was observed concomitantly with significant attenuation in upregulation of 78kDa glucose regulated protein (GRP78), CCAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153) and activation of caspase-12, specific markers of ER stress/apoptosis. The neuroprotection observed with SPB was independent of its effect on cerebral blood flow and blood glucose. In conclusion, this study demonstrates the neuroprotective effect of SPB owing to amelioration of ER stress and DNA fragmentation. It also suggest that targeting ER stress might offer a promising therapeutic approach and benefits against ischemic stroke associated with comorbid type 2 diabetes. Copyright © 2011 Elsevier B.V. All rights reserved.

Acute lipophilicity-dependent effect of intravascular simvastatin in the early phase of focal cerebral ischemia.

PubMed

Beretta, S; Pastori, C; Sala, G; Piazza, F; Ferrarese, C; Cattalini, A; de Curtis, M; Librizzi, L

2011-05-01

The acute effects of simvastatin lactone (lipophilic) and simvastatin acid (hydrophilic) on transient focal ischemia were assessed using the isolated guinea pig brain maintained in vitro by arterial perfusion. This new model of cerebral ischemia allows the assessment of the very early phase of the ischemic process, with the functional preservation of the vascular and neuronal compartments and the blood-brain barrier (bbb). The middle cerebral artery was transiently tied for 30 min followed by reperfusion for 60 min. Statins (nanomolar doses) were administered by intravascular continuous infusion starting 60 min before ischemia induction. Brain cortical activity and arterial vascular tone were continuously recorded. At the end of the experiment immunoreactivity for microtubule-associated protein 2 (MAP-2), expression of survival kinases (ERK and Akt) and total anti-oxidant capacity were assayed. Brains treated with simvastatin lactone showed i) reduced amplitude and delayed onset of ischemic depressions, ii) preservation of MAP-2 immunoreactivity, iii) activation of ERK signaling in the ischemic hemisphere and iv) increase in whole-brain anti-oxidant capacity. Treatment with the bbb-impermeable simvastatin acid was ineffective on the above-mentioned parameters. Vascular resistance recordings and Akt signaling were unchanged by any statin treatment. Our findings suggest that intravascular-delivered simvastatin exerts an acute lipophilicity-dependent protective effect in the early phase of cerebral ischemia. Copyright © 2011 Elsevier Ltd. All rights reserved.

Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism.

PubMed

Riveline, D; Zamir, E; Balaban, N Q; Schwarz, U S; Ishizaki, T; Narumiya, S; Kam, Z; Geiger, B; Bershadsky, A D

2001-06-11

The transition of cell-matrix adhesions from the initial punctate focal complexes into the mature elongated form, known as focal contacts, requires GTPase Rho activity. In particular, activation of myosin II-driven contractility by a Rho target known as Rho-associated kinase (ROCK) was shown to be essential for focal contact formation. To dissect the mechanism of Rho-dependent induction of focal contacts and to elucidate the role of cell contractility, we applied mechanical force to vinculin-containing dot-like adhesions at the cell edge using a micropipette. Local centripetal pulling led to local assembly and elongation of these structures and to their development into streak-like focal contacts, as revealed by the dynamics of green fluorescent protein-tagged vinculin or paxillin and interference reflection microscopy. Inhibition of Rho activity by C3 transferase suppressed this force-induced focal contact formation. However, constitutively active mutants of another Rho target, the formin homology protein mDia1 (Watanabe, N., T. Kato, A. Fujita, T. Ishizaki, and S. Narumiya. 1999. Nat. Cell Biol. 1:136-143), were sufficient to restore force-induced focal contact formation in C3 transferase-treated cells. Force-induced formation of the focal contacts still occurred in cells subjected to myosin II and ROCK inhibition. Thus, as long as mDia1 is active, external tension force bypasses the requirement for ROCK-mediated myosin II contractility in the induction of focal contacts. Our experiments show that integrin-containing focal complexes behave as individual mechanosensors exhibiting directional assembly in response to local force.

Global Cerebral Ischemia: Synaptic and Cognitive Dysfunction

PubMed Central

Neumann, Jake T.; Cohan, Charles H.; Dave, Kunjan R.; Wright, Clinton B.; Perez-Pinzon, Miguel A.

2018-01-01

Cardiopulmonary arrest is one of the leading causes of death and disability, primarily occurring in the aged population. Numerous global cerebral ischemia animal models induce neuronal damage similar to cardiac arrest. These global cerebral ischemia models range from vessel occlusion to total cessation of cardiac function, both of which have allowed for the investigation of this multifaceted disease and detection of numerous agents that are neuroprotective. Synapses endure a variety of alterations after global cerebral ischemia from the resulting excitotoxicity and have been a major target for neuroprotection; however, neuroprotective agents have proven unsuccessful in clinical trials, as neurological outcomes have not displayed significant improvements in patients. A majority of these neuroprotective agents have specific neuronal targets, where the success of future neuroprotective agents may depend on non-specific targets and numerous cognitive improvements. This review focuses on the different models of global cerebral ischemia, neuronal synaptic alterations, synaptic neuroprotection and behavioral tests that can be used to determine deficits in cognitive function after global cerebral ischemia. PMID:23170794

Ebselen attenuates oxidative DNA damage and enhances its repair activity in the thalamus after focal cortical infarction in hypertensive rats.

PubMed

He, Meixia; Xing, Shihui; Yang, Bo; Zhao, Liqun; Hua, Haiying; Liang, Zhijian; Zhou, Wenliang; Zeng, Jinsheng; Pei, Zhong

2007-11-21

Oxidative DNA damage has been proposed to be a major contributor to focal cerebral ischemic injury. However, little is known about the role of oxidative DNA damage in remote damage secondary to the primary infarction. In the present study, we investigated oxidative damage within the ventroposterior nucleus (VPN) after distal middle cerebral artery occlusion (MCAO) in hypertensive rats. We also examined the possible protective effect of ebselen, one glutathione peroxidase mimic, on delayed degeneration in the VPN after distal MCAO. Neuronal damage in the ipsilateral VPN was examined by Nissl staining. Oxidative DNA damage and base repair enzyme activity were assessed by analyzing immunoreactivity of 8-hydroxy-2'-deoxyguanosine (8-ohdG) and 8-oxoguanine DNA glycosylase (OGG1), respectively. The number of intact neurons in the ipsilateral VPN decreased by 52% compared to the contralateral side in ischemia group 2 weeks after distal cerebral cortical infarction. The immunoreactivity of 8-ohdG significantly increased while OGG1 immunoreactivity significantly decreased in the ipsilateral VPN 2 weeks after distal cortical infarction (all p<0.01). Compared with vehicle treatment, ebselen significantly attenuated the neuron loss, ameliorated ischemia-induced increase in 8-ohdG level as well as decrease in OGG1 level within the ipsilateral VPN (all p<0.01). OGG1 was further demonstrated to mainly express in neurons. These findings strongly suggest that oxidative DNA damage may be involved in the delayed neuronal death in the VPN region following distal MCAO. Furthermore, ebselen protects against the delayed damage in the VPN when given at 24 h following distal MCAO.

Uric acid promotes oxidative stress and enhances vascular endothelial cell apoptosis in rats with middle cerebral artery occlusion.

PubMed

Song, Chengfu; Zhao, Xiangdong

2018-05-15

In patients with cerebral infarction (CI), elevated serum uric acid (UA) level may exacerbate the occurrence and development of carotid atherosclerosis (AS). Our study intended to explore the underlying mechanism. We enrolled 86 patients with CI, and divided them into four groups: Non-AS, AS-mild, AS-moderate, and AS-severe groups; the levels of UA and oxidative stress-related factors in serum were detected. The middle cerebral artery occlusion (MCAO) model was used to stimulate CI in rats, and different doses of UA were administrated. The levels of oxidative stress-related factors in serum were detected. Hematoxylin & eosin (H&E) staining was used to observe the morphological alterations, and the apoptotic cell death detection kit was used to detect apoptotic cells. Increased UA concentration and enhanced oxidative stress were found in AS patients. H&E staining results showed that UA treatment exacerbated morphological damage in rats with MCAO, promoted oxidative stress, and enhanced vascular endothelial cell apoptosis in rats with MCAO. © 2017 The Author(s).

Visualization of cell death in mice with focal cerebral ischemia using fluorescent annexin A5, propidium iodide, and TUNEL staining

PubMed Central

Bahmani, Peyman; Schellenberger, Eyk; Klohs, Jan; Steinbrink, Jens; Cordell, Ryan; Zille, Marietta; Müller, Jochen; Harhausen, Denise; Hofstra, Leo; Reutelingsperger, Chris; Farr, Tracy Deanne; Dirnagl, Ulrich; Wunder, Andreas

2011-01-01

To monitor stroke-induced brain damage and assess neuroprotective therapies, specific imaging of cell death after cerebral ischemia in a noninvasive manner is highly desirable. Annexin A5 has been suggested as a marker for imaging cell death under various disease conditions including stroke. In this study, C57BL6/N mice received middle cerebral artery occlusion (MCAO) and were injected intravenously with either active or inactive Cy5.5-annexin A5 48 hours after reperfusion. Some mice also received propidium iodide (PI), a cell integrity marker. Only in mice receiving active Cy5.5-annexin A5 were fluorescence intensities significantly higher over the hemisphere ipsilateral to MCAO than on the contralateral side. This was detected noninvasively and ex vivo 4 and 8 hours after injection. The majority of cells positive for fluorescent annexin A5 were also positive for PI and fragmented DNA as detected by terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate-biotin nick end labeling (TUNEL) staining. This study demonstrates the high specificity of annexin A5 for visualization of cell death in a mouse model of stroke. To our knowledge, this is the first study to compare the distribution of injected active and inactive annexin A5, PI, and TUNEL staining. It provides important information on the experimental and potential clinical applications of annexin A5-based imaging agents in stroke. PMID:21245871

Protective effects of beef decoction rich in carnosine on cerebral ischemia injury by permanent middle cerebral artery occlusion in rats

PubMed Central

Wang, Ai-Hong; Ma, Qian; Wang, Xin; Xu, Gui-Hua

2018-01-01

Inflammation has a role in the cerebral injury induced by ischemia and the present study aimed to determine the mechanism of the protective effect of beef decoction (BD) with carnosine against it. A rat model of permanent middle cerebral artery occlusion was established using a suture method in the vehicle and each of the BD groups. In experiment 1, 72 Sprague Dawley (SD) rats were randomly divided into three groups: Sham, vehicle and BD-treated group. Rats in the BD group were given 600 mg/kg BD by oral gavage for 1, 3 and 7 days. The sham and vehicle group rats received an equivalent amount of normal saline. In experiment 2, 60 SD rats were randomly divided into six groups: Sham-operated I, sham-operated II, vehicle, low-dose BD, medium-dose BD and high-dose BD group. Rats in the low-, medium- and high-dose BD groups were given BD at the dose of 200, 400 and 600 mg/kg, respectively, by oral gavage for 7 days. Rats in the sham-operated II group were given 600 mg/kg BD. Rats in the sham-operated I group and vehicle group were given the same volume of normal saline by oral gavage. The body weight, neurological deficits and infarct volume were recorded at 1, 3 and 7 days after the operation. Furthermore, the effect of different doses of BD on interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin-4 (IL-4) levels in peripheral blood was measured at 7 days. BD-treated rats showed less neurological deficits and a smaller infarct volume at 7 days. BD at 400 and 600 mg/kg significantly decreased the infarct volume in rats. At 600 mg/kg BD, a decline in IL-6, TNF-α, IFN-γ and an increase in IL-4 expression was observed in the BD groups, while no difference in body weight and neurological dysfunction was detected. In conclusion, BD is a neuroprotective agent that may be used as a supplement treatment of ischemic stroke. PMID:29399121

Protective effects of beef decoction rich in carnosine on cerebral ischemia injury by permanent middle cerebral artery occlusion in rats.

PubMed

Wang, Ai-Hong; Ma, Qian; Wang, Xin; Xu, Gui-Hua

2018-02-01

Inflammation has a role in the cerebral injury induced by ischemia and the present study aimed to determine the mechanism of the protective effect of beef decoction (BD) with carnosine against it. A rat model of permanent middle cerebral artery occlusion was established using a suture method in the vehicle and each of the BD groups. In experiment 1, 72 Sprague Dawley (SD) rats were randomly divided into three groups: Sham, vehicle and BD-treated group. Rats in the BD group were given 600 mg/kg BD by oral gavage for 1, 3 and 7 days. The sham and vehicle group rats received an equivalent amount of normal saline. In experiment 2, 60 SD rats were randomly divided into six groups: Sham-operated I, sham-operated II, vehicle, low-dose BD, medium-dose BD and high-dose BD group. Rats in the low-, medium- and high-dose BD groups were given BD at the dose of 200, 400 and 600 mg/kg, respectively, by oral gavage for 7 days. Rats in the sham-operated II group were given 600 mg/kg BD. Rats in the sham-operated I group and vehicle group were given the same volume of normal saline by oral gavage. The body weight, neurological deficits and infarct volume were recorded at 1, 3 and 7 days after the operation. Furthermore, the effect of different doses of BD on interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin-4 (IL-4) levels in peripheral blood was measured at 7 days. BD-treated rats showed less neurological deficits and a smaller infarct volume at 7 days. BD at 400 and 600 mg/kg significantly decreased the infarct volume in rats. At 600 mg/kg BD, a decline in IL-6, TNF-α, IFN-γ and an increase in IL-4 expression was observed in the BD groups, while no difference in body weight and neurological dysfunction was detected. In conclusion, BD is a neuroprotective agent that may be used as a supplement treatment of ischemic stroke.

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.

Focal brain lesions induced with ultraviolet irradiation.

PubMed

Nakata, Mariko; Nagasaka, Kazuaki; Shimoda, Masayuki; Takashima, Ichiro; Yamamoto, Shinya

2018-05-22

Lesion and inactivation methods have played important roles in neuroscience studies. However, traditional techniques for creating a brain lesion are highly invasive, and control of lesion size and shape using these techniques is not easy. Here, we developed a novel method for creating a lesion on the cortical surface via 365 nm ultraviolet (UV) irradiation without breaking the dura mater. We demonstrated that 2.0 mWh UV irradiation, but not the same amount of non-UV light irradiation, induced an inverted bell-shaped lesion with neuronal loss and accumulation of glial cells. Moreover, the volume of the UV irradiation-induced lesion depended on the UV light exposure amount. We further succeeded in visualizing the lesioned site in a living animal using magnetic resonance imaging (MRI). Importantly, we also observed using an optical imaging technique that the spread of neural activation evoked by adjacent cortical stimulation disappeared only at the UV-irradiated site. In summary, UV irradiation can induce a focal brain lesion with a stable shape and size in a less invasive manner than traditional lesioning methods. This method is applicable to not only neuroscientific lesion experiments but also studies of the focal brain injury recovery process.

Occlusion therapy of unilateral amblyopia with botulinum toxin induced ptosis.

PubMed

Halkiadakis, Ioannis; Iliaki, Olga; Kalyvianaki, Maria I; Tsilimbaris, Miltiadis K

2007-01-01

In order to evaluate the role of botulinum toxin induced ptosis as an occlusion method to treat unilateral deep strabismic amblyopia in two uncooperative children, we injected 0.2 ml of diluted botulinum toxin in the levator palpaebrae; low sedation was necessary in one of the two children. In both cases a marked ptosis was achieved, which lasted about four weeks and then gradually resolved completely. The visual acuity of the ablyopic eye increased in both children, making patching easy thereafter. One child developed amblyopia in the injected eye, which was handled successfully using part-time occlusion. No other side effects were noted. Whether this new method could be a simple, safe and effective alternative method of occlusion for the treatment of deep amblyopia in uncooperative children needs to be proven with a larger series of children.

Focal BOLD-fMRI changes in bicuculline-induced tonic-clonic seizures in the rat

PubMed Central

DeSalvo, Matthew N.; Schridde, Ulrich; Mishra, Asht M.; Motelow, Joshua E.; Purcaro, Michael J.; Danielson, Nathan; Bai, Xiaoxiao; Hyder, Fahmeed; Blumenfeld, Hal

2010-01-01

Generalized tonic-clonic seizures cause widespread physiological changes throughout the cerebral cortex and subcortical structures in the brain. Using combined blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at 9.4 T and electroencephalography (EEG) these changes can be characterized with high spatiotemporal resolution. We studied BOLD changes in anesthetized Wistar rats during bicuculline-induced tonic-clonic seizures. Bicuculline, a GABAA receptor antagonist, was injected systemically and seizure activity was observed on EEG as high amplitude, high-frequency polyspike discharges followed by clonic paroxysmal activity of lower frequency, with mean electrographic seizure duration of 349 s. Our aim was to characterize the spatial localization, direction, and timing of BOLD signal changes during the pre-ictal, ictal and post-ictal periods. Group analysis was performed across seizures using paired t-maps of BOLD signal superimposed on high resolution anatomical images. Regional analysis was then performed using volumes of interest to quantify BOLD timecourses. In the pre-ictal period we found focal BOLD increases in specific areas of somatosensory cortex (S1, S2) and thalamus several seconds before seizure onset. During seizures we observed BOLD increases in cortex, brainstem and thalamus and BOLD decreases in the hippocampus. The largest ictal BOLD increases remained in the focal regions of somatosensory cortex showing pre-ictal increases. During the post-ictal period we observed widespread BOLD decreases. These findings support a model in which “generalized” tonic-clonic seizures begin with focal changes before electrographic seizure onset, which progress to non-uniform changes during seizures, possibly shedding light on the etiology and pathophysiology of similar seizures in humans. PMID:20079442

[Changes in DNA repair enzymes in rat ventroposterior nucleus of the thalamus after cerebral cortex infarction].

PubMed

He, Mei-Xia; Zeng, Jin-Sheng; Hua, Hai-Ying; Xing, Shi-Hui; Ba, Yun-Peng

2010-10-01

To investigate the damage within the ventroposterior nucleus (VPN) of the thalamus after focal cortical infarction and its mechanism, and explore the effect of ebselen on the oxidative damage after cerebral cortex infarction in hypertensive rats. Middle cerebral artery occlusion (MCAO) was induced in stroke-prone renovascular hypertensive rats (RHRSP), and the rats were divided into four groups by table of random number: sham operation group, model group, vehicle group and ebselen group, each group consisted of 8 rats. In animals subjected to sham surgery the middle cerebral artery was exposed only. Ebselen (5 ml/kg) or vehicle (a mixed solvent consisting of 0.5% carboxymethyl cellulose and 0.02% Tween 20, 5 ml/kg) was given by gastric gavage starting 24 hours after cerebral cortical infarction. Two weeks after the MCAO, the rats were sacrificed, and VPN from each group was sectioned and stained with hematoxylin-eosin (HE), and apurinic/apyrimidinic endonuclease (APE) and Escherichia coli MutY DNA glycosylase (MYH) were determined by immunohistochemistry. HE staining showed that ebselen ameliorated the VPN damage induced by ischemia. Immunohistochemical imaging analysis revealed a distinct nuclear staining of APE and nuclear and cytoplasm distribution of MYH in the entire region of the VPN. Compared with sham operation group, the number of APE and MYH positive cells decreased in model group and vehicle group (APE: 57.0±14.7, 49.4±12.5 vs. 101.0±13.6, MYH: 15.0±4.7, 10.4±2.5 vs. 56.0±13.2, all P<0.05). Compared with model group and vehicle group, the number of APE and MYH positive cells increased significantly in ebselen group (APE: 72.2±7.6 vs. 57.0±14.7, 49.4±12.5, MYH: 32.2±7.6 vs. 15.0±4.7, 10.4±2.5, all P<0.05); the difference of the number of APE and MYH positive cells between model group and vehicle group showed no statistical significance. After 2 weeks of MCAO, there is a marked decrease of APE and MYH in VPN; ebselen can obviously increase the

Revascularization experience and results in ischaemic cerebrovascular disease: Moyamoya disease and carotid occlusion.

PubMed

Arikan, Fuat; Rubiera, Marta; Serena, Joaquín; Rodríguez-Hernández, Ana; Gándara, Darío; Lorenzo-Bosquet, Carles; Tomasello, Alejandro; Chocrón, Ivette; Quintana-Corvalan, Maximiliano; Sahuquillo, Juan

2018-03-14

Cerebral revascularization techniques are an indispensable tool in the current armamentarium of vascular neurosurgeons. We present revascularization surgery experience and results in both moyamoya disease and occlusive cerebral ischaemia. Patients with ischaemic occlusive disease and moyamoya disease who underwent microsurgical revascularization between October 2014 and September 2017 were analysed. In the study period, 23 patients with occlusive ischaemic disease underwent microsurgical revascularization. Three patients presented with serious postoperative complications (2 intraparenchymal haemorrhages in the immediate postoperative period and one thrombosis of the femoral artery). All patients, except one, achieved normalization of the cerebral hemodynamic reserve (CHR) in the SPECT study. Twenty patients had a good neurological result, with no ischaemic recurrence of the revascularized territory. Among patients with moyamoya, 20 had moyamoya disease and 5 had moyamoya syndrome with unilateral involvement. Five patients were treated at paediatric age. Haemorrhagic onset occurred in 2 patients. The CHR study showed hemodynamic compromise in all patients. Cerebral SPECT at one year showed resolution of the hemodynamic failure in all patients. There have been 4 postoperative complications (acute subdural hematoma, two subdural collections and one dehiscence of the surgical wound). No patient presented with neurological worsening at 6 and 12months of follow-up. Cerebral revascularization through end-to-side anastomosis between the superficial temporal artery and a cortical branch of the middle cerebral artery is an indisputable technique in the treatment of moyamoya disease and possibly in a subgroup of patients with symptomatic occlusive ischaemic cerebrovascular disease. Copyright © 2018 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.

Cerebral collaterals and collateral therapeutics for acute ischemic stroke.

PubMed

Winship, Ian R

2015-04-01

Cerebral collaterals are vascular redundancies in the cerebral circulation that can partially maintain blood flow to ischemic tissue when primary conduits are blocked. After occlusion of a cerebral artery, anastomoses connecting the distal segments of the MCA with distal branches of the ACA and PCA (known as leptomeningeal or pial collaterals) allow for partially maintained blood flow in the ischemic penumbra and delay or prevent cell death. However, collateral circulation varies dramatically between individuals, and collateral extent is significant predictor of stroke severity and recanalization rate. Collateral therapeutics attempt to harness these vascular redundancies by enhancing blood flow through pial collaterals to reduce ischemia and brain damage after cerebral arterial occlusion. While therapies to enhance collateral flow remain relatively nascent neuroprotective strategies, experimental therapies including inhaled NO, transient suprarenal aortic occlusion, and electrical stimulation of the parasympathetic sphenopalatine ganglion show promise as collateral therapeutics with the potential to improve treatment of acute ischemic stroke. © 2014 John Wiley & Sons Ltd.

Angiotensin II effects on ischemic focal ventricular tachycardia are predominantly mediated through myocardial AT(2) receptor.

PubMed

Gopinathannair, Rakesh; Chaudhary, Ashok K; Xing, Dezhi; Ely, Debra; Zheng, Wei; Martins, James B

2009-11-01

Ischemic focal ventricular tachycardia (VT) occurs in animals and humans. Angiotensin-converting enzyme inhibitors and receptor blockers reduce sudden death in patients with ischemic heart disease. In our dog model of coronary artery occlusion (CAO), we tested the hypothesis that angiotensin II (AGII) will selectively promote focal VT and that the specific AT(2) blocker PD-123319 (PD), or AT(1) blocker losartan, will affect this VT. Anesthetized dogs (n = 90) underwent CAO, followed by three-dimensional activation mapping of inducible VT. Dogs without VT in 1-3 h after CAO received AGII, and those with VT received either PD or losartan. Focal endocardium excised from ischemic sites was studied in vitro with standard microelectrode. Of 33 dogs with no inducible VT, AGII infusion resulted in sustained VT of only focal Purkinje origin in 13 (39%) compared with 0 of 20 dogs with saline. Of 26 dogs with inducible VT at baseline, given PD, reinduction was blocked in 8 of 10 (P < 0.05) focal VT, but only 1 of 15 with reentry. In contrast, of 11 dogs given losartan, reinduction of either mechanism was not blocked. In vitro triggered activity in Purkinje was blocked by PD in 13 of 19 (P < 0.05), but not by losartan in 8. Also, triggered activity was promoted by AGII, losartan, or the combination in 9 of 12 tissues. AGII promotes only focal, mainly Purkinje ischemic VT. PD, but not losartan, preferentially blocked focal VT, which is likely due to triggered activity due to delayed afterdepolarizations in Purkinje.

Optimization of a therapeutic protocol for intravenous injection of human mesenchymal stem cells after cerebral ischemia in adult rats.

PubMed

Omori, Yoshinori; Honmou, Osamu; Harada, Kuniaki; Suzuki, Junpei; Houkin, Kiyohiro; Kocsis, Jeffery D

2008-10-21

The systemic injection of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has therapeutic benefits after cerebral artery occlusion in rats, and may have multiple therapeutic effects at various sites and times within the lesion as the cells respond to a particular pathological microenvironment. However, the comparative therapeutic benefits of multiple injections of hMSCs at different time points after cerebral artery occlusion in rats remain unclear. In this study, we induced middle cerebral artery occlusion (MCAO) in rats using intra-luminal vascular occlusion, and infused hMSCs intravenously at a single 6 h time point (low and high cell doses) and various multiple time points after MCAO. From MRI analyses lesion volume was reduced in all hMSC cell injection groups as compared to serum alone injections. However, the greatest therapeutic benefit was achieved following a single high cell dose injection at 6 h post-MCAO, rather than multiple lower cell infusions over multiple time points. Three-dimensional analysis of capillary vessels in the lesion indicated that the capillary volume was equally increased in all of the cell-injected groups. Thus, differences in functional outcome in the hMSC transplantation subgroups are not likely the result of differences in angiogenesis, but rather from differences in neuroprotective effects.

Cerebral Arterial Occlusion Did Not Promote the Prevalence of Cerebral Amyloid Angiopathy.

PubMed

Honda, Kazuhiro

2016-08-01

An impairment of amyloid-β (Aβ) clearance has been suggested in Alzheimer's disease. Perivascular drainage along cerebrovascular vessels is considered an important amyloid clearance pathway. This study examined the effect of reduced arterial pulsation that could cause an impairment in cerebral amyloid drainage on the prevalence of cortical microbleeds (CMBs), a surrogate marker for cerebral amyloid angiopathy (CAA). Patients who lost depiction of either side of the carotid artery or the middle cerebral artery on magnetic resonance angiography were studied. Those who showed acute cerebral infarction or a previous cortical cerebral infarction were excluded. The number of CMBs was counted on the occluded and non-occluded sides of the brain in each subject. The number of subjects who showed more CMBs on the occluded side of the brain was compared with the number of subjects who showed more CMBs on the non-occluded side of the brain. Twenty-eight patients were studied. The extent of lacunar infarction and white matter lesions was not different, irrespective of the occluded vessels or the distribution of CMBs. The prevalence of CMBs was not different between the occluded and non-occluded sides of the brain. In this cross-sectional study, reduction of arterial pulsation was not associated with a higher prevalence of CAA. Therefore, reduced arterial pulsation alone may not be enough to promote CAA.

[Study of neuron-protective effect and mechanism of neuregulin1β against cerebral ischemia reperfusion-induced injury in rats].

PubMed

Ji, Y Q; Zhang, R; Teng, L; Li, H Y; Guo, Y L

2017-07-18

Objective: Thecurrent study is to explore the neuron-protective mechanism of neuregulin1β (NRG1β) in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) through inhibiting the c-Jun phosphorylation. Methods: After 24 h of MCAO/R (referring to Longa's method), neurobehavioral function was measured by modified neurological severity score (mNSS) test; the cerebral infarction volume was detected by triphenyltetrazolium chloride (TTC) staining; the blood brain barrier (BBB) permeability was measured by Evans Blue (EB); the neuron morphology of brain tissue was observed by Nissl stain; the ultra-structures of the neurons were observed by transmission electron microscopy (TEM); the apoptotic neurons were counted by in situ cell death detection kit colocalized with NeuN; the expressions of phospho-c-Jun was determined by immunofluorescent labeling and Western blot analysis. Results: Compared with the sham-operation rats, the rats receiving MCAO/R showed increased mNSS (9.7±1.2), cerebral infarction volume (41.4±3.0)%, permeability of BBB, deformation of neurons, ischemia-induced apoptosis (0.63±0.04), and enhanced expression of phospho-c-Jun protein (0.90±0.07) (all P <0.05). Our data indicated that NRG1β attenuated neurologic deficits (6.4±0.9), decreased the cerebral infarction volume (10.4±0.5), reduced EB extravasation (1.55±0.13) and the deformation of neurons, protected the ultra-structure of neurons, blocked ischemia-induced apoptosis (0.23±0.02), through down-regulated phospho-c-Jun expression (0.40±0.03) in MCAO/R rats ( P <0.05). Conclusion: NRG1β exerts neuron-protective effects against ischemia reperfusion-induced injury in rats through inhibiting the c-Jun phosphorylation.

Focal cerebral ischemic tolerance and change in blood-brain barrier permeability after repetitive pure oxygen exposure preconditioning in a rodent model.

PubMed

Wang, Xi; Kang, Kai; Wang, Shiquan; Yao, Jianhua; Zhang, Xijing

2016-10-01

OBJECTIVE The goal of this study was to demonstrate that repetitive pure oxygen exposure preconditioning (O 2 PC) for 8 hours per day for 3 or 7 days, a practicable preconditioning for clinical use, is able to induce cerebral ischemic tolerance (IT) and further clarify the accompanying changes in the blood-brain barrier (BBB) that may be involved. METHODS A total of 68 adult male Sprague-Dawley rats and eight 1-day-old rat pups were used in this study. The adult rats were exposed to pure O 2 (38 rats) 8 hours a day for 3 or 7 days or to room air (in an identical setup) for 8 hours a day for 7 days as controls (30 rats). Arterial O 2 tension (PaO 2 ) was measured in 6 rats exposed to O 2 and 3 controls. Focal cerebral ischemia was elicited by middle cerebral artery occlusion (MCAO) in 37 rats, of which 21 had been exposed to pure O 2 for 3 or 7 days and 16 to room air for 7 days as controls. Neurological behavior was scored with the Garcia score in 15 MCAO rats, of which 10 had been exposed to pure O 2 for 3 or 7 days and 5 to room air for 7 days as controls, and cerebral infarct volumes were assessed with TTC (2,3,5-triphenyltetrazolium chloride) staining in 10 rats (5 from each group) after 7 days of exposure. Formamide-extraction method was used to detect leakage of Evans blue (EB) dye in 7 rats exposed to pure O 2 for 7 days and 7 exposed to room air for 7 days. Fluorescence microscopy was used to analyze the leaked EB in the nonischemic areas of 4 rats exposed to pure O 2 for 7 days and 4 exposed to room air for 7 days before MCAO and the brain of the rats that had not been subjected to MCAO. Astrocyte changes associated with O 2 PC were evaluated by means of fluorescence microscopy and electron microscopy in 14 rats that were exposed to the same O 2 or control conditions as the MCAO rats but without MCAO. Astrocytes were also obtained from 8 rat pups and cultured; levels of AQP4 and VEGF were detected by Western blot and ELISA in cells with and without O 2

Photoacoustic removal of occlusions from blood vessels

DOEpatents

Visuri, Steven R.; Da Silva, Luiz B.; Celliers, Peter M.; London, Richard A.; Maitland, IV, Duncan J.; Esch, Victor C.

2002-01-01

Partial or total occlusions of fluid passages within the human body are removed by positioning an array of optical fibers in the passage and directing treatment radiation pulses along the fibers, one at a time, to generate a shock wave and hydrodynamics flows that strike and emulsify the occlusions. A preferred application is the removal of blood clots (thrombin and embolic) from small cerebral vessels to reverse the effects of an ischemic stroke. The operating parameters and techniques are chosen to minimize the amount of heating of the fragile cerebral vessel walls occurring during this photo acoustic treatment. One such technique is the optical monitoring of the existence of hydrodynamics flow generating vapor bubbles when they are expected to occur and stopping the heat generating pulses propagated along an optical fiber that is not generating such bubbles.

Neuroprotective effect of antioxidants on ischaemia and reperfusion-induced cerebral injury.

PubMed

Gupta, Ram; Singh, Manjeet; Sharma, Ajay

2003-08-01

The present study is designed to investigate the effect of dietary flavanoid rutin, micronutrient selenium and garlic oil on ischaemia and reperfusion-induced cerebral injury. Global cerebral ischaemia was induced by occluding right and left common carotid arteries for 10min followed by reperfusion for 24h. Cerebral infarct size was estimated using triphenyltetrazolium chloride staining. Elevated plus maze was employed to estimate short-term memory. Degree of motor incoordination was evaluated using inclined beam-walking test and lateral push test. Mitochondrial thiobarbituric acid reactive substances (TBARS) assay was employed as an index of oxidative stress. Global cerebral ischaemia followed by reperfusion produced a significant impairment in short-term memory and motor coordination and produced a notable increase in mitochondrial TBARS. Administration of rutin and garlic oil before global cerebral ischaemia markedly reduced cerebral infarct size and attenuated impairment in short-term memory and motor coordination. Administration of sodium selenite either before or after global cerebral ischaemia markedly reduced cerebral infarct size and attenuated impairment in short-term memory and motor coordination. The protective effect of rutin, sodium selenite and garlic oil was accompanied by a marked decrease in mitochondrial TBARS. On the basis of these results, it may be suggested that rutin and garlic oil administrated before cerebral ischaemia may scavenge reactive oxygen species and consequently attenuate global cerebral ischaemia and reperfusion-induced cerebral injury. Sodium selenite administrated before and after cerebral ischaemia may be neuroprotective due to its antioxidant effect.

Neuroprotective effect of minocycline on cognitive impairments induced by transient cerebral ischemia/reperfusion through its anti-inflammatory and anti-oxidant properties in male rat.

PubMed

Naderi, Yazdan; Sabetkasaei, Masoumeh; Parvardeh, Siavash; Zanjani, Taraneh Moini

2017-05-01

Memory deficit is the most visible symptom of cerebral ischemia that is associated with loss of pyramidal cells in CA1 region of the hippocampus. Oxidative stress and inflammation may be involved in the pathogenesis of ischemia/reperfusion (I/R) damage. Minocycline, a semi-synthetic tetracycline derived antibiotic, has anti-inflammatory and antioxidant properties. We evaluated the neuroprotective effect of minocycline on memory deficit induced by cerebral I/R in rat. I/R was induced by occlusion of common carotid arteries for 20min. Minocycline (40mg/kg, i.p.) was administered once daily for 7days after I/R. Learning and memory were assessed using the Morris water maze test. Nissl staining was used to evaluate the viability of CA1 pyramidal cells. The effects of minocycline on the microglial activation was also investigated by Iba1 (Ionized calcium binding adapter molecule 1) immunostaining. The content of malondialdehyde (MDA) and pro-inflammatory cytokines (IL-1β and TNF-α) in the hippocampus were measured by thiobarbituric acid reaction substances method and ELISA, respectively. Minocycline reduced the increase in escape latency time and in swimming path length induced by cerebral I/R. Furthermore, the ischemia-induced reduction in time spent in the target quadrant during the probe trial was increased by treatment with minocycline. Histopathological results indicated that minocycline prevented pyramidal cells death and microglial activation induced by I/R. Minocycline also reduced the levels of MDA and pro-inflammatory cytokines in the hippocampus in rats subjected to I/R. Minocycline has neuroprotective effects on memory deficit induced by cerebral I/R in rat, probably via its anti-inflammatory and antioxidant properties. Copyright © 2017 Elsevier Inc. All rights reserved.

Studies on cerebral protection of digoxin against ischemia/reperfusion injury in mice.

PubMed

Kaur, Shaminder; Rehni, Ashish K; Singh, Nirmal; Jaggi, Amteshwar S

2009-04-01

The present study was designed to investigate the possible neuroprotective effect of digoxin induced pharmacological preconditioning (PP) and its probable mechanism. Bilateral carotid artery occlusion (BCAO) of 17 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion (I/R) induced cerebral injury in male swiss albino mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using elevated plus maze test. Degree of motor incoordination was evaluated using inclined beam walking test, rota rod test and lateral push test. Digoxin (0.08 mg/kg, i.p.) was administered 24 h before surgery in a separate group of animals to induce PP. BCAO followed by reperfusion, produced significant rise in cerebral infarct size along with impairment of memory and motor coordination. Digoxin treatment produced a significant decrease in cerebral infarct size and reversal of I/R induced impairment of memory and motor incoordination. Digoxin induced neuroprotective effect was abolished significantly by verapamil (15 mg/kg, i.p.), a L-type calcium channel blocker, ruthenium red (3 mg/kg, s.c.), an intracellular ryanodine receptor blocker and 3,4-dichlorobenzamil (Na(+)/Ca(2+) exchanger inhibitor). These findings indicate that digoxin preconditioning exerts a marked neuroprotective effect on the ischemic brain, which is possibly linked to digitalis induced increase in intracellular calcium levels eventually leading to the activation of calcium sensitive signal transduction cascades.

Blockade of N-methyl-D-aspartate Receptors May Protect against Ischemic Damage in the Brain

NASA Astrophysics Data System (ADS)

Simon, R. P.; Swan, J. H.; Griffiths, T.; Meldrum, B. S.

1984-11-01

In rats ischemia of the forebrain induced by a 30-minute occlusion of the carotid artery, followed by 120 minutes of arterial reperfusion, produced ischemic lesions of selectively vulnerable pyramidal cells in both hippocampi. Focal microinfusion into the dorsal hippocampus of 2-amino-7-phosphonoheptanoic acid, an antagonist of excitation at the N-methyl-d-asparate-preferring receptor, before ischemia was induced protected against the development of ischemic damage. It is proposed that excitatory neurotransmission plays an important role in selective neuronal loss due to cerebral ischemia.

Radiation-induced cerebrovascular disease in children

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wright, T.L.; Bresnan, M.J.

1976-06-01

Radiation-induced internal carotid artery occlusion has not been well recognized previously as a cause of childhood cerebrovascular disease. A child who had received radiation as a neonate for a hemangioma involving the left orbit at the age of 6 years experienced a recurrent right-sided paresis, vascular headaches, and speech difficulties. Angiography showed a hypoplastic left carotid artery with occlusion of both the anterior and middle cerebral arteries. Collateral vessels bypassed the occluded-stenotic segments. Review of the literature showed two additional cases of large vessel occlusion in childhood associated with anastomatic telangiectatic vessel development following early radiation therapy of facial hemangioma.

Increased calcineurin expression after pilocarpine-induced status epilepticus is associated with brain focal edema and astrogliosis.

PubMed

Liu, Jinzhi; Li, Xiaolin; Chen, Liguang; Xue, Ping; Yang, Qianqian; Wang, Aihua

2015-07-28

Calcineurin plays an important role in the development of neuronal excitability, modulation of receptor's function and induction of apoptosis in neurons. It has been established in kindling models that status epilepticus induces brain focal edema and astrocyte activation. However, the role of calcineurin in brain focal edema and astrocyte activation in status epilepticus has not been fully understood. In this study, we employed a model of lithium-pilocarpine-induced status epilepticus and detected calcineurin expression in hippocampus by immunoblotting, brain focal edema by non-invasive magnetic resonance imaging (MRI-7T) and astrocyte expression by immunohistochemistry. We found that the brain focal edema was seen at 24 h after status epilepticus, and astrocyte expression was obviously seen at 7 d after status epilepticus. Meanwhile, calcineurin expression was seen at24 h and retained to 7 d after status epilepticus. A FK506, a calcineurin inhibitor, remarkably suppressed the status epilepticus-induced brain focal edema and astrocyte expression. Our data suggested that calcineurin overexpression plays a very important role in brain focal edema and astrocyte expression. Therefore, calcineurin may be a novel candidate for brain focal edema occurring and intracellular trigger of astrogliosis in status epilepticus.

Middle-aged, but not young, rats develop cognitive impairment and cortical neurodegeneration following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion.

PubMed

Ferreira, Emilene D Fiuza; Romanini, Cássia V; Mori, Marco A; de Oliveira, Rúbia M Weffort; Milani, Humberto

2011-10-01

Permanent, stepwise occlusion of the vertebral arteries (VAs) and internal carotid arteries (ICAs) following the sequence VA→ICA→ICA, with an interstage interval (ISI, →) of 7 days, has been investigated as a four-vessel occlusion (4-VO)/ICA model of chronic cerebral hypoperfusion. This model has the advantage of not causing retinal damage. In young rats, however, 4-VO/ICA with an ISI of 7 days fails to cause behavioral sequelae. We hypothesized that such a long ISI would allow the brain to efficiently compensate for cerebral hypoperfusion, preventing the occurrence of cognitive impairment and neurodegeneration. The present study evaluated whether brain neurodegeneration and learning/memory deficits can be expressed by reducing the length of the ISI and whether aging influences the outcome. Young, male Wistar rats were subjected to 4-VO/ICA with different ISIs (5, 4, 3 or 2 days). An ISI of 4 days was used in middle-aged rats. Ninety days after 4-VO/ICA, the rats were tested for learning/memory impairment in a modified radial maze and then examined for neurodegeneration of the hippocampus and cerebral cortex. Regardless of the ISI, young rats were not cognitively impaired, although hippocampal damage was evident. Learning/memory deficits and hippocampal and cortical neurodegeneration occurred in middle-aged rats. The data indicate that 4-VO/ICA has no impact on the capacity of young rats to learn the radial maze task, despite 51% hippocampal cell death. Such resistance is lost in middle-aged animals, for which the most extensive neurodegeneration observed in both the hippocampus and cerebral cortex may be responsible. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Effects of Angiopoietin-1 on Hemorrhagic Transformation and Cerebral Edema after Tissue Plasminogen Activator Treatment for Ischemic Stroke in Rats

PubMed Central

Kawamura, Kunio; Takahashi, Tetsuya; Kanazawa, Masato; Igarashi, Hironaka; Nakada, Tsutomu; Nishizawa, Masatoyo; Shimohata, Takayoshi

2014-01-01

An angiogenesis factor, angiopoietin-1 (Ang1), is associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia. However, whether hemorrhagic transformation and cerebral edema after tissue plasminogen activator (tPA) treatment are related to the decrease in Ang1 expression in the BBB remains unknown. We hypothesized that administering Ang1 might attenuate hemorrhagic transformation and cerebral edema after tPA treatment by stabilizing blood vessels and inhibiting hyperpermeability. Sprague-Dawley rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group (permanent middle cerebral artery occlusion; PMCAO) and groups treated with tPA at 1 h or 4 h after ischemia. Endogenous Ang1 expression was observed in pericytes, astrocytes, and neuronal cells. Western blot analyses revealed that Ang1 expression levels on the ischemic side of the cerebral cortex were decreased in the tPA-1h, tPA-4h, and PMCAO groups as compared to those in the control group (P = 0.014, 0.003, and 0.014, respectively). Ang1-positive vessel densities in the tPA-4h and PMCAO groups were less than that in the control group (p = 0.002 and <0.001, respectively) as well as that in the tPA-1h group (p = 0.047 and 0.005, respectively). These results suggest that Ang1-positive vessel density was maintained when tPA was administered within the therapeutic time window (1 h), while it was decreased when tPA treatment was given after the therapeutic time window (4 h). Administering Ang1 fused with cartilage oligomeric protein (COMP) to supplement this decrease has the potential to suppress hemorrhagic transformation as measured by hemoglobin content in a whole cerebral homogenate (p = 0.007) and cerebral edema due to BBB damage (p = 0.038), as compared to administering COMP protein alone. In conclusion, Ang1 might be a promising target molecule for developing vasoprotective therapies for controlling hemorrhagic

STA-ACA bypass using the ipsilateral free STA graft as an interposition graft and A3-A3 anastomosis for treatment of bilateral ACA steno-occlusive ischemia.

PubMed

Horiuchi, Tetsuyoshi; Ichinose, Shunsuke; Agata, Masahiro; Ito, Kiyoshi; Hongo, Kazuhiro

2018-04-01

Anterior cerebral artery (ACA)-related ischemia is a rare entity in patients with atherosclerosis. Some surgical treatments are reported to date. We present the modification of intracranial-intracranial and intracranial-extracranial bypasses for symptomatic bilateral ACA steno-occlusive disease. The A3-A3 bypass followed by the superficial temporal artery-ACA bypass using the ipsilateral free superficial temporal artery graft is useful without harvesting of the radial artery. Bilateral ACA steno-occlusive induced ischemia can be treated with tailored bypass procedures.

Hypoperfusion induces overexpression of beta-amyloid precursor protein mRNA in a focal ischemic rodent model.

PubMed

Shi, J; Yang, S H; Stubley, L; Day, A L; Simpkins, J W

2000-01-17

Silent stroke is one of the risk factors of dementia. In the present study, we used a novel focal ischemic animal model to investigate the effects of comparatively small changes of cerebral blood flow (CBF) on the expression of beta-amyloid precursor protein (APP) mRNA. Focal ischemia was achieved by introducing a 4-0 monofilament to the bifurcation of anterior and middle cerebral arteries. Brain samples were harvested from ischemic core and penumbra of cortices at 1, 4 and 7 days following ischemia. The expression of APP mRNA was assessed by RT-PCR. The CBF was decreased to 50% for 1 day after stroke and recovered to 90% at the fourth day after stroke. The changes of CBF were accompanied by an increase in the expression of APP mRNA. APP mRNA increased to 208% and 152% in the penumbra and core ischemic regions, respectively, on the fourth day after MCAO and remained high through the seventh day of ischemia. This study suggests brain hypoperfusion enhances APP mRNA expression and may contribute to the progression of cognitive impairment after silent stroke.

Translocation of TRPV2 channel induced by focal administration of mechanical stress

PubMed Central

Nagasawa, Masahiro; Kojima, Itaru

2015-01-01

The effect of focal mechanical stress on the localization of TRPV2 was investigated in HT1080 cells, where only mRNA for TRPV2 was detected among members of the TRPV channel family. Mechanical stress was applied by adding negative pressure using a glass pipette. When focal mechanical stress was applied, subplasma membrane Ca2+ concentration ([Ca2+]s) was increased beneath the pipette, which propagated throughout the cell. The increase in [Ca2+]s was blocked by ruthenium red or by knocking down TRPV2. Elevation of [Ca2+]s was not observed by removal of extracellular Ca2+, by an addition of a phosphatidylinositol 3-kinase inhibitor LY29034, and by transfection of dominant-negative Rac. In cells expressing GFP-TRPV2 and RFP-Akt, administration of focal mechanical stress induced accumulation of GFP-TRPV2 beneath the pipette. RFP-Akt was also accumulated to the same site. Gadolinium blocked the elevation of [Ca2+]s induced by focal mechanical stress and also attenuated accumulation of TRPV2. When GFP-TRPV1, GFP-TRPV3, GFP-TRPV4, GFP-TRPV5, or GFP-TRPV6 was transfected ectopically in HT1080 cells, only GFP-TRPV4 was accumulated beneath the pipette in response to the focal mechanical stress. These results indicate that TRPV2 translocates to the site receiving a focal mechanical stress and increases [Ca2+]s. PMID:25677550

Protective Effect of Ischemic Preconditioning on Myocardium Against Remote Tissue Injury Following Transient Focal Cerebral Ischemia in Diabetic Rats

PubMed Central

Kumas, Meltem; Altintas, Ozge; Karatas, Ersin; Kocyigit, Abdurrahim

2017-01-01

Background Remote ischemic preconditioning (IPreC) could provide tissue-protective effect at a remote site by anti-inflammatory, neuronal, and humoral signaling pathways. Objectives The aim of the study was to investigate the possible protective effects of remote IPreC on myocardium after transient middle cerebral artery occlusion (MCAo) in streptozotocin- induced diabetic (STZ) and non-diabetic rats. Methods 48 male Spraque Dawley rats were divided into eight groups: Sham, STZ, IPreC, MCAo, IPreC+MCAo, STZ+IPreC, STZ+MCAo and STZ+IPreC+MCAo groups. We induced transient MCAo seven days after STZ-induced diabetes, and performed IPreC 72 hours before transient MCAo. Remote myocardial injury was investigated histopathologically. Bax, Bcl2 and caspase-3 protein levels were measured by Western blot analysis. Total antioxidant status (TAS), total oxidant status (TOS) of myocardial tissue were measured by colorimetric assay. Oxidative stress index(OSI) was calculated as TOS-to-TAS ratio. For all statistical analysis, p values < 0.05 were considered significant. Results We observed serious damage including necrosis, congestion and mononuclear cell infiltration in myocardial tissue of the diabetic and ischemic groups. In these groups TOS and OSI levels were significantly higher; TAS levels were lower than those of IPreC related groups (p < 0.05). IPreC had markedly improved histopathological alterations and increased TAS levels in IPreC+MCAo and STZ+IPreC+MCAo compared to MCAo and STZ+MCAo groups (p < 0.05). In non-diabetic rats, MCAo activated apoptotic cell death via increasing Bax/Bcl2 ratio and caspase-3 levels. IPreC reduced apoptotic cell death by suppressing pro-apoptotic proteins. Diabetes markedly increased apoptotic protein levels and the effect did not reversed by IPreC. Conclusions We could suggest that IPreC attenuates myocardial injury via ameliorating histological findings, activating antioxidant mechanisms, and inducing antiapoptotic activity in diabetic

Cerebral intolerance during flow arrested carotid angioplasty.

PubMed

St Louis, Myron; Park, Brian D; Dahn, Michael; Bozeman, Patricia

2012-01-01

The use of flow arrest as a means of providing cerebral protection during carotid angioplasty offers the advantages of improved efficiency of debris removal and the ability to provide protection under unfavorable (tortuous) anatomic circumstances. However, in contrast to the filtration methods of cerebral protection, this modality requires complete interruption of antegrade carotid artery flow during balloon angioplasty and stent deployment. We report our experience with 9 patients undergoing carotid angioplasty with the Mo.Ma device, which utilizes common and external carotid artery balloon occlusion during the angioplasty procedure. We assessed the clinical outcomes and intraprocedural hemodynamic data. The average duration of carotid occlusion was 8.3 minutes. Of the 9 patients, 2 patients (22%) experienced cerebral intolerance. No stroke occurred in this patient cohort. There appeared to be a poor relationship between procedure intolerance and the presence of significant contralateral stenosis or low carotid back pressure. Furthermore, the incidence of postangioplasty hypotension was not clearly related to cerebral intolerance. Carotid angioplasty with stenting can be safely conducted with flow arrest as an alternative to filter-type cerebral protection devices. However, because cerebral intolerance is not an infrequent occurrence with this approach, clinicians must be cognizant of management strategies for transient cerebral intolerance.

Critical cerebral perfusion pressure at high intracranial pressure measured by induced cerebrovascular and intracranial pressure reactivity.

PubMed

Bragin, Denis E; Statom, Gloria L; Yonas, Howard; Dai, Xingping; Nemoto, Edwin M

2014-12-01

The lower limit of cerebral blood flow autoregulation is the critical cerebral perfusion pressure at which cerebral blood flow begins to fall. It is important that cerebral perfusion pressure be maintained above this level to ensure adequate cerebral blood flow, especially in patients with high intracranial pressure. However, the critical cerebral perfusion pressure of 50 mm Hg, obtained by decreasing mean arterial pressure, differs from the value of 30 mm Hg, obtained by increasing intracranial pressure, which we previously showed was due to microvascular shunt flow maintenance of a falsely high cerebral blood flow. The present study shows that the critical cerebral perfusion pressure, measured by increasing intracranial pressure to decrease cerebral perfusion pressure, is inaccurate but accurately determined by dopamine-induced dynamic intracranial pressure reactivity and cerebrovascular reactivity. Cerebral perfusion pressure was decreased either by increasing intracranial pressure or decreasing mean arterial pressure and the critical cerebral perfusion pressure by both methods compared. Cortical Doppler flux, intracranial pressure, and mean arterial pressure were monitored throughout the study. At each cerebral perfusion pressure, we measured microvascular RBC flow velocity, blood-brain barrier integrity (transcapillary dye extravasation), and tissue oxygenation (reduced nicotinamide adenine dinucleotide) in the cerebral cortex of rats using in vivo two-photon laser scanning microscopy. University laboratory. Male Sprague-Dawley rats. At each cerebral perfusion pressure, dopamine-induced arterial pressure transients (~10 mm Hg, ~45 s duration) were used to measure induced intracranial pressure reactivity (Δ intracranial pressure/Δ mean arterial pressure) and induced cerebrovascular reactivity (Δ cerebral blood flow/Δ mean arterial pressure). At a normal cerebral perfusion pressure of 70 mm Hg, 10 mm Hg mean arterial pressure pulses had no effect on

Development of functional in vivo imaging of cerebral lenticulostriate artery using novel synchrotron radiation angiography

NASA Astrophysics Data System (ADS)

Lin, Xiaojie; Miao, Peng; Mu, Zhihao; Jiang, Zhen; Lu, Yifan; Guan, Yongjing; Chen, Xiaoyan; Xiao, Tiqiao; Wang, Yongting; Yang, Guo-Yuan

2015-02-01

The lenticulostriate artery plays a vital role in the onset and development of cerebral ischemia. However, current imaging techniques cannot assess the in vivo functioning of small arteries such as the lenticulostriate artery in the brain of rats. Here, we report a novel method to achieve a high resolution multi-functional imaging of the cerebrovascular system using synchrotron radiation angiography, which is based on spatio-temporal analysis of contrast density in the arterial cross section. This method provides a unique tool for studying the sub-cortical vascular elasticity after cerebral ischemia in rats. Using this technique, we demonstrated that the vascular elasticity of the lenticulostriate artery decreased from day 1 to day 7 after transient middle cerebral artery occlusion in rats and recovered from day 7 to day 28 compared to the controls (p < 0.001), which paralleled with brain edema formation and inversely correlated with blood flow velocity (p < 0.05). Our results demonstrated that the change of vascular elasticity was related to the levels of brain edema and the velocity of focal blood flow, suggesting that reducing brain edema is important for the improvement of the function of the lenticulostriate artery in the ischemic brain.

Characterization of White Matter Injury in a Rat Model of Chronic Cerebral Hypoperfusion.

PubMed

Choi, Bo-Ryoung; Kim, Dong-Hee; Back, Dong Bin; Kang, Chung Hwan; Moon, Won-Jin; Han, Jung-Soo; Choi, Dong-Hee; Kwon, Kyoung Ja; Shin, Chan Young; Kim, Bo-Ram; Lee, Jongmin; Han, Seol-Heui; Kim, Hahn Young

2016-02-01

Chronic cerebral hypoperfusion can lead to ischemic white matter injury resulting in vascular dementia. To characterize white matter injury in vascular dementia, we investigated disintegration of diverse white matter components using a rat model of chronic cerebral hypoperfusion. Chronic cerebral hypoperfusion was modeled in Wistar rats by permanent occlusion of the bilateral common carotid arteries. We performed cognitive behavioral tests, including the water maze task, odor discrimination task, and novel object test; histological investigation of neuroinflammation, oligodendrocytes, myelin basic protein, and nodal or paranodal proteins at the nodes of Ranvier; and serial diffusion tensor imaging. Cilostazol was administered to protect against white matter injury. Diverse cognitive impairments were induced by chronic cerebral hypoperfusion. Disintegration of white matter was characterized by neuroinflammation, loss of oligodendrocytes, attenuation of myelin density, structural derangement at the nodes of Ranvier, and disintegration of white matter tracts. Cilostazol protected against cognitive impairments and white matter disintegration. White matter injury induced by chronic cerebral hypoperfusion can be characterized by disintegration of diverse white matter components. Cilostazol might be a therapeutic strategy against white matter disintegration in patients with vascular dementia. © 2015 American Heart Association, Inc.

The sensorimotor and cognitive deficits in rats following 90- and 120-min transient occlusion of the middle cerebral artery.

PubMed

Zvejniece, Liga; Svalbe, Baiba; Liepinsh, Edgars; Pulks, Eduards; Dambrova, Maija

2012-07-15

Middle cerebral artery occlusion (MCAO) is the most commonly used method to study the neurological and histological outcomes and the pathological mechanisms of ischaemic stroke. The current work compares sensorimotor and cognitive deficits and the infarct volume in rats following a transient 90- or 120-min MCAO, which allows the appropriate behavioural tests to be chosen based on the goal and design of the experiment. In the beam-walking test, we found significant differences between the 90- and 120-min MCAO groups in the number of foot faults made with the impaired hindlimb on post-stroke days 3, 7 and 14. In the cylinder test, a difference between the 90- and 120-min groups was observed on post-operation day 14. The responses to tactile and proprioceptive stimulation were impaired to a similar extent after 90- and 120-min MCAO in the vibrissae-evoked forelimb-placing and limb-placing tests. Moreover, we found significant memory impairment in the 120-min MCAO group 6 days after the acquisition trial. The brain tissue damage was significantly higher after 120-min occlusion of the MCA compared with 90-min occlusion; the infarct volumes were 13% and 25% of the contralateral hemispheres, respectively. In conclusion, both the 90- and 120-min occlusion models result in a significant impairment of sensorimotor, tactile and proprioceptive function, but memory impairment is only observed in the 120-min MCAO group. The beam-walking and cylinder tests detected neurological dysfunction after the 120-min MCAO, whereas the limb-placing and vibrissae-evoked forelimb-placing tests were able to evaluate the neurological dysfunction in rats after 90- and 120-min MCAO. Copyright © 2012 Elsevier B.V. All rights reserved.

A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyanohara, Jun; Shirakawa, Hisashi, E-mail: shirakaw@pharm.kyoto-u.ac.jp; Sanpei, Kazuaki

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high Ca{sup 2+} permeability, which functions as a polymodal nociceptor activated by heat, protons and several vanilloids, including capsaicin and anandamide. Although TRPV1 channels are widely distributed in the mammalian brain, their pathophysiological roles in the brain remain to be elucidated. In this study, we investigated whether TRPV1 is involved in cerebral ischemic injury using a middle cerebral artery (MCA) occlusion model in wild-type (WT) and TRPV1-knockout (KO) mice. For transient ischemia, the left MCA of C57BL/6 mice was occluded for 60 min and reperfused at 1 and 2more » days after ischemia. We found that neurological and motor deficits, and infarct volumes in TRPV1-KO mice were lower than those of WT mice. Consistent with these results, intracerebroventricular injection of a TRPV1 antagonist, capsazepine (20 nmol), 30 min before the onset of ischemia attenuated neurological and motor deficits and improved infarct size without influencing cerebral blood flow in the occluded MCA territory. The protective effect of capsazepine on ischemic brain damage was not observed in TRPV1-KO mice. WT and TRPV1-KO mice did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 2 days after cerebral ischemia. Taken together, we conclude that brain TRPV1 channels are activated by ischemic stroke and cause neurological and motor deficits and infarction after brain ischemia. - Highlights: • We investigated whether TRPV1 is involved in transient ischemic brain damage in mice. • Neurological deficits and infarct volumes were lower in TRPV1-KO mice than in WT mice. • Injection of a TRPV1 antagonist, capsazepine, attenuated neurological deficits and improved infarct size. • No differences in astrocytic or microglial activation were observed between WT and TRPV1-KO

Sleep Is Critical for Remote Preconditioning-Induced Neuroprotection.

PubMed

Brager, Allison J; Yang, Tao; Ehlen, J Christopher; Simon, Roger P; Meller, Robert; Paul, Ketema N

2016-11-01

Episodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia. EEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities ( Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings. Two days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia. These results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome. © 2016 Associated Professional Sleep Societies, LLC.

Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I

PubMed Central

2014-01-01

Background Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. The clinical presentation includes bilateral striatal necrosis and spontaneous subdural and retinal hemorrhages, which has been frequently misdiagnosed as non-accidental head trauma. The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. Results Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. Focal regions of cortical followed by striatal capillaries are occluded with shunting to larger non-exchange vessels leading to early filling and dilation of deep cerebral veins. Blood–brain barrier breakdown was associated with displacement of tight-junction protein Occludin. Conclusion Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke. PMID:24468193

Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I.

PubMed

Zinnanti, William J; Lazovic, Jelena; Housman, Cathy; Antonetti, David A; Koeller, David M; Connor, James R; Steinman, Lawrence

2014-01-27

Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. The clinical presentation includes bilateral striatal necrosis and spontaneous subdural and retinal hemorrhages, which has been frequently misdiagnosed as non-accidental head trauma. The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. Focal regions of cortical followed by striatal capillaries are occluded with shunting to larger non-exchange vessels leading to early filling and dilation of deep cerebral veins. Blood-brain barrier breakdown was associated with displacement of tight-junction protein Occludin. Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.

Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury

PubMed Central

Wang, Yanzhe; He, Zhiyi; Deng, Shumin

2016-01-01

Background Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance. Methods The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed. Results UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect. Conclusion UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the

Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury.

PubMed

Wang, Yanzhe; He, Zhiyi; Deng, Shumin

2016-01-01

Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance. The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed. UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect. UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway

Enhanced contractility of intraparenchymal arterioles after global cerebral ischaemia in rat - new insights into the development of delayed cerebral hypoperfusion.

PubMed

Spray, S; Johansson, S E; Radziwon-Balicka, A; Haanes, K A; Warfvinge, K; Povlsen, G K; Kelly, P A T; Edvinsson, L

2017-08-01

Delayed cerebral hypoperfusion is a secondary complication found in the days after transient global cerebral ischaemia that worsens the ischaemic damage inflicted by the initial transient episode of global cerebral ischaemia. A recent study demonstrated increased cerebral vasoconstriction in the large arteries on the brain surface (pial arteries) after global cerebral ischaemia. However, smaller arterioles inside the brain (parenchymal arterioles) are equally important in the regulation of cerebral blood flow and yet their pathophysiology after global cerebral ischaemia is largely unknown. Therefore, we investigated whether increased contractility occurs in the intraparenchymal arterioles. Global cerebral ischaemia was induced in male Wistar rats by bilateral common carotid occlusion for 15 min combined with hypovolaemia. Regional cerebral blood flow was determined by quantitative autoradiography. Intraparenchymal arterioles were isolated and pressurized, and concentration-response curves to endothelin-1 with and without the endothelin B receptor-selective antagonist BQ788 was generated. Endothelin B receptor expression was investigated by quantitative flow cytometry and immunohistochemistry. We observed increased endothelin-1-mediated contractility of parenchymal arterioles correlating with reduced cerebral blood flow of the cortex, hippocampus and caudate nucleus 48 h after global cerebral ischaemia. The increased endothelin-1-mediated contractility was abolished by BQ788, and the vascular smooth muscle cell-specific expression of endothelin B receptors was significantly increased after global cerebral ischaemia. Increased endothelin-1-mediated contractility and expression of endothelin B receptors in the intraparenchymal vasculature contributes to the development of delayed cerebral hypoperfusion after global cerebral ischaemia in combination with vascular changes of the pial vasculature. © 2016 Scandinavian Physiological Society. Published by John Wiley

Translocation of TRPV2 channel induced by focal administration of mechanical stress.

PubMed

Nagasawa, Masahiro; Kojima, Itaru

2015-02-01

The effect of focal mechanical stress on the localization of TRPV2 was investigated in HT1080 cells, where only mRNA for TRPV2 was detected among members of the TRPV channel family. Mechanical stress was applied by adding negative pressure using a glass pipette. When focal mechanical stress was applied, subplasma membrane Ca(2+) concentration ([Ca(2+)]s) was increased beneath the pipette, which propagated throughout the cell. The increase in [Ca(2+)]s was blocked by ruthenium red or by knocking down TRPV2. Elevation of [Ca(2+)]s was not observed by removal of extracellular Ca(2+), by an addition of a phosphatidylinositol 3-kinase inhibitor LY29034, and by transfection of dominant-negative Rac. In cells expressing GFP-TRPV2 and RFP-Akt, administration of focal mechanical stress induced accumulation of GFP-TRPV2 beneath the pipette. RFP-Akt was also accumulated to the same site. Gadolinium blocked the elevation of [Ca(2+)]s induced by focal mechanical stress and also attenuated accumulation of TRPV2. When GFP-TRPV1, GFP-TRPV3, GFP-TRPV4, GFP-TRPV5, or GFP-TRPV6 was transfected ectopically in HT1080 cells, only GFP-TRPV4 was accumulated beneath the pipette in response to the focal mechanical stress. These results indicate that TRPV2 translocates to the site receiving a focal mechanical stress and increases [Ca(2+)]s. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Immune cell infiltration in malignant middle cerebral artery infarction: comparison with transient cerebral ischemia

PubMed Central

Chu, Hannah X; Kim, Hyun Ah; Lee, Seyoung; Moore, Jeffrey P; Chan, Christopher T; Vinh, Antony; Gelderblom, Mathias; Arumugam, Thiruma V; Broughton, Brad RS; Drummond, Grant R; Sobey, Christopher G

2014-01-01

We tested whether significant leukocyte infiltration occurs in a mouse model of permanent cerebral ischemia. C57BL6/J male mice underwent either permanent (3 or 24 hours) or transient (1 or 2 hours+22- to 23-hour reperfusion) middle cerebral artery occlusion (MCAO). Using flow cytometry, we observed ∼15,000 leukocytes (CD45+high cells) in the ischemic hemisphere as early as 3 hours after permanent MCAO (pMCAO), comprising ∼40% lymphoid cells and ∼60% myeloid cells. Neutrophils were the predominant cell type entering the brain, and were increased to ∼5,000 as early as 3 hours after pMCAO. Several cell types (monocytes, macrophages, B lymphocytes, CD8+ T lymphocytes, and natural killer cells) were also increased at 3 hours to levels sustained for 24 hours, whereas others (CD4+ T cells, natural killer T cells, and dendritic cells) were unchanged at 3 hours, but were increased by 24 hours after pMCAO. Immunohistochemical analysis revealed that leukocytes typically had entered and widely dispersed throughout the parenchyma of the infarct within 3 hours. Moreover, compared with pMCAO, there were ∼50% fewer infiltrating leukocytes at 24 hours after transient MCAO (tMCAO), independent of infarct size. Microglial cell numbers were bilaterally increased in both models. These findings indicate that a profound infiltration of inflammatory cells occurs in the brain early after focal ischemia, especially without reperfusion. PMID:24326388

Rotational vertebral artery occlusion: mechanisms and long-term outcome.

PubMed

Choi, Kwang-Dong; Choi, Jae-Hwan; Kim, Ji-Soo; Kim, Hyo Jung; Kim, Min-Ji; Lee, Tae-Hong; Lee, Hyung; Moon, In Soo; Oh, Hui Jong; Kim, Jae-Il

2013-07-01

To elucidate the mechanisms and prognosis of rotational vertebral artery occlusion (RVAO). We analyzed clinical and radiological characteristics, patterns of induced nystagmus, and outcome in 21 patients (13 men, aged 29-77 years) with RVAO documented by dynamic cerebral angiography during an 8-year period at 3 University Hospitals in Korea. The follow-up periods ranged from 5 to 91 months (median, 37.5 months). Most patients (n=19; 90.5%) received conservative treatments. All the patients developed vertigo accompanied by tinnitus (38%), fainting (24%), or blurred vision (19%). Only 12 (57.1%) patients showed the typical pattern of RVAO during dynamic cerebral angiography, a compression of the dominant vertebral artery at the C1-2 level during contralateral head rotation. The induced nystagmus was mostly downbeat with horizontal and torsional components beating toward the compressed vertebral artery side. None of the patients with conservative treatments developed posterior circulation stroke, and 4 of them (21.1%) showed resolution of symptoms during the follow-ups. RVAO has various patterns of vertebral artery compression, and favorable long-term outcome with conservative treatments. In most patients with RVAO, the symptoms may be ascribed to asymmetrical excitation of the bilateral labyrinth induced by transient ischemia or by disinhibition from inferior cerebellar hypoperfusion. Conservative management might be considered as the first-line treatment of RVAO.

Revisiting cerebral thromboangiitis obliterans.

PubMed

Hurelbrink, Carrie B; Barnett, Yael; Buckland, Michael E; Wilkinson, Mark; Leicester, Jon; Anderson, Craig; Brennan, Jeffrey; Barnett, Michael

2012-06-15

We describe a 56-year-old patient with progressive cognitive decline in the context of heavy tobacco use and migraine, and imaging evidence of an occlusive terminal cerebral vasculopathy. The results of brain biopsy recapitulated the pathological features described by Lindenberg and Spatz in their classic 1939 treatise on cerebral thromboangiitis obliterans, or cerebral Buerger's disease. Although the condition is associated with heavy smoking, the identification of a hypercoagulable state in our patient suggests a multifactorial pathogenesis. The diagnosis of cerebral thromboangiitis obliterans in life is facilitated by modern neuroimaging and should prompt immediate cessation of smoking and a search for an underlying prothrombotic tendency. Copyright © 2012 Elsevier B.V. All rights reserved.

Distal hyperintense vessels alleviate insula infarction in proximal middle cerebral artery occlusion.

PubMed

Song, Jiacheng; Ma, Zhanlong; Meng, Huan; Yu, Jing; Li, Yan; Hong, Xunning; Shi, Haibin

2016-11-01

Insula involvement in acute cerebral ischemia more likely causes penumbral loss and poor clinical outcome than infarct-sparing insula. Our objective was to prove the hypothesis that abundant collateral circulation represented by distal hyperintense vessels (HV) on MRI alleviates insula infarction and facilitates prognosis. One hundred and fourteen stroke cases with M1 totally occlusion on MR angiography were documented consecutively from 2012 to 2014. The degree of HV was graded as absent, subtle or prominent. Clinical data were recorded retrospectively by reviewing the medical records. The infarct volume on diffusion-weighted image, along with National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS), was used to evaluate the clinical severity and prognosis. The degree of HV was more abundant in insula-uninvolved stroke compared with stroke involving insula infarction (p = 0.026). Insula-involved stroke patients were older (p = 0.039) with a higher percentage of atrial fibrillation history (p = 0.042). Univariate analysis revealed that insula infarction, age, infarct volume and NIHSS predicted unfavorable prognosis of stroke, whereas HV had a favorable effect. The protective effect of HV was confirmed by multivariate analysis. HV is a protective barrier between insula infarction and severity of clinical symptoms among stroke patients.

Real-time imaging of cerebral infarction in rabbits using electrical impedance tomography.

PubMed

Yang, Bin; Shi, Xuetao; Dai, Meng; Xu, Canhua; You, Fushen; Fu, Feng; Liu, Ruigang; Dong, Xiuzhen

2014-02-01

To investigate the possible use of electrical impedance tomography (EIT) in monitoring focal cerebral infarction in a rabbit model. A model of focal cerebral infarction was established in eight New Zealand rabbits using a photochemical method without craniectomy. Focal cerebral infarction was confirmed by histopathological examination. Intracranial impedance variation was measured using 16 electrodes placed in a circle on the scalp. EIT images were obtained using a damped least-squares reconstruction algorithm. The average resistivity value (ARV) of the infarct region on EIT images was calculated to quantify relative resistivity changes. A symmetry index was calculated to evaluate the relative difference in resistivity between the two sides of the cerebrum. EIT images and ARV curves showed that impedance changes caused by cerebral infarction increased linearly with irradiation time. A difference in ARV was found between measurements taken before and after infarct induction. Focal cerebral infarction can be monitored by EIT in the proposed animal model. The results are sufficiently encouraging that the authors plan to extend this study to humans, after further technical improvements.

Improvement in Cerebral and Ocular Hemodynamics Early after Carotid Endarterectomy in Patients of Severe Carotid Artery Stenosis with or without Contralateral Carotid Occlusion.

PubMed

Wang, Jian; Wang, Weici; Jin, Bi; Zhang, Yanrong; Xu, Ping; Xiang, Feixiang; Zheng, Yi; Chen, Juan; Sheng, Shi; Ouyang, Chenxi; Li, Yiqing

2016-01-01

Purpose. To investigate the alternation in cerebral and ocular blood flow velocity (BFV) in patients of carotid stenosis (CS) with or without contralateral carotid occlusion (CO) early after carotid endarterectomy (CEA). Patients and Methods. Nineteen patients underwent CEA for ≥50% CS. Fourteen patients had the unilateral CS, and five patients had the ipsilateral CS and the contralateral CO. Transcranial Doppler (TCD) and Color Doppler Imaging (CDI) were performed before and early after CEA. Results. In patients with unilateral CS, significant improvements in BFV were observed in anterior cerebral artery (ACA) and middle cerebral artery (MCA) on the ipsilateral side after CEA. In patients of ipsilateral CS and contralateral CO, significant improvements in BFV were observed in the ACA and MCA not only on the ipsilateral side but also on the contralateral side postoperatively. The ipsilateral ophthalmic artery (OA) retrograde flows in two patients were recovered to anterograde direction following CEA. The BFV in short posterior ciliary artery (SPCA) of the ipsilateral side significantly increased postoperatively irrespective of the presence of contralateral CO. Conclusions. CEA improved cerebral anterior circulation hemodynamics especially in patients of unilateral CS and contralateral CO, normalized the OA reverse flow, and increased the blood perfusion of SPCA.

Transplanted Dental Pulp Stem Cells Migrate to Injured Area and Express Neural Markers in a Rat Model of Cerebral Ischemia.

PubMed

Zhang, Xuemei; Zhou, Yinglian; Li, Hulun; Wang, Rui; Yang, Dan; Li, Bing; Cao, Xiaofang; Fu, Jin

2018-01-01

Ischemic stroke is a major cause of disability and mortality worldwide, while effective restorative treatments are limited at present. Stem cell transplantation holds therapeutic potential for ischemic vascular diseases and may provide an opportunity for neural regeneration. Dental pulp stem cells (DPSCs) origin from neural crest and have neuro-ectodermal features including proliferation and multilineage differentiation potentials. The rat model of middle cerebral artery occlusion (MCAO) was used to evaluate whether intravenous administration of DPSCs can reduce infarct size and to estimate the migration and trans-differentiation into neuron-like cells in focal cerebral ischemia models. Brain tissues were collected at 4 weeks following cell transplantation and analyzed with immunofluorescence, immunohistochemistry and real-time polymerase chain reaction (RT-PCR) methods. Intravenously administration of rat-derived DPSCs were found to migrate into the boundary of ischemic areas and expressed neural specific markers, reducing infarct volume and cerebral edema. These results suggest that DPSCs treatment may serve as a potential therapy for clinical stroke patients in the future. © 2018 The Author(s). Published by S. Karger AG, Basel.

Caspase-Independent Apoptosis Induced by Reperfusion Following Ischemia without Bile Duct Occlusion in Rat Liver.

PubMed

Matsui, Nobuaki; Yoshioka, Rie; Nozawa, Asako; Kobayashi, Naonobu; Shichijo, Yukari; Yoshikawa, Tadatoshi; Akagi, Masaaki

2017-01-01

The contribution of caspases to hepatic ischemia/reperfusion (I/R)-induced apoptosis has not been completely understood yet. Several studies have demonstrated increased caspase activity during I/R and the protective effect of caspase inhibitors against I/R injuries. However, reports with opposing results also exist. Herein, we examined the contribution of caspases to the I/R-induced hepatic apoptosis in rats using caspase inhibitors and specific substrates of caspases. Hepatic I/R was induced via a 2-h occlusion of the portal vein and the hepatic artery, without conducting bile duct occlusion. DNA laddering and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL)-positive cells were increased at 3 h after reperfusion. Pretreatment with caspase inhibitors (Z-Asp-2,6-dichlorobenzoyloxymethylketone (Z-Asp-cmk) 2 or 10 mg/kg intravenously (i.v.), 20 mg/kg intraperitoneally (i.p.), Z-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-fmk) 3 mg/kg i.v.) failed to reduce apoptosis induced by I/R. Interestingly, apoptosis induced by the portal triad (hepatic artery, portal vein, and bile duct) occlusion/reperfusion could be marginally attenuated using Z-Asp-cmk (2 mg/kg i.v.). The cleavage activity for Ac-DEVD-α-(4-methylcoumaryl-7-amide) (MCA), a caspase-3/7/8/9 substrate, was significantly increased by I/R. Conversely, the cleavage activities for Ac-DNLD-MCA and MCA-VDQVDGW[K-DNP]-NH 2 , specific substrates for caspase-3 and -7 respectively, were decreased by I/R. Protein expression of the cellular inhibitor of apoptosis protein 2 (c-IAP2), an endogenous caspase inhibitor, was increased by ischemia. Nuclear translocation of the apoptosis-inducing factor (AIF), an initiator protein of caspase-independent apoptosis, was also increased during I/R. These results suggest that caspases are inhibited by c-IAP2 induced during ischemia and that AIF may be involved in initiation of apoptosis induced by hepatic I/R without

Talampanel improves the functional deficit after transient focal cerebral ischemia in rats. A 30-day follow up study.

PubMed

Erdo, Franciska; Berzsenyi, Pál; Német, László; Andrási, Ferenc

2006-01-15

The neuroprotective effect of talampanel, a negative allosteric modulator of alpha-amino-3-hydroxy-methyl-4-isoxazolyl-propionic acid (AMPA) receptors has been described previously. However, in these studies the histological changes and not the functional consequences of the brain damage were evaluated. The aim of present investigation was to analyze the sensorimotor function after stroke and to test the influence of talampanel (GYKI-53773, LY-300164) by 30-day monitoring in rats. After 1h middle cerebral artery occlusion (MCAO) general 'well-being', neurological status, spontaneous motor activity, rotation, motor coordination, balancing, muscle strength and reaction time were followed for 1 month. Talampanel (6 x 10 mg/kg i.p. given on the day of stroke) improved the motor coordination in rotarod (p < 0.01) and beam walking (p < 0.01) tests, reduced the number of stroke-induced rotations (p < 0.05), shortened the reflex time on the forelimb contralateral to brain ischemia and improved the survival rate comparing with vehicle treated control. After stroke, serious sensorimotor deficits appeared in rats but they showed partial spontaneous recovery after 30 days. Talampanel treatment enhanced the rate of functional improvement without changing the morphology at the end of the experiment. Our results indicate that modulation of AMPA receptors by talampanel can be a promising therapeutic approach to the treatment of stroke.

Blocking of platelets or intrinsic coagulation pathway-driven thrombosis does not prevent cerebral infarctions induced by photothrombosis.

PubMed

Kleinschnitz, Christoph; Braeuninger, Stefan; Pham, Mirko; Austinat, Madeleine; Nölte, Ingo; Renné, Thomas; Nieswandt, Bernhard; Bendszus, Martin; Stoll, Guido

2008-04-01

Models of photochemically-induced thrombosis are widely used in cerebrovascular research. Photothrombotic brain infarctions can be induced by systemic application of photosensitizing dyes followed by focal illumination of the cerebral cortex. Although the ensuing activation of platelets is well established, their contribution for thrombosis and tissue damage has not formally been proved. Infarction to the cerebral cortex was induced in mice by Rose Bengal and a cold light source. To assess the functional role of platelets, animals were platelet-depleted by anti-GPIbalpha antibodies or treated with GPIIb/IIIa-blocking F(ab)(2) fragments. The significance of the plasmatic coagulation cascade was determined by using blood coagulation factor XII (FXII)-deficient mice or heparin. Infarct development and infarct volumes were determined by serial MRI and conventional and electron microscopy. There was no difference in development and final size of photothrombotic infarctions in mice with impaired platelet function. Moreover, deficiency of FXII, which initiates the intrinsic pathway of coagulation and is essential for thrombus formation, or blockade of FXa, the key protease during the waterfall cascade of plasmatic coagulation, by heparin likewise did not affect lesion development. Our data demonstrate that platelet activation, factor XII-driven thrombus formation, and plasmatic coagulation pathways downstream of FX are not a prerequisite for ensuing tissue damage in models of photothrombotic vessel injury indicating that other pathomechanisms are involved. We suggest that this widely used model does not depend on platelet- or plasmatic coagulation-derived thrombosis.

Mid-term Results of Endovascular Treatment for Infrarenal Aortic Stenosis and Occlusion.

PubMed

Sohgawa, Etsuji; Sakai, Yukimasa; Nango, Mineyoshi; Cho, Hisayuki; Jogo, Atsushi; Hamamoto, Shinichi; Yamamoto, Akira; Miki, Yukio

2015-06-01

Focal stenosis or occlusion of the infrarenal aorta is rare, and treatment is usually conventional bypass or endarterectomy. However, endovascular treatment has advanced in recent years. The purpose of this retrospective study is to report the results of primary stenting for focal infrarenal aortic occlusive disease and clarify the usefulness of endovascular treatment. This study includes 6 consecutive patients (3 men, 3 women; mean age, 59.3 years) with infrarenal aortic stenosis or occlusion who underwent endovascular intervention at our hospital between April 2009 and February 2014. All patients had bilateral intermittent claudication. The mean preoperative ankle-brachial index (ABI) showed a slight to moderate decrease: right 0.668 and left 0.636. The mean lesion site length was 12.5 mm, the percent stenosis was 90.7%, and calcification was present in 3 patients. Primary stenting was performed in all patients. The stent selected was generally a self-expanding stent (SES). For patients with severe calcification, the stent selected was a balloon-expandable stent (BES). Four patients received an SES and two patients received a BES. The technical success rate was 100%, no complications occurred, and the mean pressure gradient disappeared or decreased. Symptoms resolved in all patients and the postoperative ABI improved: right 0.923 and left 0.968. During a mean follow-up period of 27 months, there were no recurrent symptoms and no restenosis on CT angiography. Endovascular treatment should be considered as a first line treatment for focal infrarenal aortic stenosis and occlusion.

Tetramethylpyrazine analogue CXC195 protects against cerebral ischemia/reperfusion-induced apoptosis through PI3K/Akt/GSK3β pathway in rats.

PubMed

Chen, Lin; Wei, Xinbing; Hou, Yunfeng; Liu, Xiaoqian; Li, Senpeng; Sun, Baozhu; Liu, Xinyong; Liu, Huiqing

2014-01-01

CXC195 showed strongest protective effects among the ligustrazine derivatives in cells and prevented apoptosis induced by H2O2 injury. We recently demonstrated that CXC195 protected against cerebral ischemia/reperfusion (I/R) injury by its antioxidant activity. However, whether the anti-apoptotic action of CXC195 is involved in cerebral I/R injury is unknown. Here, we investigated the role of CXC195 in apoptotic processes induced by cerebral I/R and the possible signaling pathways. Male Wistar rats were submitted to transient middle cerebral artery occlusion for 2h, followed by 24h reperfusion. CXC195 was injected intraperitoneally at 2h and 12h after the onset of ischemia. The number of apoptotic cells was measured by TUNEL assay, apoptosis-related protein cleaved caspase-3, Bcl-2, Bax and the phosphorylation levels of Akt and GSK3β in ischemic penumbra were assayed by western blot. The results showed that administration of CXC195 at the doses of 3mg/kg and 10mg/kg significantly inhibited the apoptosis by decreasing the number of apoptotic cells, decreasing the level of cleaved caspase-3 and Bax, and increasing the level of Bcl-2 in rats subjected to I/R injury. Simultaneously, CXC195 treatment markedly increased the phosphorylation of Akt and GSK3β. Blockade of PI3K activity by wortmannin, dramatically abolished its anti-apoptotic effect and lowered both Akt and GSK3β phosphorylation levels. Our study firstly demonstrated that CXC195 protected against cerebral I/R injury by reducing apoptosis in vivo and PI3K/Akt/GSK3β pathway involved in the anti-apoptotic effect. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Overexpression of Thioredoxin in Transgenic Mice Attenuates Focal Ischemic Brain Damage

NASA Astrophysics Data System (ADS)

Takagi, Yasushi; Mitsui, Akira; Nishiyama, Akira; Nozaki, Kazuhiko; Sono, Hiroshi; Gon, Yasuhiro; Hashimoto, Nobuo; Yodoi, Junji

1999-03-01

Thioredoxin (TRX) plays important biological roles both in intra- and extracellular compartments, including in regulation of various intracellular molecules via thiol redox control. We produced TRX overexpressing mice and confirmed that there were no anatomical and physiological differences between wild-type (WT) mice and TRX transgenic (Tg) mice. In the present study we subjected mice to focal brain ischemia to shed light on the role of TRX in brain ischemic injury. At 24 hr after middle cerebral artery occlusion, infarct areas and volume were significantly smaller in Tg mice than in WT mice. Moreover neurological deficit was ameliorated in Tg mice compared with WT mice. Protein carbonyl content, a marker of cellular protein oxidation, in Tg mice showed less increase than did that of WT mice after the ischemic insult. Furthermore, c-fos expression in Tg mice was stronger than in WT mice 1 hr after ischemia. Our results suggest that transgene expression of TRX decreased ischemic neuronal injury and that TRX and the redox state modified by TRX play a crucial role in brain damage during stroke.

Initial experience of coiling cerebral aneurysms using the new Comaneci device

PubMed Central

Lawson, Aimee Louise Deborah; Chandran, Arun; Puthuran, Mani; Goddard, Tony; Nahser, Hans; Patankar, Tufail

2015-01-01

We present our initial patient experience with an innovative temporary bridging device, the Comaneci (Rapid Medical, Israel), to assist in the coiling of cerebral aneurysms. The Comaneci device confers the same benefits as balloon remodeling but without the risks of parent artery occlusion. This alleviates time pressure on the clinician, and could reduce the risk of parent artery thrombosis. Three patients were treated with the Comaneci device. Two patients had acute ruptured posterior communicating aneurysms and one patient was treated electively for a carotico-ophthalmic aneurysm. Excellent occlusion of all three aneurysms was obtained. One patient developed a distal middle cerebral artery clot, that was treated with intravenous aspirin, with minor neurological consequences. These early results show that the Comaneci device can be used to achieve good cerebral aneurysm occlusion. Vessel patency is maintained throughout the procedure with potential advantages over conventional balloon assisted coiling. PMID:26123460

Influence of Slippery Pacemaker Leads on Lead-Induced Venous Occlusion

NASA Astrophysics Data System (ADS)

Yang, Weiguang; Bhatia, Sagar; Obenauf, Dayna; Resse, Max; Esmaily-Moghadam, Mahdi; Feinstein, Jeffrey; Pak, On Shun

2016-11-01

The use of medical devices such as pacemakers and implantable cardiac defibrillators have become commonplace to treat arrhythmias. Pacing leads with electrodes are used to send electrical pulses to the heart to treat either abnormally slow heart rates, or abnormal rhythms. Lead induced vessel occlusion, which is commonly seen after placement of pacemaker or ICD leads, may result in lead malfunction and/or SVC syndrome, and makes lead extraction difficult. The association between the anatomic locations at risk for thrombosis and regions of venous stasis have been reported previously. The computational studies reveal obvious flow stasis in the proximity of the leads, due to the no-slip boundary condition imposed on the lead surface. With the advent of recent technologies capable of creating slippery surfaces that can repel complex fluids including blood, we explore computationally how local flow structures may be altered in the regions around the leads when the no-slip boundary condition on the lead surface is relaxed using various slip lengths. The findings evaluate the possibility of mitigating risks of lead-induced thrombosis and occlusion by implementing novel surface conditions (i.e. theoretical coatings) on the leads.

Occlusion of M1 segment after superficial temporal artery-middle cerebral artery bypass in a giant M1 aneurysm with Onyx-34 injected via a double-lumen balloon under balloon inflation.

PubMed

Clarençon, Frédéric; Nouet, Aurelien; Redondo, Aimée; Di Maria, Federico; Iosif, Christina; Le Jean, Lise; Chiras, Jacques; Sourour, Nader

2013-05-31

A 29-year-old patient attended our institution for recurrent strokes related to a giant partially thrombosed M1 aneurysm. Superficial temporal artery-middle cerebral artery (STA-MCA) bypass and subsequent occlusion of both the aneurysm and the dysplastic M1 segment were planned. However, owing to the shortness of the non-dysplastic segment of M1 and the risk of occlusion of the lenticulostriate arteries, the use of a double-lumen balloon was considered for coiling and subsequent injection of Onyx. STA-MCA bypass was performed using a regular technique. Endovascular occlusion of both the aneurysm and the parent artery was subsequently performed by means of coils and Onyx-34 that was injected via the Ascent balloon under balloon inflation. No complications were recorded and no stroke was observed on control MRI. The injection of Onyx-34 through a double-lumen balloon under balloon inflation is a quick and safe technique for precise occlusion of a parent artery.

Occlusion of M1 segment after superficial temporal artery-middle cerebral artery bypass in a giant M1 aneurysm with Onyx-34 injected via a double-lumen balloon under balloon inflation.

PubMed

Clarençon, Frédéric; Nouet, Aurelien; Redondo, Aimée; Di Maria, Federico; Iosif, Christina; Le Jean, Lise; Chiras, Jacques; Sourour, Nader

2014-05-01

A 29-year-old patient attended our institution for recurrent strokes related to a giant partially thrombosed M1 aneurysm. Superficial temporal artery-middle cerebral artery (STA-MCA) bypass and subsequent occlusion of both the aneurysm and the dysplastic M1 segment were planned. However, owing to the shortness of the non-dysplastic segment of M1 and the risk of occlusion of the lenticulostriate arteries, the use of a double-lumen balloon was considered for coiling and subsequent injection of Onyx. STA-MCA bypass was performed using a regular technique. Endovascular occlusion of both the aneurysm and the parent artery was subsequently performed by means of coils and Onyx-34 that was injected via the Ascent balloon under balloon inflation. No complications were recorded and no stroke was observed on control MRI. The injection of Onyx-34 through a double-lumen balloon under balloon inflation is a quick and safe technique for precise occlusion of a parent artery.

Occlusion of M1 segment after superficial temporal artery-middle cerebral artery bypass in a giant M1 aneurysm with Onyx-34 injected via a double-lumen balloon under balloon inflation

PubMed Central

Clarençon, Frédéric; Nouet, Aurelien; Redondo, Aimée; Di Maria, Federico; Iosif, Christina; Le Jean, Lise; Chiras, Jacques; Sourour, Nader

2013-01-01

A 29-year-old patient attended our institution for recurrent strokes related to a giant partially thrombosed M1 aneurysm. Superficial temporal artery-middle cerebral artery (STA-MCA) bypass and subsequent occlusion of both the aneurysm and the dysplastic M1 segment were planned. However, owing to the shortness of the non-dysplastic segment of M1 and the risk of occlusion of the lenticulostriate arteries, the use of a double-lumen balloon was considered for coiling and subsequent injection of Onyx. STA-MCA bypass was performed using a regular technique. Endovascular occlusion of both the aneurysm and the parent artery was subsequently performed by means of coils and Onyx-34 that was injected via the Ascent balloon under balloon inflation. No complications were recorded and no stroke was observed on control MRI. The injection of Onyx-34 through a double-lumen balloon under balloon inflation is a quick and safe technique for precise occlusion of a parent artery. PMID:23729720

Cortical spreading depression preconditioning mediates neuroprotection against ischemic stroke by inducing AMP-activated protein kinase-dependent autophagy in a rat cerebral ischemic/reperfusion injury model.

PubMed

Shen, Pingping; Hou, Shuai; Zhu, Mingqin; Zhao, Mingming; Ouyang, Yibing; Feng, Jiachun

2017-03-01

Cortical spreading depression (CSD), based on its similarities with peri-infarct depolarization, is an ideal model for investigating transformation from the ischemic penumbra to infarct core. However, the underlying mechanisms remain unclear. To our knowledge, this is the first study to use a middle cerebral artery occlusion ischemic-reperfusion (I/R) injury model to determine whether AMP-activated protein kinase (AMPK)-dependent autophagy contributes to the neuroprotection of CSD preconditioning in rat cortex. In this study, we topically applied a pledget soaked in 1 mol/L KCl solution on rat cortex for 2 h to elicite CSD or 1 mol/L NaCl solution as a control. The results demonstrated that CSD preconditioning significantly decreased the infarct volume, neurological deficits and neuronal apoptosis in the cortical penumbra of middle cerebral artery occlusion rats, which was inhibited by the autophagy inhibitor 3-methyladenine (3-MA, 200 nmol). Furthermore, CSD increased the protein levels of the autophagy markers LC3-II, Beclin-1 and the p-AMPK (Thr 172 )/AMPK ratio at 12 h and decreased P62 and p-P70S6K (Thr 389 ). Moreover, the AMPK inhibitor Compound C (20 mg/kg) down-regulated the LC3-II, p-AMPK (Thr 172 )/AMPK and ULK1 levels, up-regulated the P62 and p-P70S6K (Thr 389 ) levels induced by CSD. The neuroprotection of CSD is likely a result of AMPK-mediated autophagy activity and autophagy-induced neuronal cells apoptosis inhibition. These novel findings support a central role for AMPK and autophagy in CSD-induced ischemic tolerance. AMPK-mediated autophagy may represent a new target for stroke. © 2016 International Society for Neurochemistry.

Tenacity of Collateral Perfusion in Proximal Cerebral Arterial Occlusions 6-12 h after Onset.

PubMed

Kim, Beom Joon; Kim, Hyeran; Jeong, Han-Gil; Yang, Mi Hwa; Jung, Cheol Kyu; Han, Moon-Ku; Kim, Jae Hyoung; Demchuk, Andrew M; Bae, Hee-Joon

2018-06-07

Clinical trials have shown that benefits of endovascular recanalization (EVT) for acute ischemic stroke patients with sizable penumbral tissues seems plausible even beyond 6 h after their last seen normal (LSN). Persistency of ischemic penumbra remains unclear in delayed periods. From a prospective stroke registry database, we identified 111 acute ischemic stroke patients who had internal carotid artery or middle cerebral artery occlusion with baseline National Institutes of Health Stroke Scale scores ≥6 points and arrived 6-12 h after LSN. Baseline information and functional outcomes were prospectively collected as a clinical registry. Attending physicians made treatment decisions for EVT based on the current guidelines and institutional protocols. MR image parameters, including the volume of diffusion-restricted lesions and mapping of the -hypoperfused area, were quantified using automated commercial software. Binary logistic regression analysis models, with modified Rankin Scale (mRS) scores of 0-1 at 3 months after stroke included as a dependent variable, were constructed. Between 6 and 12 h after onset, 58% had a mismatch ratio of ≥1.8 at baseline and 42% had favorable imaging profiles as determined by DEFUSE 2 study. After 9 h, there was a mismatch ratio of ≥1.8 in 47 and 38% favorable profiles. EVT was performed in 54% of cases. A 3-month mRS score of 0-1 was found in 19% (25% in EVT and 12% in medical treatment groups) of cases. EVT was associated with an increased OR of having a mRS score of 0-1 at 3 months after stroke (adjusted OR 7.59 [95% CI 1.28-61.60]). Penumbral tissues were persistent in a substantial proportion of anterior circulation occlusion cases 6-12 h after LSN. EVT at 6-12 h in a predominantly Asian cohort resulted in better outcomes. © 2018 S. Karger AG, Basel.

Assessment of Blood-Brain Barrier Permeability by Dynamic Contrast-Enhanced MRI in Transient Middle Cerebral Artery Occlusion Model after Localized Brain Cooling in Rats.

PubMed

Kim, Eun Soo; Lee, Seung-Koo; Kwon, Mi Jung; Lee, Phil Hye; Ju, Young-Su; Yoon, Dae Young; Kim, Hye Jeong; Lee, Kwan Seop

2016-01-01

The purpose of this study was to evaluate the effects of localized brain cooling on blood-brain barrier (BBB) permeability following transient middle cerebral artery occlusion (tMCAO) in rats, by using dynamic contrast-enhanced (DCE)-MRI. Thirty rats were divided into 3 groups of 10 rats each: control group, localized cold-saline (20℃) infusion group, and localized warm-saline (37℃) infusion group. The left middle cerebral artery (MCA) was occluded for 1 hour in anesthetized rats, followed by 3 hours of reperfusion. In the localized saline infusion group, 6 mL of cold or warm saline was infused through the hollow filament for 10 minutes after MCA occlusion. DCE-MRI investigations were performed after 3 hours and 24 hours of reperfusion. Pharmacokinetic parameters of the extended Tofts-Kety model were calculated for each DCE-MRI. In addition, rotarod testing was performed before tMCAO, and on days 1-9 after tMCAO. Myeloperoxidase (MPO) immunohisto-chemistry was performed to identify infiltrating neutrophils associated with the inflammatory response in the rat brain. Permeability parameters showed no statistical significance between cold and warm saline infusion groups after 3-hour reperfusion 0.09 ± 0.01 min(-1) vs. 0.07 ± 0.02 min(-1), p = 0.661 for K(trans); 0.30 ± 0.05 min(-1) vs. 0.37 ± 0.11 min(-1), p = 0.394 for kep, respectively. Behavioral testing revealed no significant difference among the three groups. However, the percentage of MPO-positive cells in the cold-saline group was significantly lower than those in the control and warm-saline groups (p < 0.05). Localized brain cooling (20℃) does not confer a benefit to inhibit the increase in BBB permeability that follows transient cerebral ischemia and reperfusion in an animal model, as compared with localized warm-saline (37℃) infusion group.

Klotho upregulation contributes to the neuroprotection of ligustilide against cerebral ischemic injury in mice.

PubMed

Long, Fang-Yi; Shi, Meng-Qi; Zhou, Hong-Jing; Liu, Dong-Ling; Sang, Na; Du, Jun-Rong

2018-02-05

Klotho, an aging-suppressor gene, encodes a protein that potentially acts as a neuroprotective factor. Our previous studies showed that ligustilide minimizes the cognitive dysfunction and brain damage induced by cerebral ischemia; however, the underlying mechanisms remain unclear. This study aims to investigate whether klotho is involved in the protective effects of ligustilide against cerebral ischemic injury in mice. Cerebral ischemia was induced by bilateral common carotid arterial occlusion. Neurobehavioral tests as well as Nissl and Fluoro-Jade B staining were used to evaluate the protective effects of ligustilide in cerebral ischemia, and Western blotting and ELISA approaches were used to investigate the underlying mechanisms. Administration of ligustilide prevented the development of neurological deficits and reduced neuronal loss in the hippocampal CA1 region and the caudate putamen after cerebral ischemia. The protective effects were associated with inhibition of the RIG-I/NF-κB p65 and Akt/FoxO1 pathways and with prevention of inflammation and oxidative stress in the brain. Further, downregulation of klotho could attenuate the neuroprotection of ligustilide against cerebral ischemic injury. Ligustilide exerted neuroprotective effects in mice after cerebral ischemia by regulating anti-inflammatory and anti-oxidant signaling pathways. Furthermore, klotho upregulation contributes to the neuroprotection of LIG against cerebral ischemic injury. These results indicated that ligustilide may be a promising therapeutic agent for the treatment of cerebral ischemia. Copyright © 2017 Elsevier B.V. All rights reserved.

Acute effect of coffee drinking on dynamic cerebral autoregulation.

PubMed

Sasaki, Hiroyuki; Hirasawa, Ai; Washio, Takuro; Ogoh, Shigehiko

2016-05-01

Drinking coffee causes caffeine-induced physiological alterations such as increases in arterial blood pressure, sympathetic nerve activity, cerebral vasoconstriction, etc., and these physiological alterations may be associated with a reduced risk of cerebral vascular disease. However, the effect of coffee drinking on dynamic cerebral blood flow (CBF) regulation remains unclear. The aim of this study was to test our hypothesis that coffee drinking enhances dynamic cerebral autoregulation. Twelve healthy young subjects participated in the present study. After a 5 min baseline measurement in a semi-recumbent position on the hospital bed, each subject drank water (CON) as a placebo condition or coffee beverage (Coffee INT). Arterial blood pressure and middle cerebral artery blood velocity (MCAv) were measured continuously throughout the experiment. At 30 min after the intake of either water or coffee, dynamic cerebral autoregulation was examined using a thigh cuffs occlusion and release technique. Each condition was randomly performed on a different day. Under Coffee INT condition, mean arterial blood pressure was increased (P = 0.01) and mean MCAv was decreased (P = 0.01) from the baseline. The rate of regulation (RoR), as an index of dynamic cerebral autoregulation, during coffee condition was significantly higher than that during CON (P = 0.0009). The findings of the present study suggest that coffee drinking augments dynamic CBF regulation with cerebral vasoconstriction. This phenomenon may be associated with a reduction in the risk of cerebral vascular disease.

Antibody-induced albuminuria and accelerated focal glomerulosclerosis in the Thy-1.1 transgenic mouse.

PubMed

Assmann, Karel J M; van Son, Jacco P H F; Dïjkman, Henry B P M; Mentzel, Stef; Wetzels, Jack F M

2002-07-01

Podocytes play an important role in the development of proteinuria and focal glomerulosclerosis. Previously we have demonstrated that a combination of two monoclonal antibodies (mAb) against aminopeptidase A (APA), an enzyme present on podocytes, induces a massive acute albuminuria in mice. The present study examined the relationship between the acute antibody-induced albuminuria and the development of focal glomerulosclerosis in the Thy-1.1 transgenic mouse. This mouse expresses a hybrid human-mouse Thy-1.1 antigen on the podocytes, and slowly but spontaneously develops albuminuria and focal glomerulosclerosis. Five-week-old non-albuminuric Thy-1.1 transgenic and non-transgenic control mice were injected with anti-APA and anti-Thy-1.1 mAb or saline. Albuminuria was measured at days 1, 7, 14 and 21. At day 21 kidneys were processed for light microscopy, immunofluorescence, and electron microscopy. Injection of anti-APA and anti-Thy1.1 mAb in Thy-1.1 transgenic mice induced an albuminuria at day 1 that persisted at day 21. The acute albuminuria after injection of anti-APA mAb was more prominent but transient in non-transgenic mice. In non-trangenic mice no albuminuria could be induced with anti-Thy 1.1 mAb. Light microscopy revealed normal glomeruli at day 1 in all transgenic mice, however, at day 21 advanced glomerulosclerotic lesions were seen in mice injected with either anti-APA mAb (37+/-19% of glomeruli affected) or anti-Thy-1.1 mAb (71+/-5%). Non-transgenic mice did not reveal sclerotic lesions at any time investigated. In the transgenic mice the percentage of focal glomerulosclerosis at day 21 did not correlate with albuminuria at day 21. However, we found a highly significant correlation between percentage of focal glomerulosclerosis and the time-averaged albuminuria over the three-week study period (P < 0.001). Injection of a combination of anti-APA or anti-Thy-1.1 mAb into one mo old, non-albuminuric Thy-1.1 transgenic mice induces an acute albuminuria at

Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice

PubMed Central

ZHAO, PENG; ZHOU, RU; ZHU, XIAO-YUN; HAO, YIN-JU; LI, NAN; WANG, JIE; NIU, YANG; SUN, TAO; LI, YU-XIANG; YU, JIAN-QIANG

2015-01-01

Matrine, an active constituent of the Chinese herb, Sophora flavescens Ait., and it is known for its antioxidant, anti-inflammatory and antitumor activities. It has been demonstrated that matrine exerts protective effects against heart failure by decreasing the expression of caspase-3 and Bax, and increasing Bcl-2 levels. In this study, we aimed to determine whether these protective effects of matrine can be applied to cerebral ischemia. Following 7 successive days of treatment with matrine (7.5, 15 and 30 mg/kg) and nimodipine (1 mg/kg) by intraperitoneal injection, male Institute of Cancer Research (ICR) mice were subjected to middle cerebral artery occlusion (MCAO). Following reperfusion, the neurobehavioral score and brain infarct volume were estimated, and morphological changes were analyzed by hematoxylin and eosin (H&E) staining and electron microscopy. The percentage of apoptotic neurons was determined by flow cytometry. The levels of oxidative stress were assessed by measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), and the total antioxidant capacity (T-AOC). Western blot analysis and immunofluorescence staining were used to examine the expression of the apoptosis-related proteins, caspase-3, Bax and Bcl-2. Our results revealed that pre-treatment with matrine significantly decreased the infarct volume and improved the neurological scores. Matrine also reduced the percentage of apoptotic neurons and relieved neuronal morphological damage. Furthermore, matrine markedly decreased the MDA levels, and increased SOD, GSH-Px and CAT activity, and T-AOC. Western blot analysis and immunofluorescence staining revealed a marked decrease in caspase-3 expression and an increase in the Bcl-2/Bax ratio in the group pre-treated with matrine (30 mg/kg) as compared with the vehicle-treated group. The findings of the present study demonstrate that matrine exerts neuroprotective effects against

VEGF attenuated increase of outward delayed-rectifier potassium currents in hippocampal neurons induced by focal ischemia via PI3-K pathway.

PubMed

Wu, K W; Yang, P; Li, S S; Liu, C W; Sun, F Y

2015-07-09

We recently indicated that the vascular endothelial growth factor (VEGF) protects neurons against hypoxic death via enhancement of tyrosine phosphorylation of Kv1.2, an isoform of the delayed-rectifier potassium channels through activation of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway. The present study investigated whether VEGF could attenuate ischemia-induced increase of the potassium currents in the hippocampal pyramidal neurons of rats after ischemic injury. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) to induce brain ischemia. The whole-cell patch-clamp technique was used to record the potassium currents of hippocampal neurons in brain slices from the ischemically injured brains of the rats 24h after MCAO. We detected that transient MCAO caused a significant increase of voltage-gated potassium currents (Kv) and outward delayed-rectifier potassium currents (IK), but not outward transient potassium currents (IA), in the ipsilateral hippocampus compared with the sham. Moreover, we found that VEGF could acutely, reversibly and voltage-dependently inhibit the ischemia-induced IK increase. This inhibitory effect of VEGF could be completely abolished by wortmannin, an inhibitor of PI3-K. Our data indicate that VEGF attenuates the ischemia-induced increase of IK via activation of the PI3-K signaling pathway. Published by Elsevier Ltd.

Cerebral infarction in association with Ecstasy abuse.

PubMed

Manchanda, S; Connolly, M J

1993-11-01

A previously fit 35 year old man presented with a right hemiparesis and dysphasia 36 hours after abuse of Ecstasy (3,4-methylenedioxymethamphetamine). Computerized axial tomography scan demonstrated an extensive acute left cerebral infarction and carotid digital subtraction angiogram, 2 days after admission, revealed left middle cerebral artery occlusion. There were no other known risk factors and all other investigations were negative. The patient made a partial recovery. We propose an association between Ecstasy abuse and cerebral infarction.

Protective effects of intraperitoneal injection of TAT-SOD against focal cerebral ischemia/reperfusion injury in rats.

PubMed

Ye, Nanhui; Liu, Shutao; Lin, Yanyun; Rao, Pingfan

2011-12-05

The intracellular superoxide anion has been shown to be involved in brain injury. TAT-Superoxide dismutase (TAT-SOD) can be transduced across the cell membrane to scavenge superoxide. This protein's unique properties make it a promising therapeutic candidate to attenuate cerebral damage. In this study, we sought further the understanding of the fusion protein's cerebral protective effects and the mechanism which is exerted in these effects. Male Sprague Dawley rats (n=100, 230±20 g) were divided randomly into five experimental groups: a sham group, a cerebral Ischemia/Reperfusion (I/R) group treated with saline (20 ml/Kg, i.p.), and three cerebral I/R groups treated with TAT-SOD (25 KU/ml/Kg, i.p.) at either 2h before I/R, 2h after I/R or 4h after I/R. Cerebral I/R injury was facilitated by inducing ischemia for two hours followed by 24h reperfusion. The levels of SOD, Malondialdehyde (MDA), and ATPase in cerebral tissues were determined. The apoptotic indexes were evaluated, and apoptosis genes were analyzed immunohistochemically. TAT-SOD treatment significantly increased cerebral SOD and ATPase activities, decreased MDA content, and remarkably reduced apoptosis indexes. TAT-SOD treatments 2h before or after I/R significantly reduced caspase-3 and bax proteins and boosted bcl-2 protein, while the treatment at 4h after I/R showed no influence on the three proteins. TAT-SOD treatment effectively enhanced cerebral antioxidant ability, reduced lipid peroxidation, preserved mitochondrial ATPase and thus inhibited nerve cell apoptosis. The effective treatment window extended from 2h before to 2h after I/R. Copyright © 2011 Elsevier B.V. All rights reserved.

Focal Contacts as Mechanosensors

PubMed Central

Riveline, Daniel; Zamir, Eli; Balaban, Nathalie Q.; Schwarz, Ulrich S.; Ishizaki, Toshimasa; Narumiya, Shuh; Kam, Zvi; Geiger, Benjamin; Bershadsky, Alexander D.

2001-01-01

The transition of cell–matrix adhesions from the initial punctate focal complexes into the mature elongated form, known as focal contacts, requires GTPase Rho activity. In particular, activation of myosin II–driven contractility by a Rho target known as Rho-associated kinase (ROCK) was shown to be essential for focal contact formation. To dissect the mechanism of Rho-dependent induction of focal contacts and to elucidate the role of cell contractility, we applied mechanical force to vinculin-containing dot-like adhesions at the cell edge using a micropipette. Local centripetal pulling led to local assembly and elongation of these structures and to their development into streak-like focal contacts, as revealed by the dynamics of green fluorescent protein–tagged vinculin or paxillin and interference reflection microscopy. Inhibition of Rho activity by C3 transferase suppressed this force-induced focal contact formation. However, constitutively active mutants of another Rho target, the formin homology protein mDia1 (Watanabe, N., T. Kato, A. Fujita, T. Ishizaki, and S. Narumiya. 1999. Nat. Cell Biol. 1:136–143), were sufficient to restore force-induced focal contact formation in C3 transferase-treated cells. Force-induced formation of the focal contacts still occurred in cells subjected to myosin II and ROCK inhibition. Thus, as long as mDia1 is active, external tension force bypasses the requirement for ROCK-mediated myosin II contractility in the induction of focal contacts. Our experiments show that integrin-containing focal complexes behave as individual mechanosensors exhibiting directional assembly in response to local force. PMID:11402062

Is chlormethiazole neuroprotective in experimental global cerebral ischemia? A microdialysis and behavioral study.

PubMed

Thaminy, S; Reymann, J M; Heresbach, N; Allain, H; Lechat, P; Bentué-Ferrer, D

1997-04-01

Chlormethiazole, an anticonvulsive agent, has been shown to have a possible neuroprotective effect against cerebral ischemia. In addition, chlormethiazole inhibits methamphetamine-induced release of dopamine, protecting against this neurotransmitter's neurotoxicity. The aim of this work was to ascertain whether, in experimental cerebral ischemia, chlormethiazole administration attenuated the ischemia-induced rise of the extracellular concentration of aminergic neurotransmitters and whether it reduces ischemia-induced deficits in memory and learning. Histology for assessment of ischemic damage was a so included. The four-vessel occlusion rat model was used to induce global cerebral ischemia. Aminergic neurotransmitters and their metabolites in the striatal extracellular fluid obtained by microdialysis were assayed by high-performance liquid chromatography-electrochemical detection. The drug was administered either IP (50 mg/kg-1) or directly through the dialysis probe (30 microM) 80 min before ischemia. For the behavioral test and histology, the drug was given IP (100 mg/kg-1) 1 h postischemia. The results obtained did not demonstrate any statistically significant evidence that chlormethiazole has an effect on the ischemia-induced rise in extracellular dopamine and serotonin levels. There was also no variation in metabolite levels. Behavioral measures (learning, recall) were not changed appreciably by the treatment. We observed no significant cell protection in the hippocampus (CA1, CA1), striatum, and entorhinal cortex in animals treated with chlormethiazole. We conclude that, under our experimental conditions, chlormethiazole has little or no effect on the neurochemical, neurobehavioral, and histological consequences of global cerebral ischemia.

Fluoxetine ameliorates cognitive impairments induced by chronic cerebral hypoperfusion via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats.

PubMed

Luo, Pan; Zhang, Xiaoxue; Lu, Yun; Chen, Cheng; Li, Changjun; Zhou, Mei; Lu, Qing; Xu, Xulin; Shen, Guanxin; Guo, Lianjun

2016-01-01

Chronic cerebral hypoperfusion (CCH) causes cognitive impairments and increases the risk of Alzheimer's disease (AD) and vascular dementia (VD) through several biologically plausible pathways, yet the underlying neurobiological mechanisms are still poorly understood. In this study, we investigated whether fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could play a neuroprotective role against chronic cerebral hypoperfusion injury and to clarify underlying mechanisms of its efficacy. Rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). Two weeks later, rats were treated with 30 mg/kg fluoxetine (intragastric injection, i.g.) for 6 weeks. Cognitive function was evaluated by Morris water maze (MWM) and novel objects recognition (NOR) test. Long-term potentiation (LTP) was used to address the underlying synaptic mechanisms. Western blotting was used to quantify the protein levels. Our results showed that fluoxetine treatment significantly improved the cognitive impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, 2VO caused an up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) surface expressions in the hippocampal CA1 area and fluoxetine also effectively recovered the disorder of HCN2 surface expressions, which may be a possible mechanism that fluoxetine treatment ameliorates cognitive impairments in rats with CCH. Copyright © 2015 Elsevier Inc. All rights reserved.

A microarray study of gene and protein regulation in human and rat brain following middle cerebral artery occlusion

PubMed Central

Mitsios, Nick; Saka, Mohamad; Krupinski, Jerzy; Pennucci, Roberta; Sanfeliu, Coral; Wang, Qiuyu; Rubio, Francisco; Gaffney, John; Kumar, Pat; Kumar, Shant; Sullivan, Matthew; Slevin, Mark

2007-01-01

Background Altered gene expression is an important feature of ischemic cerebral injury and affects proteins of many functional classes. We have used microarrays to investigate the changes in gene expression at various times after middle cerebral artery occlusion in human and rat brain. Results Our results demonstrated a significant difference in the number of genes affected and the time-course of expression between the two cases. The total number of deregulated genes in the rat was 335 versus 126 in the human, while, of 393 overlapping genes between the two array sets, 184 were changed only in the rat and 36 in the human with a total of 41 genes deregulated in both cases. Interestingly, the mean fold changes were much higher in the human. The expression of novel genes, including p21-activated kinase 1 (PAK1), matrix metalloproteinase 11 (MMP11) and integrase interactor 1, was further analyzed by RT-PCR, Western blotting and immunohistochemistry. Strong neuronal staining was seen for PAK1 and MMP11. Conclusion Our findings confirmed previous studies reporting that gene expression screening can detect known and unknown transcriptional features of stroke and highlight the importance of research using human brain tissue in the search for novel therapeutic agents. PMID:17997827

Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation.

PubMed

Jin, Rong; Xiao, Adam Y; Chen, Rui; Granger, D Neil; Li, Guohong

2017-12-01

Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147 (cluster of differentiation 147), also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses. Focal cerebral ischemia was induced in C57BL/6 mice by a 60-minute transient middle cerebral artery occlusion. Animals were treated with anti-CD147 function-blocking antibody (αCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24 hours after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia. CD147 expression was rapidly increased in ischemic brain endothelium after transient middle cerebral artery occlusion. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after transient middle cerebral artery occlusion. The neuroprotective effects were associated with (1) prevented blood-brain barrier damage, (2) decreased intravascular fibrin and platelet deposition, which in turn reduced thrombosis and increased cerebral perfusion, and (3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced NF-κB (nuclear factor κB) activation, MMP-9 (matrix metalloproteinase-9) activity, and PAI-1 (plasminogen activator inhibitor-1) expression in brain microvascular endothelial cells. Inhibition of CD147 ameliorates acute ischemic stroke by reducing thromboinflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thromboinflammatory disorders. © 2017 American Heart

Cerebroprotective Actions of Triticum aestivum Linn Powder and Bauhinia purpurea Flower Powder in Surgically Induced Cerebral Infraction in Rats.

PubMed

Annapurna, Akula; Vishala, Thonangi C; Bitra, Veera R; Rapaka, Deepthi; Shaik, Asmath

2018-01-01

The prime objective of this study is to evaluate the cerebroprotective actions of Triticum aestivum (wheatgrass) powder and Bauhinia purpurea flower (dev kanchan) powder against the experimentally induced global ischemia reperfusion injury in rats. In the first phase of the studies, 1 h before the surgical procedure, the Wistar rats were orally served with varied doses of wheatgrass powder (5, 10, 30, and 100 μg/kg) and Bauhinia flower powder (30, 100, 200, and 300 μg/kg), respectively. The ischemia was induced by 30-min bilateral carotid artery occlusion in succession to reperfusion for 4 h. It was proved that the wheatgrass powder and Bauhinia flower powder yielded a significant, dose-dependent cerebroprotection in terms of reduction in cerebral infarct size when compared with the control group. Coming to the second phase of the studies, a certain potential dose of 10 μg/kg of wheatgrass and 200 μg/kg of Bauhinia flower powders was selected keeping the protective action in view, and the animals were treated for 15 days. The major findings of the study are that wheatgrass and Bauhinia flower powders significantly augmented the magnitude of the antioxidant enzymes, viz., super oxide dismutase and catalase, and further reduced the levels of lipid peroxidation. The present study clearly showed that the wheatgrass powder and Bauhinia flower powder possess significant antioxidant properties that may act as a key ingredient in various ayurvedic preparations for the treatment of various diseases like cerebral ischemic reperfusion injury. The wheat grass contains high amount of bioflavonoids, alkaloids, SOD etc which are responsible for anti oxidant activity.The Bauhinia purpurea contains glycosides, flavonoids and also plays a major role in DPPH activity which is responsible for anti oxidant activity.The wheat grass (10 mg/kg) and bauhinia (200 mg/kg) significantly(P < 0.0001) reduced the percentage of infract size when compared to Ischemia reperfusion control group

Cerebroprotective Actions of Triticum aestivum Linn Powder and Bauhinia purpurea Flower Powder in Surgically Induced Cerebral Infraction in Rats

PubMed Central

Annapurna, Akula; Vishala, Thonangi C.; Bitra, Veera R.; Rapaka, Deepthi; Shaik, Asmath

2017-01-01

Objective: The prime objective of this study is to evaluate the cerebroprotective actions of Triticum aestivum (wheatgrass) powder and Bauhinia purpurea flower (dev kanchan) powder against the experimentally induced global ischemia reperfusion injury in rats. Materials and Methods: In the first phase of the studies, 1 h before the surgical procedure, the Wistar rats were orally served with varied doses of wheatgrass powder (5, 10, 30, and 100 μg/kg) and Bauhinia flower powder (30, 100, 200, and 300 μg/kg), respectively. The ischemia was induced by 30-min bilateral carotid artery occlusion in succession to reperfusion for 4 h. It was proved that the wheatgrass powder and Bauhinia flower powder yielded a significant, dose-dependent cerebroprotection in terms of reduction in cerebral infarct size when compared with the control group. Coming to the second phase of the studies, a certain potential dose of 10 μg/kg of wheatgrass and 200 μg/kg of Bauhinia flower powders was selected keeping the protective action in view, and the animals were treated for 15 days. Results: The major findings of the study are that wheatgrass and Bauhinia flower powders significantly augmented the magnitude of the antioxidant enzymes, viz., super oxide dismutase and catalase, and further reduced the levels of lipid peroxidation. Conclusions: The present study clearly showed that the wheatgrass powder and Bauhinia flower powder possess significant antioxidant properties that may act as a key ingredient in various ayurvedic preparations for the treatment of various diseases like cerebral ischemic reperfusion injury. SUMMARY The wheat grass contains high amount of bioflavonoids, alkaloids, SOD etc which are responsible for anti oxidant activity.The Bauhinia purpurea contains glycosides, flavonoids and also plays a major role in DPPH activity which is responsible for anti oxidant activity.The wheat grass (10 mg/kg) and bauhinia (200 mg/kg) significantly(P < 0.0001) reduced the percentage of

Neuroprotective effects of pretreatment with minocycline on memory impairment following cerebral ischemia in rats.

PubMed

Naderi, Yazdan; Sabetkasaei, Masoumeh; Parvardeh, Siavash; Moini Zanjani, Taraneh

2017-04-01

Cerebral ischemia leads to memory impairment that is associated with loss of hippocampal CA1 pyramidal neurons. Neuroinflammation and oxidative stress may be implicated in the pathogenesis of ischemia/reperfusion damage. Minocycline has anti-inflammatory and antioxidant properties. We investigated the neuroprotective effects of minocycline in rats subjected to cerebral ischemia/reperfusion injury. Thirty male rats were divided into three groups: control, sham, and minocycline-pretreated group. Minocycline (40 mg/kg) was injected intraperitoneally immediately before surgery, and then ischemia was induced by occlusion of common carotid arteries for 20 min. Seven days after reperfusion, the Morris water-maze task was used to evaluate memory. Nissl staining was also performed to analyze pyramidal cell damage. We measured the contents of malondialdehyde and proinflammatory cytokines in the hippocampus by the thiobarbituric acid method and enzyme-linked immunosorbent assay, respectively. Microglial activation was also investigated by Iba1 immunostaining. The results showed that pretreatment with minocycline prevented memory impairment induced by cerebral ischemia/reperfusion. Minocycline pretreatment also significantly attenuated ischemia-induced pyramidal cell death and microglial activation in the CA1 region and reduced the levels of malondialdehyde and proinflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of ischemic rats. Minocycline showed neuroprotective effects on cerebral ischemia-induced memory deficit probably through its anti-inflammatory and antioxidant activities.

The Effect of PSD-93 Deficiency on the Expression of Early Inflammatory Cytokines Induced by Ischemic Brain Injury.

PubMed

Zhang, Qingxiu; Cheng, Hongyu; Rong, Rong; Yang, Hui; Ji, Qiuhong; Li, Qingjie; Rong, Liangqun; Hu, Gang; Xu, Yun

2015-12-01

The aim of the study was to explore the effect of PSD-93 deficiency on the expression of early inflammatory cytokines induced by cerebral ischemia/reperfusion injury. Ten- to twelve-week-old male PSD-93 knockout (PSD-93 KO) mice (C57BL/6 genetic background) and wild-type (WT) littermates were randomly divided into sham and ischemia/reperfusion (I/R) group. The focal cerebral I/R model was established by middle cerebral artery occlusion (MCAO) suture method. RT-PCR was used to detect the mRNA expression of IL-6, IL-10, Cox-2, iNOS, and TNF-α4h following reperfusion. Infarct volume at different time points after I/R was analyzed using 2,3,5-triphenyl tetrazolium staining, and neurological damage score (neurological severity scores, NSS) was used to evaluate the effect of PSD-93 gene knockout on the MCAO-induced neurological injury. In WT mice, early I/R injury led to the increase in the mRNA expression of proinflammatory cytokines IL-6, Cox-2, iNOS, and TNF-α that coincided with the decrease in the expression of anti-inflammatory cytokine IL-10, as compared to the sham group (P < 0.05). This effect was markedly attenuated by depleting PSD-93 levels by gene knockout. As compared to sham group, in PSD-93 KO mice I/R4h led to downregulation of Cox-2 and iNOS expression, and increase in the mRNA levels of IL-10 (P < 0.05). In addition, following MCAO, PSD-93 KO mice exhibited improved NSS and reduced infarct volumes, as compared with WT animals. PSD-93 knockout may play a neuroprotective role by mediating the early release of inflammatory cytokines induced by cerebral ischemia.

TRPV1 receptor-mediated expression of Toll-like receptors 2 and 4 following permanent middle cerebral artery occlusion in rats

PubMed Central

Hakimizadeh, Elham; Shamsizadeh, Ali; Roohbakhsh, Ali; Arababadi, Mohammad Kazemi; Hajizadeh, Mohammad Reza; Shariati, Mehdi; Fatemi, Iman; Moghadam-ahmadi, Amir; Bazmandegan, Gholamreza; Rezazadeh, Hossein; Allahtavakoli, Mohammad

2017-01-01

Objective(s): Stroke is known as a main cause of mortality and prolonged disability in adults. Both transient receptor potential V1 (TRPV1) channels and toll-like receptors (TLRs) are involved in mediating the inflammatory responses. In the present study, the effects of TRPV1 receptor activation and blockade on stroke outcome and gene expression of TLR2 and TLR4 were assessed following permanent middle cerebral artery occlusion in rats Materials and Methods: Eighty male Wistar rats were divided into four groups as follows: sham, vehicle, AMG9810 (TRPV1 antagonist) -treated and capsaicin (TRPV1 agonist) -treated. For Stroke induction, the middle cerebral artery was permanently occluded and then behavioral functions were evaluated 1, 3 and 7 days after stroke. Results: TRPV1 antagonism significantly reduced the infarct volume compared to the stroke group. Also, neurological deficits were decreased by AMG9810 seven days after cerebral ischemia. In the ledged beam-walking test, the slip ratio was enhanced following ischemia. AMG9810 decreased this index in stroke animals. However, capsaicin improved the ratio 3 and 7 days after cerebral ischemia. Compared to the sham group, the mRNA expression of TLR2 and TLR4 was significantly increased in the stroke rats. AMG9810 Administration significantly reduced the mRNA expression of TLR2 and TLR4. However, capsaicin did not significantly affect the gene expression of TLR2 and TLR4. Conclusion: Our results demonstrated that TRPV1 antagonism by AMG9810 attenuates behavioral function and mRNA expression of TLR2 and TLR4. Thus, it might be useful to shed light on future therapeutic strategies for the treatment of ischemic stroke. PMID:29085577

Dipeptidyl peptidase IV, aminopeptidase N and DPIV/APN-like proteases in cerebral ischemia

PubMed Central

2012-01-01

Background Cerebral inflammation is a hallmark of neuronal degeneration. Dipeptidyl peptidase IV, aminopeptidase N as well as the dipeptidyl peptidases II, 8 and 9 and cytosolic alanyl-aminopeptidase are involved in the regulation of autoimmunity and inflammation. We studied the expression, localisation and activity patterns of these proteases after endothelin-induced occlusion of the middle cerebral artery in rats, a model of transient and unilateral cerebral ischemia. Methods Male Sprague-Dawley rats were used. RT-PCR, immunohistochemistry and protease activity assays were performed at different time points, lasting from 2 h to 7 days after cerebral ischemia. The effect of protease inhibitors on ischemia-dependent infarct volumes was quantified 7 days post middle cerebral artery occlusion. Statistical analysis was conducted using the t-test. Results Qualitative RT-PCR revealed these proteases in ipsilateral and contralateral cortices. Dipeptidyl peptidase II and aminopeptidase N were up-regulated ipsilaterally from 6 h to 7 days post ischemia, whereas dipeptidyl peptidase 9 and cytosolic alanyl-aminopeptidase were transiently down-regulated at day 3. Dipeptidyl peptidase 8 and aminopeptidase N immunoreactivities were detected in cortical neurons of the contralateral hemisphere. At the same time point, dipeptidyl peptidase IV, 8 and aminopeptidase N were identified in activated microglia and macrophages in the ipsilateral cortex. Seven days post artery occlusion, dipeptidyl peptidase IV immunoreactivity was found in the perikarya of surviving cortical neurons of the ipsilateral hemisphere, whereas their nuclei were dipeptidyl peptidase 8- and amino peptidase N-positive. At the same time point, dipeptidyl peptidase IV, 8 and aminopeptidase N were targeted in astroglial cells. Total dipeptidyl peptidase IV, 8 and 9 activities remained constant in both hemispheres until day 3 post experimental ischemia, but were increased (+165%) in the ipsilateral cortex at day 7

Cerebral infarction in association with Ecstasy abuse.

PubMed Central

Manchanda, S.; Connolly, M. J.

1993-01-01

A previously fit 35 year old man presented with a right hemiparesis and dysphasia 36 hours after abuse of Ecstasy (3,4-methylenedioxymethamphetamine). Computerized axial tomography scan demonstrated an extensive acute left cerebral infarction and carotid digital subtraction angiogram, 2 days after admission, revealed left middle cerebral artery occlusion. There were no other known risk factors and all other investigations were negative. The patient made a partial recovery. We propose an association between Ecstasy abuse and cerebral infarction. PMID:7904748

Clonidine preconditioning improved cerebral ischemia-induced learning and memory deficits in rats via ERK1/2-CREB/ NF-κB-NR2B pathway.

PubMed

Li, Yanli; Yu, Min; Zhao, Bo; Wang, Yan; Zha, Yunhong; Li, Zicheng; Yu, Lingling; Yan, Lingling; Chen, Zhangao; Zhang, Wenjuan; Zeng, Xiaoli; He, Zhi

2018-01-05

Clonidine, a classical α-2 adrenergic agonists, has been shown to antagonize brain damage caused by hypoxia, cerebral ischemia and excitotoxicity and reduce cerebral infarction volume in recent studies. We herein investigate the regulatory effect and possible underlying mechanism of clonidine on learning and memory in rats with cerebral ischemia. The cerebral ischemia rat model was established by right middle cerebral artery occlusion for 2h and reperfusion for 28 days. Drugs were administrated to the rats for consecutive 7 days intraperitoneally and once again on the day of surgery. The learning and memory in rats was assayed by Morris water maze. Moreover, protein expression levels of NMDAR2B (NR2B)/ phosphor - NR2B, ERK1/2/phosphor- ERK1/2, CREB/phosphor-CREB and NF-κB/phosphor-NF-κB in the cortex and hippocampus of the rats were assayed by western blotting. Our results demonstrated that clonidine treatment significantly abrogated the negative effect induced by cerebral ischemia on the learning and memory in the rats. In the Western blotting assay, clonidine treatment led to significant up-regulation of the expression level of NR2B and Phospho-NR2B in the hippocampus of the rats when compared with the cerebral ischemia group. Furthermore, clonidine also significantly decreased the protein expression levels of ERK1/2, Phospho-ERK1/2, CREB, Phospho-CREB and Phospho-NF-κB in the hippocampus of the rats when compared with the cerebral ischemia group. In conclusion, clonidine could improve the learning and memory ability of rats with cerebral ischemia, and NR2B, ERK1/2, CREB, NF-κB were involved in this effect. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuroimaging findings in children with retinopathy-confirmed cerebral malaria.

PubMed

Potchen, Michael J; Birbeck, Gretchen L; Demarco, J Kevin; Kampondeni, Sam D; Beare, Nicholas; Molyneux, Malcolm E; Taylor, Terrie E

2010-04-01

To describe brain CT findings in retinopathy-confirmed, paediatric cerebral malaria. In this outcomes study of paediatric cerebral malaria, a subset of children with protracted coma during initial presentation was scanned acutely. Survivors experiencing adverse neurological outcomes also underwent a head CT. All children had ophthalmological examination to confirm the presence of the retinopathy specific for cerebral malaria. Independent interpretation of CT images was provided by two neuroradiologists. Acute brain CT findings in three children included diffuse oedema with obstructive hydrocephalus (2), acute cerebral infarctions in multiple large vessel distributions with secondary oedema and herniation (1), and oedema of thalamic grey matter (1). One child who was reportedly normal prior to admission had parenchymal atrophy suggestive of pre-existing CNS injury. Among 56 survivors (9-84 months old), 15 had adverse neurologic outcomes-11/15 had a follow-up head CT, 3/15 died and 1/15 refused CT. Follow-up head CTs obtained 7-18 months after the acute infection revealed focal and multifocal lobar atrophy correlating to regions affected by focal seizures during the acute infection (5/11). Other findings were communicating hydrocephalus (2/11), vermian atrophy (1/11) and normal studies (3/11). The identification of pre-existing imaging abnormalities in acute cerebral malaria suggests that population-based studies are required to establish the rate and nature of incidental imaging abnormalities in Malawi. Children with focal seizures during acute cerebral malaria developed focal cortical atrophy in these regions at follow-up. Longitudinal studies are needed to further elucidate mechanisms of CNS injury and death in this common fatal disease. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Endothelial dysfunction in rat mesenteric resistance artery after transient middle cerebral artery occlusion.

PubMed

Martinez-Revelles, Sonia; Jiménez-Altayó, Francesc; Caracuel, Laura; Pérez-Asensio, Fernando J; Planas, Anna M; Vila, Elisabet

2008-05-01

Stroke triggers a local and systemic inflammatory response leading to the production of cytokines that can influence blood vessel reactivity. In this study, we aimed to assess whether cerebral ischemia/reperfusion could affect vasoconstriction and vasodilatation on mesenteric resistance arteries (MRA) from Wistar Kyoto rats. The right middle cerebral artery was occluded (90 min) and reperfused (24 h). Sham-operated animals were used as controls. Plasma levels of interleukin (IL)-6 and IL-1beta were measured at 24 h. Vasoconstrictor and vasodilator responses were recorded in a wire myograph. Protein expression was determined by Western blot and immunofluorescence, and superoxide anion (O(2)(.)) production was evaluated by ethidium fluorescence. In MRA, ischemia/reperfusion increased plasma levels of IL-6, O2. production, protein expression of cyclooxygenase-2, and protein tyrosine nitrosylation, but it impaired acetylcholine (ACh) vasodilatation without modifying the vasodilatations to sodium nitroprusside or the contractions to phenylephrine and KCl. Superoxide dismutase (SOD) and indomethacin reversed the impairment of ACh relaxation induced by ischemia/reperfusion. However, N(omega)-nitro-l-arginine methyl ester affected similarly ACh-induced vasodilatations in MRA of ischemic and sham-operated rats. Protein expression of endothelial and inducible nitric-oxide synthase, copper/zinc SOD, manganese SOD, and extracellular SOD was similar in both groups of rats. Our results show MRA endothelial dysfunction 24 h after brain ischemia/reperfusion. Excessive production of O2. in MRA mediates endothelial dysfunction, and the increase in plasma cytokine levels after brain ischemia/reperfusion might be involved in this effect.

Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor {kappa}B p65 activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xue, Xia; Center for New Drugs Evaluation, Shandong University, Jinan 250012; Qu, Xian-Jun

Research highlights: {yields} Permanent NF-{kappa}B p65 activation contributes to the infarction after ischemia-reperfusion injury in rats. {yields} Baicalin can markedly inhibit the nuclear NF-{kappa}B p65 expression and m RNA levels after ischemia-reperfusion injury in rats. {yields} Baicalin decreased the cerebral infarction area via inhibiting the activation of nuclear NF-{kappa}B p65. -- Abstract: Baicalin is a flavonoid compound purified from plant Scutellaria baicalensis Georgi. We aimed to evaluate the neuroprotective effects of baicalin against cerebral ischemic reperfusion injury. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. Baicalin at dosesmore » of 50, 100 and 200 mg/kg was intravenously injected after ischemia onset. Twenty-four hours after reperfusion, the neurological deficit was scored and infarct volume was measured. Hematoxylin and eosin (HE) staining was performed to analyze the histopathological changes of cortex and hippocampus neurons. We examined the levels of NF-{kappa}B p65 in ischemic cortexes by Western blot analysis and RT-PCR assay. The results showed that the neurological deficit scores were significantly decreased from 2.0 {+-} 0.7 to 1.2 {+-} 0.4 and the volume of infarction was reduced by 25% after baicalin injection. Histopathological examination showed that the increase of neurons with pycnotic shape and condensed nuclear in cortex and hippocampus were not observed in baicalin treated animals. Further examination showed that NF-{kappa}B p65 in cortex was increased after ischemia reperfusion injury, indicating the molecular mechanism of ischemia reperfusion injury. The level of NF-{kappa}B p65 was decreased by 73% after baicalin treatment. These results suggest that baicalin might be useful as a potential neuroprotective agent in stroke therapy. The neuroprotective effects of baicalin may relate to inhibition of NF-{kappa}B p65.« less

Relationship between regional cerebral metabolism and consciousness disturbance in traumatic diffuse brain injury without large focal lesions: an FDG-PET study with statistical parametric mapping analysis.

PubMed

Nakayama, N; Okumura, A; Shinoda, J; Nakashima, T; Iwama, T

2006-07-01

The cerebral metabolism of patients in the chronic stage of traumatic diffuse brain injury (TDBI) has not been fully investigated. To study the relationship between regional cerebral metabolism (rCM) and consciousness disturbance in patients with TDBI. 52 patients with TDBI in the chronic stage without large focal lesions were enrolled, and rCM was evaluated by fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) with statistical parametric mapping (SPM). All the patients were found to have disturbed consciousness or cognitive function and were divided into the following three groups: group A (n = 22), patients in a state with higher brain dysfunction; group B (n = 13), patients in a minimally conscious state; and group C (n = 17), patients in a vegetative state. rCM patterns on FDG-PET among these groups were evaluated and compared with those of normal control subjects on statistical parametric maps. Hypometabolism was consistently indicated bilaterally in the medial prefrontal regions, the medial frontobasal regions, the cingulate gyrus and the thalamus. Hypometabolism in these regions was the most widespread and prominent in group C, and that in group B was more widespread and prominent than that in group A. Bilateral hypometabolism in the medial prefrontal regions, the medial frontobasal regions, the cingulate gyrus and the thalamus may reflect the clinical deterioration of TDBI, which is due to functional and structural disconnections of neural networks rather than due to direct cerebral focal contusion.

The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hua, Fang, E-mail: fhua2@emory.edu; Wang, Jun; Sayeed, Iqbal

TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-{kappa}B). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined themore » activation of NF-{kappa}B and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-{kappa}B activity and phosphorylation of the inhibitor of kappa B (I{kappa}B{alpha}) increased in ischemic brains, but IRF3, inhibitor of {kappa}B kinase complex-{epsilon} (IKK{epsilon}), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-{kappa}B activity or p-I{kappa}B{alpha} induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-{kappa}B signaling and brain injury after acute cerebral I/R.« less

Blast-induced phenotypic switching in cerebral vasospasm

PubMed Central

Alford, Patrick W.; Dabiri, Borna E.; Goss, Josue A.; Hemphill, Matthew A.; Brigham, Mark D.; Parker, Kevin Kit

2011-01-01

Vasospasm of the cerebrovasculature is a common manifestation of blast-induced traumatic brain injury (bTBI) reported among combat casualties in the conflicts in Afghanistan and Iraq. Cerebral vasospasm occurs more frequently, and with earlier onset, in bTBI patients than in patients with other TBI injury modes, such as blunt force trauma. Though vasospasm is usually associated with the presence of subarachnoid hemorrhage (SAH), SAH is not required for vasospasm in bTBI, which suggests that the unique mechanics of blast injury could potentiate vasospasm onset, accounting for the increased incidence. Here, using theoretical and in vitro models, we show that a single rapid mechanical insult can induce vascular hypercontractility and remodeling, indicative of vasospasm initiation. We employed high-velocity stretching of engineered arterial lamellae to simulate the mechanical forces of a blast pulse on the vasculature. An hour after a simulated blast, injured tissues displayed altered intracellular calcium dynamics leading to hypersensitivity to contractile stimulus with endothelin-1. One day after simulated blast, tissues exhibited blast force dependent prolonged hypercontraction and vascular smooth muscle phenotype switching, indicative of remodeling. These results suggest that an acute, blast-like injury is sufficient to induce a hypercontraction-induced genetic switch that potentiates vascular remodeling, and cerebral vasospasm, in bTBI patients. PMID:21765001

Acute tryptophan pretreatment protects against behavioral changes caused by cerebral ischemia.

PubMed

Carney, J M

1986-05-15

Male gerbils (Meronies ungulata) were treated with various doses of tryptophan and the changes in spontaneous motor activity determined. Tryptophan decreased behavior at a dose of 200 mg/kg. Cerebral ischemia was produced by bilateral carotid occlusion for 5 min. This duration of ischemia produced a large increase in activity at both 6 h and 24 h postischemia. Tryptophan (200 mg/kg) prevented the ischemia-induced increases in locomotor activity. These data suggest that dietary amino acids may play a role in determining the effects of ischemia.

The effects of neck flexion on cerebral potentials evoked by visual, auditory and somatosensory stimuli and focal brain blood flow in related sensory cortices

PubMed Central

2012-01-01

Background A flexed neck posture leads to non-specific activation of the brain. Sensory evoked cerebral potentials and focal brain blood flow have been used to evaluate the activation of the sensory cortex. We investigated the effects of a flexed neck posture on the cerebral potentials evoked by visual, auditory and somatosensory stimuli and focal brain blood flow in the related sensory cortices. Methods Twelve healthy young adults received right visual hemi-field, binaural auditory and left median nerve stimuli while sitting with the neck in a resting and flexed (20° flexion) position. Sensory evoked potentials were recorded from the right occipital region, Cz in accordance with the international 10–20 system, and 2 cm posterior from C4, during visual, auditory and somatosensory stimulations. The oxidative-hemoglobin concentration was measured in the respective sensory cortex using near-infrared spectroscopy. Results Latencies of the late component of all sensory evoked potentials significantly shortened, and the amplitude of auditory evoked potentials increased when the neck was in a flexed position. Oxidative-hemoglobin concentrations in the left and right visual cortices were higher during visual stimulation in the flexed neck position. The left visual cortex is responsible for receiving the visual information. In addition, oxidative-hemoglobin concentrations in the bilateral auditory cortex during auditory stimulation, and in the right somatosensory cortex during somatosensory stimulation, were higher in the flexed neck position. Conclusions Visual, auditory and somatosensory pathways were activated by neck flexion. The sensory cortices were selectively activated, reflecting the modalities in sensory projection to the cerebral cortex and inter-hemispheric connections. PMID:23199306

Postischemic changes in the immunophilin FKBP12 in the rat brain.

PubMed

Kato, H; Oikawa, T; Otsuka, K; Takahashi, A; Itoyama, Y

2000-12-08

An immunosuppressant tacrolimus (FK506) protects against neuronal damage following cerebral ischemia. On the other hand, the major physiological role of the immunophilin FK506-binding protein-12 (FKBP12) is a modulation of intracellular calcium flux. Since an increase in intracellular calcium concentration is a major mediator of ischemic neuronal death, we investigated the changes in FKBP12 following cerebral ischemia in the rat. We induced focal cerebral ischemia by intraluminal occlusion of the middle cerebral artery for 1 h, and global cerebral ischemia for 10 min by bilateral carotid artery occlusion combined with hypotension. The animals were killed at 4 h to 7 days after reperfusion. Immunohistochemistry was performed on paraffin sections using a monoclonal antibody raised against recombinant FKBP12. Immunoreactivity to FKBP12 in control brains was most pronounced in the CA1 subfield of the hippocampus and the striatum, the localization being primarily neuronal. Following focal ischemia, FKBP12 immunoreactivity decreased rapidly in the ischemic core by 4 h, but increased in surviving neurons in penumbra areas (4 h-7 days). Within an area of infarction, invading leukocytes and macrophages exhibited immunoreactivity to FKBP12 (3-7 days). Following global ischemia, FKBP12 immunoreactivity in CA1 neurons decreased after 1 day, and then it was lost between 2 and 7 days, although many CA1 neurons showed a transient increase in FKBP12 at 2 days. No FKBP12 immunoreactivity was observed in reactive glial cells. Thus, FKBP12 declined in dying neurons, whereas FKBP12 was upregulated in less severely injured neurons. The findings suggest that (1) FKBP12 plays an important role in the process of neuronal survival and death following cerebral ischemia, and (2) FKBP12 is involved in inflammatory reactions that occur within an area of infarction.

Rapamycin decreased blood-brain barrier permeability in control but not in diabetic rats in early cerebral ischemia.

PubMed

Chi, Oak Z; Kiss, Geza K; Mellender, Scott J; Liu, Xia; Weiss, Harvey R

2017-07-27

Diabetes causes functional and structural changes in blood-brain barrier (BBB). The mammalian target of rapamycin (mTOR) has been associated with glucose metabolism, diabetes, and altering BBB permeability. Since there is only a narrow therapeutic window (3h) for stroke victims, it is important to investigate BBB disruption in the early stage of cerebral ischemia. We compared the degree of BBB disruption in diabetic and in control rats at two hours of reperfusion after one hour of middle cerebral artery (MCA) occlusion with or without inhibition of mTOR. Two weeks after streptozotocin ip to induce diabetes, MCA occlusion was performed. In half of the rats, an mTOR inhibitor, rapamycin was given for 2days before MCA occlusion. After one hour of MCA occlusion and two hours of the reperfusion, the transfer coefficient (K i ) of 14 C-α-aminoisobutyric acid was determined to quantify degree of BBB disruption. Ischemia-reperfusion increased the K i in the control animals. Streptozotocin increased the K i in the ischemic-reperfused (IR-C, +22%) as well as in the contralateral cortex (CC, +40%). Rapamycin decreased the K i in the IR-C (-32%) as well as in the CC (-26%) in the control rats. However, rapamycin did not affect K i in the IR-C or in the CC in the diabetic rats. Our data demonstrated a greater BBB disruption in diabetes in the ischemic as well as non-ischemic cortex even in the early stage of cerebral ischemia-reperfusion and that acute administration of rapamycin did not significantly affect BBB permeability in diabetes. From our quantitative analysis of BBB disruption, the vulnerability of BBB in diabetes has been emphasized in the early stage of cerebral ischemia-reperfusion and a less important role of the mTOR pathway is suggested in altering BBB permeability in diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

Long-Term Follow-Up for a Giant Basilar Trunk Aneurysm Surgically Treated by Proximal Occlusion and External Carotid Artery to Posterior Cerebral Artery Bypass Using a Saphenous Vein Graft.

PubMed

Yanagisawa, Toshiharu; Kinouchi, Hiroyuki; Sasajima, Toshio; Shimizu, Hiroaki

2016-11-01

The authors describe a case of a basilar trunk aneurysm with long-term follow-up after successful bypass and proximal occlusion. A 64-year-old woman had a giant aneurysm of the basilar trunk and underwent external carotid artery-to-posterior cerebral artery vein graft bypass surgery and proximal clipping of the basilar artery, which was followed by low-dose aspirin (100 mg/d) treatment. No ischemic symptoms and lesions developed and the thrombosed aneurysm was stable during 11 years of follow-up. An extracranial-intracranial high flow bypass combined with immediate proximal occlusion and aspirin administration may be an acceptable treatment option for patients with giant posterior circulation aneurysms. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Urgent Bypass Surgery Following Failed Endovascular Treatment in Acute Symptomatic Stroke Patient With MCA Occlusion.

PubMed

Lee, Chang Yeob; Kim, Chang Hyun; Lee, Chang-Young; Sohn, Sung-Il; Hong, Jeong-Ho

2017-01-01

Although the benefits of extracranial-intracranial bypass surgery remain controversial, there is some surgical rationale for the augmentation of cerebral blood flow in cases of acute ischemic stroke with hemodynamic instability. We report a case of a 62-year-old woman who suddenly developed right hemiplegia and global aphasia. Initial magnetic resonance imaging and magnetic resonance angiography revealed a small acute ischemic lesion in left parietal lobe with occlusion at the left middle cerebral artery. We performed an endovascular thrombectomy, which failed. Her neurological deficits remained unchanged. On the basis of immediate postendovascular magnetic resonance perfusion, diffusion-weighted imaging (DWI), and neurological examination, an obvious clinical-DWI and a DWI-perfusion-weighted imaging mismatch were detected. We decided to perform emergency superficial temporal artery to middle cerebral artery bypass to prevent further progression of cerebral ischemia. On a 3-month follow-up, neurological deficits remained minimal motor aphasia and dysarthria. Following failed endovascular treatment in patients with acute symptoms attributed to major cerebral artery occlusion, we recommend immediate multimodal neuroimaging. If there are clinical-DWI and DWI-perfusion-weighted imaging mismatch indications, surgical revascularization could be considered as the next salvageable strategy.

Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia.

PubMed

Sun, Li; Zhou, Wei; Mueller, Christian; Sommer, Clemens; Heiland, Sabine; Bauer, Alexander T; Marti, Hugo H; Veltkamp, Roland

2010-09-01

Hyperbaric oxygen (HBO) and normobaric hyperoxia (NBO) protect the brain parenchyma and the cerebral microcirculation against ischemia. We studied their effect on secondary hemorrhage after thrombolysis in two thromboembolic middle cerebral artery occlusion (MCAO) (tMCAO) models. Beginning 60 minutes after tMCAO with either thrombin-induced thromboemboli (TT) or calcium-induced thromboemboli (CT), spontaneously hypertensive rats (n=96) breathed either air, 100% O(2) (NBO), or 100% O(2) at 3 bar (HBO) for 1 hour. Immediately thereafter, recombinant tissue plasminogen activator (rt-PA, 9 mg/kg) was injected. Although significant reperfusion was observed after thrombolysis in TT-tMCAO, vascular occlusion persisted in CT-tMCAO. In TT-tMCAO, NBO and HBO significantly reduced diffusion-weighted imaging-magnetic resonance imaging (MRI) lesion volume and postischemic blood-brain barrier (BBB) permeability on postcontrast T1-weighted images. NBO and, significantly more potently, HBO reduced macroscopic hemorrhage on T2* MRI and on corresponding postmortem cryosections. Oxygen therapy lowered hemoglobin content and attenuated activation of matrix metalloproteinases in the ischemic hemisphere. In contrast, NBO and HBO failed to reduce infarct size in CT but both decreased BBB damage and microscopic hemorrhagic transformation. Only HBO reduced hemoglobin extravasation in the ischemic hemisphere. In conclusion, NBO and HBO decrease infarct size after thromboembolic ischemia only if recanalization is successful. As NBO and HBO also reduce postthrombolytic intracerebral hemorrhage, combining the two with thrombolysis seems promising.

Ultrasonic assessment of cerebral blood flow changes during ischemia-reperfusion in 7-day-old rats.

PubMed

Bonnin, Philippe; Debbabi, Haythem; Mariani, Jean; Charriaut-Marlangue, Christiane; Renolleau, Sylvain

2008-06-01

A model of ischemic brain injury in 7-day-old rat pups has been developed to study perinatal ischemia. It combines permanent occlusion of the distal left middle cerebral artery (LMCA) and transient occlusion of homolateral common carotid artery (LCCA). At removal of the clip on LCCA, reflow allowed brain reperfusion through cortical anastomoses. In 10 rat pups, we measured blood flow velocities (BFV) in main cerebral arteries with 12-MHz ultrasound imaging. At basal states, peak systolic BFV in proximal LMCA was 16.0 +/- 3.0 cm.s(-1). Occlusion of LMCA did not yield significant modifications. Occlusion of LCCA involved only a decrease in BFV to 9.5 +/- 2.6 cm.s(-1) (p < 0.001). Indeed, LMCA was then supply by the right internal carotid and the vertebral arteries through the circle of Willis. In three rat pups, release of occlusion of LCCA was followed by restoration of BFV in the left internal carotid artery and in LMCA, in seven pups, by a reversed flow in the LICA and lower BFV in LMCA (11.9 +/- 2.3, p < 0.05). BFV returned to basal values from h5 to h48 in all animals. In addition, ultrasound imaging is a useful, reproducible, non invasive, easy-to-repeat, method to assess and monitor arterial cerebral blood flow supply in small animals. It helps to characterize changes occurring during cerebral ischemia and reperfusion, particularly the depth of the hypoperfusion, as well as the variability of reflow. In preclinical studies, this method could help to identify what can be assigned to a neuroprotective treatment and what depends on changes in cerebral blood flow supply.

Hyperkinetic transient ischemic attacks preceding deep ganglionic infarction in a patient with a treated parasellar chondrosarcoma.

PubMed

Ruff, Michael W; Bhargav, Adip G; English, Stephen W; Klaas, James P

2018-02-01

A 44-year-old right-handed female with a past medical history of parasellar chondrosarcoma status post-surgical debulking and proton beam therapy (70 Gy) three years prior to presentation experienced several hours of brief, repetitive episodes of transient hemiballism and dystonia; this was followed by abrupt onset of fixed hemiparesis and dysarthria weeks later, ipsilateral to her prior hyperkinetic movements. She was found to have total occlusion of the right middle cerebral artery with focal stenosis of the proximal right A-1 segment of the anterior cerebral artery adjacent to the remnants of the chondrosarcoma. These focal areas of narrowing were attributed to accelerated atherosclerotic disease, an adverse effect of the radiotherapy used to treat her chondrosarcoma. As treatments improve and mean survival increases for intracranial malignancy, radiation-induced atherosclerotic disease with protean manifestations such as those presented in this case may be encountered more frequently. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dynamic change in cerebral microcirculation and focal cerebral metabolism in experimental subarachnoid hemorrhage in rabbits.

PubMed

Song, Jin-Ning; Chen, Hu; Zhang, Ming; Zhao, Yong-Lin; Ma, Xu-Dong

2013-03-01

Regional cerebral blood flow (rCBF) in the cerebral metabolism and energy metabolism measurements can be used to assess blood flow of brain cells and to detect cell activity. Changes of rCBF in the cerebral microcirculation and energy metabolism were determined in an experimental model of subarachnoid hemorrhage (SAH) model in 56 large-eared Japanese rabbits about 12 to 16-month old. Laser Doppler flowmetry was used to detect the blood supply to brain cells. Internal carotid artery and vein blood samples were used for duplicate blood gas analysis to assess the energy metabolism of brain cells. Cerebral blood flow (CBF) was detected by single photon emission computed tomography (SPECT) perfusion imaging using Tc-99m ethyl cysteinate dimer (Tc-99m ECD) as an imaging reagent. The percentage of injected dose per gram of brain tissue was calculated and analyzed. There were positive correlations between the percentage of radionuclide injected per gram of brain tissue and rCBF supply and cerebral metabolic rate for oxygen (P < 0.05). However, there was a negative correlation between radioactivity counts per unit volume detected on the SPECT rheoencephalogram and lactic acid concentration in the homolateral internal carotid artery and vein. In summary, this study found abnormal CBF in metabolism and utilization of brain cells after SAH, and also found that deterioration of energy metabolism of brain cells played a significant role in the development of SAH. There are matched reductions in CBF and metabolism. Thus, SPECT imaging could be used as a noninvasive method to detect CBF.

Interferon-β Modulates Inflammatory Response in Cerebral Ischemia.

PubMed

Kuo, Ping-Chang; Scofield, Barbara A; Yu, I-Chen; Chang, Fen-Lei; Ganea, Doina; Yen, Jui-Hung

2016-01-08

Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-β (IFNβ), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade. Its anti-inflammatory properties and well-characterized safety profile suggest that IFNβ has therapeutic potential for the treatment of ischemic stroke. We investigated the therapeutic effect of IFNβ in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNβ not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNβ modulates ischemic brain inflammation were identified. IFNβ reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4(+) T cells, and γδ T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain. Our results demonstrate that IFNβ exerts a protective effect against ischemic stroke through its anti-inflammatory properties and suggest that IFNβ is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Optimization of confocal laser induced fluorescence for long focal length applications

NASA Astrophysics Data System (ADS)

Jemiolo, Andrew J.; Henriquez, Miguel F.; Thompson, Derek S.; Scime, Earl E.

2017-10-01

Laser induced fluorescence (LIF) is a non-perturbative diagnostic for measuring ion and neutral particle velocities and temperatures in a plasma. The conventional method for single-photon LIF requires intersecting optical paths for light injection and collection. The multiple vacuum windows needed for such measurements are unavailable in many plasma experiments. Confocal LIF eliminates the need for perpendicular intersecting optical paths by using concentric injection and collection paths through a single window. One of the main challenges with using confocal LIF is achieving high resolution measurements at the longer focal lengths needed for many plasma experiments. We present confocal LIF measurements in HELIX, a helicon plasma experiment at West Virginia University, demonstrating spatial resolution dependence on focal length and spatial filtering. By combining aberration mitigating optics with spatial filtering, our results show high resolution measurements at focal lengths of 0.5 m, long enough to access the interiors of many laboratory plasma experiments. This work was supported by U.S. National Science Foundation Grant No. PHY-1360278.

Assessment of Blood-Brain Barrier Permeability by Dynamic Contrast-Enhanced MRI in Transient Middle Cerebral Artery Occlusion Model after Localized Brain Cooling in Rats

PubMed Central

Kim, Eun Soo; Kwon, Mi Jung; Lee, Phil Hye; Ju, Young-Su; Yoon, Dae Young; Kim, Hye Jeong; Lee, Kwan Seop

2016-01-01

Objective The purpose of this study was to evaluate the effects of localized brain cooling on blood-brain barrier (BBB) permeability following transient middle cerebral artery occlusion (tMCAO) in rats, by using dynamic contrast-enhanced (DCE)-MRI. Materials and Methods Thirty rats were divided into 3 groups of 10 rats each: control group, localized cold-saline (20℃) infusion group, and localized warm-saline (37℃) infusion group. The left middle cerebral artery (MCA) was occluded for 1 hour in anesthetized rats, followed by 3 hours of reperfusion. In the localized saline infusion group, 6 mL of cold or warm saline was infused through the hollow filament for 10 minutes after MCA occlusion. DCE-MRI investigations were performed after 3 hours and 24 hours of reperfusion. Pharmacokinetic parameters of the extended Tofts-Kety model were calculated for each DCE-MRI. In addition, rotarod testing was performed before tMCAO, and on days 1-9 after tMCAO. Myeloperoxidase (MPO) immunohisto-chemistry was performed to identify infiltrating neutrophils associated with the inflammatory response in the rat brain. Results Permeability parameters showed no statistical significance between cold and warm saline infusion groups after 3-hour reperfusion 0.09 ± 0.01 min-1 vs. 0.07 ± 0.02 min-1, p = 0.661 for Ktrans; 0.30 ± 0.05 min-1 vs. 0.37 ± 0.11 min-1, p = 0.394 for kep, respectively. Behavioral testing revealed no significant difference among the three groups. However, the percentage of MPO-positive cells in the cold-saline group was significantly lower than those in the control and warm-saline groups (p < 0.05). Conclusion Localized brain cooling (20℃) does not confer a benefit to inhibit the increase in BBB permeability that follows transient cerebral ischemia and reperfusion in an animal model, as compared with localized warm-saline (37℃) infusion group. PMID:27587960

A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice

PubMed Central

Cueva Vargas, Jorge L.; Di Polo, Adriana

2016-01-01

The use of rodent models of glaucoma has been essential to understand the molecular mechanisms that underlie the pathophysiology of this multifactorial neurodegenerative disease. With the advent of numerous transgenic mouse lines, there is increasing interest in inducible murine models of ocular hypertension. Here, we present an occlusion model of glaucoma based on the injection of magnetic microbeads into the anterior chamber of the eye using a modified microneedle with a facetted bevel. The magnetic microbeads are attracted to the iridocorneal angle using a handheld magnet to block the drainage of aqueous humour from the anterior chamber. This disruption in aqueous dynamics results in a steady elevation of intraocular pressure, which subsequently leads to the loss of retinal ganglion cells, as observed in human glaucoma patients. The microbead occlusion model presented in this manuscript is simple compared to other inducible models of glaucoma and also highly effective and reproducible. Importantly, the modifications presented here minimize common issues that often arise in occlusion models. First, the use of a bevelled glass microneedle prevents backflow of microbeads and ensures that minimal damage occurs to the cornea during the injection, thus reducing injury-related effects. Second, the use of magnetic microbeads ensures the ability to attract most beads to the iridocorneal angle, effectively reducing the number of beads floating in the anterior chamber avoiding contact with other structures (e.g., iris, lens). Lastly, the use of a handheld magnet allows flexibility when handling the small mouse eye to efficiently direct the magnetic microbeads and ensure that there is little reflux of the microbeads from the eye when the microneedle is withdrawn. In summary, the microbead occlusion mouse model presented here is a powerful investigative tool to study neurodegenerative changes that occur during the onset and progression of glaucoma. PMID:27077732

Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.

PubMed

Powers, William J; Clarke, William R; Grubb, Robert L; Videen, Tom O; Adams, Harold P; Derdeyn, Colin P

2011-11-09

Patients with symptomatic atherosclerotic internal carotid artery occlusion (AICAO) and hemodynamic cerebral ischemia are at high risk for subsequent stroke when treated medically. To test the hypothesis that extracranial-intracranial (EC-IC) bypass surgery, added to best medical therapy, reduces subsequent ipsilateral ischemic stroke in patients with recently symptomatic AICAO and hemodynamic cerebral ischemia. Parallel-group, randomized, open-label, blinded-adjudication clinical treatment trial conducted from 2002 to 2010. Forty-nine clinical centers and 18 positron emission tomography (PET) centers in the United States and Canada. The majority were academic medical centers. Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET. Of 195 patients who were randomized, 97 were randomized to receive surgery and 98 to no surgery. Follow-up for the primary end point until occurrence, 2 years, or termination of trial was 99% complete. No participant withdrew because of adverse events. Anastomosis of superficial temporal artery branch to a middle cerebral artery cortical branch for the surgical group. Antithrombotic therapy and risk factor intervention were recommended for all participants. For all participants who were assigned to surgery and received surgery, the combination of (1) all stroke and death from surgery through 30 days after surgery and (2) ipsilateral ischemic stroke within 2 years of randomization. For the nonsurgical group and participants assigned to surgery who did not receive surgery, the combination of (1) all stroke and death from randomization to randomization plus 30 days and (2) ipsilateral ischemic stroke within 2 years of randomization. The trial was terminated early for futility. Two-year rates for the primary end point were 21.0% (95% CI, 12.8% to 29.2%; 20 events) for the surgical group and

Fermented soybeans, Chungkookjang, prevent hippocampal cell death and β-cell apoptosis by decreasing pro-inflammatory cytokines in gerbils with transient artery occlusion

PubMed Central

Park, Sunmin; Kim, Da Sol; Moon, Bo Reum

2015-01-01

Since Chungkookjang, a short-term fermented soybean, is known to improve glucose metabolism and antioxidant activity, it may prevent the neurological symptoms and glucose disturbance induced by artery occlusion. We investigated the protective effects and mechanisms of traditional (TFC) and standardized Chungkookjang fermented with Bacillus licheniformis (BLFC) against ischemia/reperfusion damage in the hippocampal CA1 region and against hyperglycemia after transient cerebral ischemia in gerbils. Gerbils were subjected to either an occlusion of the bilateral common carotid arteries for 8 min to render them ischemic or a sham operation. Ischemic gerbils were fed either a 40% fat diet containing 10% of either cooked soybean (CSB), TFC, or BLFC for 28 days. Neuronal cell death and cytokine expression in the hippocampus, neurological deficit, serum cytokine levels, and glucose metabolism were measured. TFC and BLFC contained more isoflavonoid aglycones than CSB. Artery occlusion increased the expressions of IL-1β and TNF-α as well as cell death in the hippocampal CA1 region and induced severe neurological symptoms. CSB, TFC, and BLFC prevented the neuronal cell death and the symptoms such as dropped eyelid, bristling hair, reduced muscle tone and flexor reflex, and abnormal posture and walking patterns, and suppressed cytokine expressions. CSB was less effective than TFC and BLFC. Artery occlusion induced glucose intolerance due to decreased insulin secretion and β-cell mass. TFC and BLFC prevented the impairment of glucose metabolism by artery occlusion. Especially TFC and BLFC increased β-cell proliferation and suppressed the β-cell apoptosis by suppressing TNF-α and IL-1β which in turn decreased cleaved caspase-3 that caused apoptosis. In conclusion, TFC and BLFC may prevent and alleviate neuronal cell death in the hippocampal CA1 region and neurological symptoms and poststroke hyperglycemia in gerbils with artery occlusion. This might be associated with

A severe case of ipilimumab-induced guillain-barré syndrome revealed by an occlusive enteric neuropathy: a differential diagnosis for ipilimumab-induced colitis.

PubMed

Gaudy-Marqueste, Caroline; Monestier, Sandrine; Franques, Jérome; Cantais, Emmanuel; Richard, Marie-Aleth; Grob, Jean-Jacques

2013-01-01

Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 recently approved for the treatment of metastatic melanoma and currently under investigation in the adjuvant setting of high-risk stage III melanoma. The blockade of CTLA-4 induces activation of T cells, with an expected increase in the immunological reaction directed to cancer. We report a case of ipilimumab-induced Guillain-Barré syndrome revealed by an occlusive enteric neuropathy. Two weeks after the second dose of ipilimumab, our patient started to complain of abdominal meteorism and nausea. Within a few days, an occlusive syndrome developed. Wall biopsies during colonoscopy revealed a slight edema of the mucosa and a high number of lymphocytic follicles, leading to the diagnosis of ipilimumab-induced immune colitis. A respiratory failure occurred and a neurological deficiency developed rapidly. The diagnosis of polyradiculoneuritis was retained. Despite IV steroids, tacrolimus than plasmatic exchanges, the patient died within a few days because of multivisceral failure. Polyradiculoneuritis is a rare but very severe immune-mediated complication of ipilimumab. Occlusive enteric neuropathy may mimic the digestive symptoms of colitis, which is so frequent under ipilimumab.

Preconditioning of intravenous parecoxib attenuates focal cerebral ischemia/reperfusion injury in rats.

PubMed

Wang, Na; Guo, Qu-lian; Ye, Zhi; Xia, Ping-ping; Wang, E; Yuan, Ya-jing

2011-07-05

Several studies suggest that cyclooxygenase-2 (COX-2) contributes to the delayed progression of ischemic brain damage. This study was designed to investigate whether COX-2 inhibition with parecoxib reduces focal cerebral ischemia/reperfusion injury in rats. Ninety male Sprague-Dawley rats were randomly assigned to three groups: the sham group, ischemia/reperfusion (I/R) group and parecoxib group. The parecoxib group received 4 mg/kg of parecoxib intravenously via the vena dorsalis penis 15 minutes before ischemia and again at 12 hours after ischemia. The neurological deficit scores (NDSs) were evaluated at 24 and 72 hours after reperfusion. The rats then were euthanized. Brains were removed and processed for hematoxylin and eosin staining, Nissl staining, and measurements of high mobility group Box 1 protein (HMGB1) and tumor necrosis factor-α (TNF-α) levels. Infarct volume was assessed with 2,3,5-triphenyltetrazolium chloride (TTC) staining. The rats in the I/R group had lower NDSs (P < 0.05), larger infarct volume (P < 0.05), lower HMGB1 levels (P < 0.05), and higher TNF-α levels (P < 0.05) compared with those in the sham group. Parecoxib administration significantly improved NDSs, reduced infarct volume, and decreased HMGB1 and TNF-α levels (P < 0.05). Pretreatment with intravenous parecoxib was neuroprotective. Its effects may be associated with the attenuation of inflammatory reaction and the inhibition of inflammatory mediators.

Thromboxane A2-induced bi-directional regulation of cerebral arterial tone.

PubMed

Neppl, Ronald L; Lubomirov, Lubomir T; Momotani, Ko; Pfitzer, Gabriele; Eto, Masumi; Somlyo, Avril V

2009-03-06

Myosin light chain phosphatase plays a critical role in modulating smooth muscle contraction in response to a variety of physiologic stimuli. A downstream target of the RhoA/Rho-kinase and nitric oxide (NO)/cGMP/cyclic GMP-dependent kinase (cGKI) pathways, myosin light chain phosphatase activity reflects the sum of both calcium sensitization and desensitization pathways through phosphorylation and dephosphorylation of the myosin phosphatase targeting subunit (MYPT1). As cerebral blood flow is highly spatio-temporally modulated under normal physiologic conditions, severe perturbations in normal cerebral blood flow, such as in cerebral vasospasm, can induce neurological deficits. In nonpermeabilized cerebral vessels stimulated with U-46619, a stable mimetic of endogenous thromboxane A2 implicated in the etiology of cerebral vasospasm, we observed significant increases in contractile force, RhoA activation, regulatory light chain phosphorylation, as well as phosphorylation of MYPT1 at Thr-696, Thr-853, and surprisingly Ser-695. Inhibition of nitric oxide signaling completely abrogated basal MYPT1 Ser-695 phosphorylation and significantly increased and potentiated U-46619-induced MYPT1 Thr-853 phosphorylation and contractile force, indicating that NO/cGMP/cGKI signaling maintains basal vascular tone through active inhibition of calcium sensitization. Surprisingly, a fall in Ser-695 phosphorylation did not result in an increase in phosphorylation of the Thr-696 site. Although activation of cGKI with exogenous cyclic nucleotides inhibited thromboxane A2-induced MYPT1 membrane association, RhoA activation, contractile force, and regulatory light chain phosphorylation, the anticipated decreases in MYPT1 phosphorylation at Thr-696/Thr-853 were not observed, indicating that the vasorelaxant effects of cGKI are not through dephosphorylation of MYPT1. Thus, thromboxane A2 signaling within the intact cerebral vasculature induces "buffered" vasoconstrictions, in which both the

MiR-138/SIRT1 axis is implicated in impaired learning and memory abilities of cerebral ischemia/reperfusion injured rats.

PubMed

Tian, Feng; Yuan, Chao; Yue, Hongmei

2018-06-15

The present study aimed to explore whether deregulated miR-138 is implicated in cerebral I/R injury-impaired learning and memory abilities. Rats were subjected to bilateral common carotid occlusion followed by reperfusion to induce cerebral I/R injury. A model of oxygen-glucose deprivation and reperfusion (OGD/R) was conducted to mimic cerebral I/R conditions in vitro. MiR-138 expression levels were reduced in the hippocampus of cerebral I/R injured rats. Inhibition of miR-138 ameliorated the impaired learning and memory abilities of rats, and promoted autophagy and thus attenuated apoptosis in the OGD/R-treated hippocampal neurons. Moreover, miR-138 targets the 3'-UTR of SIRT1 and repressed its expression. These results showed that miR-138 could improve the learning and memory abilities via promoting autophagy under cerebral I/R injured conditions. Copyright © 2018 Elsevier Inc. All rights reserved.

Alterations in anxiety and social behaviour in Npas4 deficient mice following photochemically-induced focal cortical stroke.

PubMed

Klarić, T S; Jaehne, E J; Koblar, S A; Baune, B T; Lewis, M D

2017-01-01

In addition to causing widespread cell death and loss of brain function, cerebral ischaemia also induces extensive neuroplasticity. In humans, stroke is often accompanied by severe cognitive and psychiatric changes that are thought to arise as a consequence of this infarct-induced remodelling. A candidate for producing these post-stroke neuropsychiatric changes is Npas4, an activity-dependent transcription factor involved in synaptic plasticity whose expression is aberrantly up-regulated following ischaemic injury. In this study we investigated the role of Npas4 in modulating these stroke-induced neuropsychiatric responses by comparing the performance of wildtype and Npas4 -/- mice in various cognitive and behavioural tasks in a photochemical model of focal cortical stroke. We show that this stroke model results in impaired spatial recognition memory and a reduction in despair-like behaviour that affect both genotypes to a similar degree. Moreover, mice lacking Npas4 also show differences in some aspects of post-stroke sociability and anxiety. Specifically, we show that while stroke had no effect on anxiety levels in wildtype mice, Npas4 -/- mice became significantly more anxious following stroke. In addition, Npas4 -/- mice retained a greater level of sociability in the acute post-stroke period in comparison to their wildtype littermates. Thus, our findings suggest that Npas4 may be involved in post-stroke psychiatric changes related to anxiety and sociability. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke.

PubMed

Choi, Sang-Ho; Arai, Allison L; Mou, Yongshan; Kang, Byeongteck; Yen, Cecil Chern-Chyi; Hallenbeck, John; Silva, Afonso C

2018-03-01

MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia. SHR (spontaneously hypertensive rats) and normotensive WKY (Wistar Kyoto) rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery via craniectomy, or transient occlusion of the middle cerebral artery by the intraluminal suture method. JZL184 or MJN110 was administered 60 minutes after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between days 1 to 28 by magnetic resonance imaging, histology, and behavioral tests. Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors. Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke. © 2018 American Heart Association, Inc.

Primary Self-Expandable Nitinol Stent Placement in Focal Lesions of Infrarenal Abdominal Aorta: Long Term Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lastovickova, Jarmila, E-mail: jala@medicon.cz; Peregrin, Jan H.

Purpose. To evaluate the technical and clinical success, safety and long term results of percutaneous transluminal angioplasty/self-expandable nitinol stent placement of infrarenal abdominal aorta focal lesions. Materials and Methods. Eighteen patients underwent PTA of focal atherosclerotic occlusive disease of distal abdominal aorta. Two symptomatic occlusions and 16 stenoses in 10 male and 8 female patients (mean age 68.2 years) were treated with primary self-expandable nitinol stent placement. Results. Primary self-expandable nitinol stent placement was technically successful in all 18 procedures; clinical success was achieved in 100% of patients. No complications associated with the procedure occurred. During the 49.4 months ofmore » mean follow up (range 3-96, 4 months) all treated aortic segments remained patent. Conclusions. Endovascular treatment (primary self-expandable nitinol stent placement) of focal atherosclerotic lesions of distal abdominal aorta is a safe method with excellent primary technical and clinical success rates and favourable Long term results.« less

Detection of necrotic neural response in super-acute cerebral ischemia using activity-induced manganese-enhanced (AIM) MRI.

PubMed

Inoue, Yasuo; Aoki, Ichio; Mori, Yuki; Kawai, Yuko; Ebisu, Toshihiko; Osaka, Yasuhiko; Houri, Takashi; Mineura, Katsuyoshi; Higuchi, Toshihiro; Tanaka, Chuzo

2010-04-01

Immediate and certain determination of the treatable area is important for choosing risky treatments such as thrombolysis for brain ischemia, especially in the super-acute phase. Although it has been suggested that the mismatch between regions displaying 'large abnormal perfusion' and 'small abnormal diffusion' indicates a treatable area on an MRI, it has also been reported that the mismatch region is an imperfect approximation of the treatable region named the 'penumbra'. Manganese accumulation reflecting calcium influx into cells was reported previously in a middle cerebral artery occlusion (MCAO) model using activity-induced manganese-enhanced (AIM) MRI. However, in the super-acute phase, there have been no reports about mismatches between areas showing changes to the apparent diffusion coefficient (ADC) and regions that are enhanced in AIM MRI. It is expected that the AIM signal can be enhanced immediately after cerebral ischemia in the necrotic core region due to calcium influx. In this study, a remote embolic rat model, created using titanium-oxide macrospheres, was used to observe necrotic neural responses in the super-acute phase after ischemia. In addition, images were evaluated by comparison between ADC, AIM MRI, and histology. The signal enhancement in AIM MRI was detected at 2 min after the cerebral infarction using a remote embolic method. The enhanced area on the AIM MRI was significantly smaller than that on the ADC map. The tissue degeneration highlighted by histological analysis corresponded more closely to the enhanced area on the AIM MRI than that on the ADC map. Thus, the manganese-enhanced region in brain ischemia might indicate 'necrotic' irreversible tissue that underwent calcium influx. 2010 John Wiley & Sons, Ltd.

Intraoperative Matas test using microscope-integrated intraoperative indocyanine green videoangiography with temporary unilateral occlusion of the A1 segment of the anterior cerebral artery.

PubMed

Murai, Yasuo; Adachi, Koji; Takagi, Ryo; Koketsu, Kenta; Matano, Fumihiro; Teramoto, Akira

2011-11-01

The aim of the present study was to assess a new technique of surgical microscope-based indocyanine green (ICG) videoangiography (VAG) to confirm the patency of the anterior communicating artery (AcomA) after clipping AcomA aneurysms. Aneurysmal clipping of five cases of unruptured, broad-neck AcomA aneurysm was performed using the Carl Zeiss Surgical Microscope OPMI Pentero INFRARED 800. In all five patients, after clipping AcomA aneurysms, the patency of AcomA was confirmed using ICGVAG findings and temporary unilateral occlusion of the A1 segment of the anterior cerebral artery using temporary clips. Images were excellent and enabled a real-time surgical assessment because the structures of interest, including vessels, perforating arteries, or residual aneurysm neck, were visible to the surgeon's eye under the microscope in all five patients. ICGVAG and temporary unilateral occlusion with clips provides a simple, reliable, real-time, and rapid intraoperative assessment of the patency of AcomA. This technique may help to improve the quality of neurosurgical procedures. Copyright © 2011 Elsevier Inc. All rights reserved.

Activation of the Nrf2 defense pathway contributes to neuroprotective effects of phloretin on oxidative stress injury after cerebral ischemia/reperfusion in rats.

PubMed

Liu, Yu; Zhang, Lei; Liang, Jiangjiu

2015-04-15

Oxidative stress is considered a major contributing factor in cerebral ischemia/reperfusion injury. Phloretin, a dihydrochalcone belonging to the flavonoid family, is particularly rich in apples and apple-derived products. A large body of evidence demonstrates that phloretin exhibits anti-oxidant properties, and phloretin has potential implications for treating oxidative stress injuries in cerebral ischemia/reperfusion. Therefore, the neuroprotective and antioxidant effects of phloretin against ischemia/reperfusion injury, as well as related probable mechanisms, were investigated. The cerebral ischemic/reperfusion injury model was reproduced in male Sprague-Dawley rats through middle cerebral artery occlusion. At 24h after reperfusion, neurological score, infarct volume, and brain water content were assessed. Oxidative stress was evaluated by superoxide dismutases (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) levels. Nrf2 expression was measured by RT-PCR and western blot. Consequently, results showed that phloretin pretreatment for 14days significantly reduced infarct volume and brain edema, and ameliorated neurological scores in focal cerebral ischemia/reperfusion rats. SOD, GSH and GSH-Px activities were greatly decreased, and MDA levels significantly increased after ischemia/reperfusion injury. However, phloretin pretreatment dramatically suppressed these oxidative stress processes. Furthermore, phloretin upregulated Nrf2 mRNA and protein expression of in ischemia/reperfusion brain tissue. Taken together, phloretin exhibited neuroprotective effects in cerebral ischemia/reperfusion, and the mechanisms are associated with oxidative stress inhibition and Nrf2 defense pathway activation. Copyright © 2015 Elsevier B.V. All rights reserved.

Direct visualization of minimal cerebral capillary flow during retrograde cerebral perfusion: an intravital fluorescence microscopy study in pigs.

PubMed

Duebener, Lennart F; Hagino, Ikuo; Schmitt, Katharina; Sakamoto, Takahiko; Stamm, Christof; Zurakowski, David; Schäfers, Hans-Joachim; Jonas, Richard A

2003-04-01

Retrograde cerebral perfusion (RCP) is used in some centers during aortic arch surgery for brain protection during hypothermic circulatory arrest. It is still unclear however whether RCP provides adequate microcirculatory blood flow at a capillary level. We used intravital microscopy to directly visualize the cerebral capillary blood flow in a piglet model of RCP. Twelve pigs (weight 9.7 +/- 0.9 kg) were divided into two groups (n = 6 each): deep hypothermic circulatory arrest (DHCA) and RCP. After the creation of a window over the parietal cerebral cortex, pigs underwent 10 minutes of normothermic bypass and 40 minutes of cooling to 15 degrees C on cardiopulmonary bypass ([CPB] pH-stat, hemocrit 30%, pump flow 100 mL x kg(-1) x min(-1)). This was followed by 45 minutes of DHCA and rewarming on CPB to 37 degrees C. In the RCP group the brain was retrogradely perfused (pump flow 30 mL x kg(-1) x min(-1)) during DHCA through the superior vena cava after inferior vena cava occlusion. Plasma was labeled with fluorescein-isothiocyanate-dextran for assessing microvascular diameter and functional capillary density (FCD), defined as total length of erythrocyte-perfused capillaries per observation area. Cerebral tissue oxygenation was determined by nicotinamide adenine dinucleotide hydrogen (NADH) autofluorescence, which increases during tissue ischemia. During normothermic and hypothermic antegrade cerebral perfusion the FCD did not significantly change from base line (97% +/- 14% and 96% +/- 12%, respectively). During retrograde cerebral perfusion the FCD decreased highly significantly to 2% +/- 2% of base line values (p < 0.001). Thus there was no evidence of significant capillary blood flow during retrograde cerebral perfusion. The microvascular diameter of cerebral arterioles that were slowly perfused significantly decreased to 27% +/- 6% of base line levels during RCP. NADH fluorescence progressively and significantly increased during RCP, indicating poorer tissue

Regulation of body temperature and neuroprotection by endogenous interleukin-6 in cerebral ischemia.

PubMed

Herrmann, Oliver; Tarabin, Victoria; Suzuki, Shigeaki; Attigah, Nicolas; Coserea, Irinel; Schneider, Armin; Vogel, Johannes; Prinz, Simone; Schwab, Stefan; Monyer, Hannah; Brombacher, Frank; Schwaninger, Markus

2003-04-01

Although the function of fever is still unclear, it is now beyond doubt that body temperature influences the outcome of brain damage. An elevated body temperature is often found in stroke patients and denotes a bad prognosis. However, the pathophysiologic basis and treatment options of elevated body temperature after stroke are still unknown. Cerebral ischemia rapidly induced neuronal interleukin-6 (IL-6) expression in mice. In IL-6-deficient mice, body temperature was markedly decreased after middle cerebral artery occlusion (MCAO), but infarct size was comparable to that in control mice. If body temperature was controlled by external warming after MCAO, IL-6-deficient mice had a reduced survival, worse neurologic status, and larger infarcts than control animals. In cell culture, IL-6 exerted an antiapoptotic and neuroprotective effect. These data suggest that IL-6 is a key regulator of body temperature and an endogenous neuroprotectant in cerebral ischemia. Neuroprotective properties apparently compensate for its pyretic action after MCAO and enhance the safety of this endogenous pyrogen.

Epigallocatechin-3-Gallate Reduces Neuronal Apoptosis in Rats after Middle Cerebral Artery Occlusion Injury via PI3K/AKT/eNOS Signaling Pathway

PubMed Central

Zhonghang, Xu; Tongtong, Liu; Wanshu, Guo

2018-01-01

Background/Aims Epigallocatechin-3-gallate (EGCG) has neuroprotective effects and the ability to resist amyloidosis. This study observed the protective effect of EGCG against neuronal injury in rat models of middle cerebral artery occlusion (MCAO) and investigated the mechanism of action of PI3K/AKT/eNOS signaling pathway. Methods Rat models of permanent MCAO were established using the suture method. Rat behavior was measured using neurological deficit score. Pathology and apoptosis were measured using HE staining and TUNEL. Oxidative stress and brain injury markers were examined using ELISA. Apoptosis-related proteins and PI3K/AKT/eNOS signaling pathway were determined using western blot assay and immunohistochemistry. Results EGCG decreased neurological function score, protected nerve cells, inhibited neuronal apoptosis, and inhibited oxidative stress injury and brain injury markers level after MCAO. EGCG reduced the apoptotic rate of neurons, increased the expression of Bcl-2, and decreased the expression of Caspase-3 and Bax. After LY294002 suppressed the PI3K pathway, the protective effect of EGCG decreased after administration of PI3K inhibitors. Conclusion EGCG has a protective effect on rat brain injury induced by MCAO, possibly by modulating the PI3K/AKT/eNOS signaling pathway. PMID:29770336

Corticotropin-releasing factor: effect on cerebral blood flow in physiologic and ischaemic conditions.

PubMed

De Michele, Manuela; Touzani, Omar; Foster, Alan C; Fieschi, Cesare; Sette, Giuliano; McCulloch, James

2005-09-01

The expression of corticotrophin-releasing factor (CRF) receptors in cerebral arteries and arterioles suggests that CRF may modulate cerebral blood flow (CBF). In the present study, the effects of CRF, CRF-like peptides and the CRF broad spectrum antagonist DPhe-CRF on CBF have been investigated under normal physiologic conditions and in the margins of focal ischaemic insult. The experiments were carried out in anaesthetised and ventilated rats. Changes in CBF after subarachnoid microapplication of CRF and related peptides were assessed with a laser-Doppler flowmetry (LDF) probe. In the ischaemic animals, agents were injected approximately 60 minutes after permanent middle cerebral artery occlusion (MCAo). Microapplication of CRF and related peptides in normal rats into the subarachnoid space produced sustained concentration-dependent increases in CBF. This effect was attenuated by co-application with DPhe-CRF, which did not alter CBF itself. A second microapplication of CRF 30 min after the first failed to produce increases in CBF in normal animals. Microapplication of CRF in the subarachnoid space overlying the ischaemic cortex effected minor increases in CBF whereas D-Phe-CRF had no significant effect on CBF. Activation of the CRF peptidergic system increases CBF in the rat. Repeated activation of CRF receptors results in tachyphylaxis of the vasodilator response. CRF vasodilator response is still present after MCAo in the ischaemic penumbra, suggesting that the CRF peptidergic system may modulate CBF in ischaemic stroke.

Microvascular basis for growth of small infarcts following occlusion of single penetrating arterioles in mouse cortex

PubMed Central

Taylor, Zachary J; Hui, Edward S; Watson, Ashley N; Nie, Xingju; Deardorff, Rachael L; Jensen, Jens H; Helpern, Joseph A

2015-01-01

Small cerebral infarcts, i.e. microinfarcts, are common in the aging brain and linked to vascular cognitive impairment. However, little is known about the acute growth of these minute lesions and their effect on blood flow in surrounding tissues. We modeled microinfarcts in the mouse cortex by inducing photothrombotic clots in single penetrating arterioles. The resultant hemodynamic changes in tissues surrounding the occluded vessel were then studied using in vivo two-photon microscopy. We were able to generate a spectrum of infarct volumes by occluding arterioles that carried a range of blood fluxes. Those resulting from occlusion of high-flux penetrating arterioles (flux of 2 nL/s or higher) exhibited a radial outgrowth that encompassed unusually large tissue volumes. The gradual expansion of these infarcts was propagated by an evolving insufficiency in capillary flow that encroached on territories of neighboring penetrating arterioles, leading to the stagnation and recruitment of their perfusion domains into the final infarct volume. Our results suggest that local collapse of microvascular function contributes to tissue damage incurred by single penetrating arteriole occlusions in mice, and that a similar mechanism may add to pathophysiology induced by microinfarcts of the human brain. PMID:26661182

Prefrontal Hemodynamic Changes Associated with Subjective Sense of Occlusal Discomfort

PubMed Central

Kobayashi, Goh; Hayama, Rika; Ikuta, Ryuhei; Onozouka, Minoru; Wake, Hiroyuki; Shimada, Atsushi; Shibuya, Tomoaki; Tamaki, Katsushi

2015-01-01

We used functional near-infrared spectroscopy to measure prefrontal brain activity accompanying the physical sensation of oral discomfort that arose when healthy young-adult volunteers performed a grinding motion with mild occlusal elevation (96 μm). We simultaneously evaluated various forms of occlusal discomfort using the visual analogue scale (VAS) and hemodynamic responses to identify the specific prefrontal activity that occurs with increased occlusal discomfort. The Oxy-Hb responses of selected channels in the bilateral frontopolar and dorsolateral prefrontal cortices increased in participants who reported increased severity of occlusal discomfort, while they decreased in those who reported no change or decreased occlusal discomfort during grinding. Moreover, the cumulative values of Oxy-Hb response in some of these channels were statistically significant predictive factors for the VAS scores. A generalized linear model analysis of Oxy-Hb signals in a group of participants who reported increased discomfort further indicated significant cerebral activation in the right frontopolar and dorsolateral prefrontal cortices that overlapped with the results of correlation analyses. Our results suggest that the increased hemodynamic responses in the prefrontal area reflect the top-down control of attention and/or self-regulation against the uncomfortable somatosensory input, which could be a possible marker to detect the subjective sense of occlusal discomfort. PMID:26090407

Endovascular Mechanical Thrombectomy in Basilar Artery Occlusion: Initial Experience

PubMed Central

Park, Bum-Soo; Kwon, Hyon-Jo; Choi, Seung-Won; Kim, Seon-Hwan; Koh, Hyeon-Song; Youm, Jin-Young; Song, Shi-Hun

2013-01-01

Objective This study was conducted to assess the efficacy and safety of endovascular mechanical thrombectomy (EMT) for patients diagnosed with basilar artery (BA) occlusion. Materials and Methods We retrospectively analyzed clinical and imaging data of 16 patients diagnosed with BA occlusion who were treated with endovascular intervention from July 2012 to February 2013. Direct suction using the Penumbra system and thrombus retrieval by the Solitaire stent were the main endovascular techniques used to restore BA flow. The outcomes were evaluated based on rate of angiographic recanalization, rate of improvement of National Institutes of Health Stroke Scale (NIHSS) score, rate of modified Rankin Scale (mRS) at discharge and after 3 months, and rate of cerebral hemorrhagic complications. Successful recanalization was defined as achieving Thrombolysis In Cerebral Infarction (TICI) of II or III. Results Sixteen patients received thrombectomy. The mean age was 67.8 ± 11 years and the mean NIHSS score was 12.3 ± 8.2. Eight patients treated within 6 hours of symptom onset were grouped as A and the other 8 patients treated beyond 6 hours (range, 6-120) were grouped as B. Successful recanalization was met in six patients (75%) for group A and 7 (87.5%) for group B. Favorable outcome occurred in 4 patients (50%) for group A and 5 (62.5%) for group B. Conclusion Our study supports the effectiveness and safety of endovascular mechanical thrombectomy in treating BA occlusion even 6 hours after symptom onset. PMID:24167791

Atorvastatin protects GABAergic and dopaminergic neurons in the nigrostriatal system in an experimental rat model of transient focal cerebral ischemia.

PubMed

Sabogal, Angélica María; Arango, César Augusto; Cardona, Gloria Patricia; Céspedes, Ángel Enrique

2014-01-01

Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.

Effects of gemfibrozil on outcome after permanent middle cerebral artery occlusion in mice

PubMed Central

Guo, Qingmin; Wang, Guangming; Liu, Xiaowei; Namura, Shobu

2009-01-01

Fibrates are lipid lowering drugs and found as ligands for peroxisome proliferator-activated receptors (PPARs). A clinical study has shown that one type of fibrate gemfibrozil reduces stroke incidence in men. However, it remains unknown whether gemfibrozil improves outcome after stroke. We hypothesized that prophylactic administration of gemfibrozil improves outcome after ischemic stroke. In this study, we measured the impact of gemfibrozil in two permanent middle cerebral artery occlusion (MCAO) models in young adult male mice on normal diet. First, we tested gemfibrozil in a filamentous MCAO model. Pretreatment with gemfibrozil (30 mg/kg) for 7 days moderately but significantly reduced infarct size at 24 h after MCAO. A higher dose (120 mg/kg) did not attenuate infarct size. Rather, it tended to increase brain swelling. Second, we tested in a distal MCAO model. Gemfibrozil (30 mg/kg) for 7 days before and after stroke significantly attenuated cortical lesion size at 7 days after MCAO. Cortical blood flow measured by laser speckle imaging was improved by gemfibrozil in the ischemic hemisphere. In non-stroke animals gemfibrozil also altered gene expression levels of PPARs in both the aorta and brain in organ specific manners; however, endothelial nitric oxide synthase (eNOS) was not significantly affected. These findings suggested the possibility that the observed infarct reductions and cortical blood flow improvements in ischemic brains were not through eNOS-mediated mechanisms. Further investigations may be meritorious to examine whether prophylactic usage of gemfibrozil against stroke is beneficial. PMID:19427843

Effects of gemfibrozil on outcome after permanent middle cerebral artery occlusion in mice.

PubMed

Guo, Qingmin; Wang, Guangming; Liu, Xiaowei; Namura, Shobu

2009-07-07

Fibrates are lipid lowering drugs and found as ligands for peroxisome proliferator-activated receptors (PPARs). A clinical study has shown that one type of fibrate gemfibrozil reduces stroke incidence in men. However, it remains unknown whether gemfibrozil improves outcome after stroke. We hypothesized that prophylactic administration of gemfibrozil improves outcome after ischemic stroke. In this study, we measured the impact of gemfibrozil in two permanent middle cerebral artery occlusion (MCAO) models in young adult male mice on normal diet. First, we tested gemfibrozil in a filamentous MCAO model. Pretreatment with gemfibrozil (30 mg/kg) for 7 days moderately but significantly reduced infarct size at 24 h after MCAO. A higher dose (120 mg/kg) did not attenuate infarct size. Rather, it tended to increase brain swelling. Second, we tested in a distal MCAO model. Gemfibrozil (30 mg/kg) for 7 days before and after stroke significantly attenuated cortical lesion size at 7 days after MCAO. Cortical blood flow measured by laser speckle imaging was improved by gemfibrozil in the ischemic hemisphere. In non-stroke animals gemfibrozil also altered gene expression levels of PPARs in both the aorta and brain in organ specific manners; however, endothelial nitric oxide synthase (eNOS) was not significantly affected. These findings suggested the possibility that the observed infarct reductions and cortical blood flow improvements in ischemic brains were not through eNOS-mediated mechanisms. Further investigations may be meritorious to examine whether prophylactic usage of gemfibrozil against stroke is beneficial.

2-(2-Benzofuranyl)-2-Imidazoline Mediates Neuroprotection by Regulating the Neurovascular Unit Integrity in a Rat Model of Focal Cerebral Ischemia.

PubMed

Zhang, Zheng; Zhang, Linlei; Chen, Jiaou; Cao, Yungang; Qu, Man; Lin, Xinda; Han, Zhao; Ji, Xunming

2018-06-01

We showed previously that 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a ligand to type 2 imidazoline receptor (I2R) exerts neuroprotective effects in ischemia stroke via an unknown mechanism. The present study was to investigate whether 2-BFI can protect the neurovascular unit (NVU) using a rat model of 90 min focal cerebral ischemia. Rats were randomly divided into three groups: thesham-operated group; the vehicle control group and the 2-BFI group which received 2-BFI (3 mg/kg) immediately after the start of middle cerebralartery occlusion (MCAO). Neurological deficit score, infarct size, apoptosis level, brain water content and Evans Blue extravasation were assessed at 24 h after stroke. Expressions of occludin and zonula occludens 1 (ZO-1), collagen IV, aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9) and MMP-2 were assessed by Western blotting. 2-BFI treatment was associated with significant improvement of neurological performance and decreased infarct volume at 24 h after stroke. Apoptosis level reduced significantly by 2-BFI compared to the vehicle group (34.3 ± 5.4% vs 56.1 ± 7.9%, p < 0.05). Significant decreased of brain water content (79.5 ± 2.6% vs 84.62 ± 2%, p < 0.05) and Evans Blue extravasation (1.2 ± 0.5 vs 2.5 ± 0.41 µg/g, p < 0.05) of ipsilateral hemisphere was observed in 2-BFI group compared to vehicle group. Expressions of occludin, ZO-1 and collagen IV were significantly higher while MMP-9 level significantly lower in 2-BFI group. AQP-4 and MMP-2 showed no difference between 2-BFI and the vehicle groups. These results suggest that the neuroprotective effects of 2-BFI in acute ischemic brain damage are at least partly due to the drug's ability to improve the functions of NVU. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Effect of fibrin glue occlusion of the hepatobiliary tract on thioacetamide-induced liver failure.

PubMed

Schmandra, T C; Bauer, H; Petrowsky, H; Herrmann, G; Encke, A; Hanisch, E

2001-07-01

Expression and activation of hepatocyte growth factor (HGF) is stimulated by a complex system of interacting proteins, with thrombin playing an initial role in this process. The impact of temporary occlusion of the hepatobiliary tract with fibrin glue (major component thrombin) on the HGF system in acute and chronic liver damage in a rat model was investigated. Chronic liver damage was induced in 40 rats by daily intraperitoneal application of thioacetamide (100 mg/kg) for 14 days. After 7 days half of them received an injection of 0.2 mL fibrin glue into the hepatobiliary system. Daily intraperitoneal administration of thioacetamide continued for 7 consecutive days. The rats were then sacrificed for blood and tissue analysis. Acute liver failure was induced in 12 rats by intraperitoneal administration of a lethal dose of thioacetamide (500 mg/kg per day for 3 days) after an injection with 0.2 mL fibrin glue into their hepatobiliary tract. Survival rates and histological outcome were investigated and compared with control animals. Fibrin glue occluded rats showed significantly lower liver enzyme activities and serum levels of bilirubin, creatinine and urea nitrogen. Immunohistochemistry revealed a significant increase in c-met-, HGFalpha- and especially HGFbeta-positive cells. Rats subjected to a lethal dose of thioacetamide survived when fibrin glue was applied 24 hours prior to the toxic challenge. These animals showed normal liver structure and no clinical abnormalities. Fibrin glue occlusion of the hepatobiliary tract induces therapeutic and prophylactic effects on chronic and acute liver failure by stimulating the HGF system. Therefore, fibrin glue occlusion might be useful in treating toxic liver failure.

Decrease of tight junction integrity in the ipsilateral thalamus during the acute stage after focal infarction and ablation of the cerebral cortex in rats.

PubMed

Li, Jing-Jing; Xing, Shi-Hui; Zhang, Jian; Hong, Hua; Li, Yi-Liang; Dang, Chao; Zhang, Yu-Sheng; Li, Chuo; Fan, Yu-Hua; Yu, Jian; Pei, Zhong; Zeng, Jin-Sheng

2011-11-01

1. Whether damage to the blood-brain barrier (BBB) occurs in remote areas after a focal cortical lesion remains unknown. The present study investigated tight junction-related proteins and tight junction microstructure in the ipsilateral thalamus during the acute stage after middle cerebral artery occlusion (MCAO) and cortical aspiration lesion (CAL) in rats. 2. Thirty-six hypertensive and normotensive rats were subjected to MCAO or CAL; another 18 rats in each group were submitted to sham operation. Zonula Occluden (ZO)-1, occludin and albumin were detected by western blotting 12 and 24 h after surgery. Tight junction microstructure was evaluated using electron microscopy, whereas albumin location in the ipsilateral thalamus was determined using double immunostaining for albumin and occludin or albumin and neuronal nuclei (NeuN) 24 h after surgery. 3. Twenty-four hours after MCAO or CAL, occludin expression was reduced to 78.4% and 81.3%, respectively, compared with control. A reduction in ZO-1 expression in the ipsilateral thalamus (to 79%) was seen only after CAL (P < 0.05). Membrane contact at the tight junction was discontinuous in the ipsilateral thalamus in both MCAO and CAL rats. Albumin levels were 23.2% and 82.5% higher in the ipsilateral thalamus after MCAO and CAL, respectively (P < 0.05). The percentage of the albumin-positive area that coincided with the occludin-positive area in the MCAO and CAL groups was 76.8% and 64.6%, respectively, indicating that albumin was mainly localized around the microvessels. 4. The results of the present study suggest that tight junction integrity decreases during the acute stage in the ipsilateral thalamus after MCAO and CAL in rats. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.

Neuroprotection of the leaf and stem of Vitis amurensis and their active compounds against ischemic brain damage in rats and excitotoxicity in cultured neurons.

PubMed

Kim, Joo Youn; Jeong, Ha Yeon; Lee, Hong Kyu; Kim, SeungHwan; Hwang, Bang Yeon; Bae, KiHwan; Seong, Yeon Hee

2012-01-15

Vitis amurensis (Vitaceae) has been reported to have anti-oxidant and anti-inflammatory activities. The present study investigated a methanol extract from the leaf and stem of V. amurensis for neuroprotective effects on cerebral ischemic damage in rats and on excitotoxicity induced by glutamate in cultured rat cortical neurons. Transient focal cerebral ischemia was induced by 2h middle cerebral artery occlusion followed by 24h reperfusion (MCAO/reperfusion) in rats. Orally administered V. amurensis (25-100 mg/kg) reduced MCAO/reperfusion-induced infarct and edema formation, neurological deficits, and neuronal death. Depletion of glutathione (GSH) level and lipid peroxidation induced by MCAO/reperfusion was inhibited by administration of V. amurensis. The increase of phosphorylated mitogen-activated protein kinases (MAPKs), cyclooxygenase-2 (COX-2), and pro-apoptotic proteins and the decrease of anti-apoptotic protein in MCAO/reperfusion rats were significantly inhibited by treatment with V. amurensis. Exposure of cultured cortical neurons to 500 μM glutamate for 12h induced neuronal cell death. V. amurensis (1-50 μg/ml) and (+)-ampelopsin A, γ-2-viniferin, and trans-ε-viniferin isolated from the leaf and stem of V. amurensis inhibited glutamate-induced neuronal death, the elevation of intracellular calcium ([Ca(2+)](i)), the generation of reactive oxygen species (ROS), and changes of apoptosis-related proteins in cultured cortical neurons, suggesting that the neuroprotective effect of V. amurensis may be partially attributed to these compounds. These results suggest that the neuroprotective effect of V. amurensis against focal cerebral ischemic injury might be due to its anti-apoptotic effect, resulting from anti-excitotoxic, anti-oxidative, and anti-inflammatory effects and that the leaf and stem of V. amurensis have possible therapeutic roles for preventing neurodegeneration in stroke. Copyright © 2011 Elsevier GmbH. All rights reserved.

Reduced microvascular volume and hemispherically deficient vasoreactivity to hypercapnia in acute ischemia: MRI study using permanent middle cerebral artery occlusion rat model

PubMed Central

Suh, J Y; Shim, Woo H; Cho, Gyunggoo; Fan, Xiang; Kwon, Seon J; Kim, Jeong K; Dai, George; Wang, Xiaoying; Kim, Young R

2015-01-01

Vasoreactivity to hypercapnia has been used for assessing cerebrovascular tone and control altered by ischemic stroke. Despite the high prognostic potential, traits of hypercapnia-induced hemodynamic changes have not been fully characterized in relation with baseline vascular states and brain tissue damage. To monitor cerebrovascular responses, T2- and T2*-weighted magnetic resonance imaging (MRI) images were acquired alternatively using spin- and gradient-echo echo plannar imaging (GESE EPI) sequence with 5% CO2 gas inhalation in normal (n=5) and acute stroke rats (n=10). Dynamic relative changes in cerebrovascular volume (CBV), microvascular volume (MVV), and vascular size index (VSI) were assessed from regions of interest (ROIs) delineated by the percent decrease of apparent diffusion coefficient (ADC). The baseline CBV was not affected by middle cerebral artery occlusion (MCAO) whereas the baseline MVV in ischemic areas was significantly lower than that in the rest of the brain and correlated with ADC. Vasoreactivity to hypercapnic challenge was considerably attenuated in the entire ipsilesional hemisphere including normal ADC regions, in which unsolicited, spreading depression-associated increases of CBV and MVV were observed. The lesion-dependent inhomogeneity in baseline MVV indicates the effective perfusion reserve for accurately delineating the true ischemic damage while the cascade of neuronal depolarization is probably responsible for the hemispherically lateralized changes in overall neurovascular physiology. PMID:25690471

Reduced microvascular volume and hemispherically deficient vasoreactivity to hypercapnia in acute ischemia: MRI study using permanent middle cerebral artery occlusion rat model.

PubMed

Suh, J Y; Shim, Woo H; Cho, Gyunggoo; Fan, Xiang; Kwon, Seon J; Kim, Jeong K; Dai, George; Wang, Xiaoying; Kim, Young R

2015-06-01

Vasoreactivity to hypercapnia has been used for assessing cerebrovascular tone and control altered by ischemic stroke. Despite the high prognostic potential, traits of hypercapnia-induced hemodynamic changes have not been fully characterized in relation with baseline vascular states and brain tissue damage. To monitor cerebrovascular responses, T2- and T2*-weighted magnetic resonance imaging (MRI) images were acquired alternatively using spin- and gradient-echo echo plannar imaging (GESE EPI) sequence with 5% CO2 gas inhalation in normal (n=5) and acute stroke rats (n=10). Dynamic relative changes in cerebrovascular volume (CBV), microvascular volume (MVV), and vascular size index (VSI) were assessed from regions of interest (ROIs) delineated by the percent decrease of apparent diffusion coefficient (ADC). The baseline CBV was not affected by middle cerebral artery occlusion (MCAO) whereas the baseline MVV in ischemic areas was significantly lower than that in the rest of the brain and correlated with ADC. Vasoreactivity to hypercapnic challenge was considerably attenuated in the entire ipsilesional hemisphere including normal ADC regions, in which unsolicited, spreading depression-associated increases of CBV and MVV were observed. The lesion-dependent inhomogeneity in baseline MVV indicates the effective perfusion reserve for accurately delineating the true ischemic damage while the cascade of neuronal depolarization is probably responsible for the hemispherically lateralized changes in overall neurovascular physiology.

Nerve growth factor release from the urothelium increases via activation of bladder C-fiber in rats with cerebral infarction.

PubMed

Yokokawa, Ryusei; Akino, Hironobu; Ito, Hideaki; Zha, Xinmin; Yokoyama, Osamu

2017-08-01

There are some reports that bladder C-fibers are partially involved in detrusor overactivity in patients with brain lesions. We investigated the contribution of bladder C-fiber to decreased bladder capacity in rats with cerebral infarction. Cerebral infarction was induced under halothane anesthesia by left middle cerebral artery occlusion with 4-0 nylon thread in female Sprague-Dawley rats. Intramural amounts of ATP and prostaglandin E 2 , in vivo and in vitro ATP, NGF, and prostaglandin E 2 release from the distended bladder urothelium, and changes in mRNA expressions of sensor molecules and receptors were monitored 6 h after the occlusion. Cystometry was performed in rats with or without resiniferatoxin pretreatment. Overexpression of sensor molecule, transient receptor potential vanilloid-type channel 1, acid-sensing ion channel 2, purinergic receptors P2X 3 , and M 2 /M 3 muscarinic receptors was found in the bladder. These changes were accompanied by increases in ATP and NGF release from the urothelium. In contrast, when bladder C-fibers were desensitized by resiniferatoxin, no increase in NGF release from the urothelium was found either in vivo or in vitro. There was no difference in the percentage decrease in bladder capacity between cerebral infarction rats pretreated with resiniferatoxin and cerebral infarction rats without pretreatment. Results indicate that expression of sensor molecules in the bladder is altered by distant infarction in the brain. ATP and NGF release from the urothelium also increased. NGF release was related to activation of bladder C-fibers. Bladder C-fibers might not contribute much to decreased bladder capacity caused by cerebral infarction. © 2016 Wiley Periodicals, Inc.

Electroacupuncture: a new approach to open the blood-brain barrier in rats recovering from middle cerebral artery occlusion.

PubMed

Zhang, Jiangsong; Lin, Xianming; Zhou, Hui; Chen, Yuanyuan; Xiao, Shuangkai; Jiao, Junyue; Zhao, Yibin; Di, Zhong

2018-06-14

To examine for an opening effect on the blood-brain barrier (BBB) in intact rats and rats with experimental ischaemia-reperfusion (I/R) during the recovery period after various electroacupuncture (EA) treatments with different time courses, and to determine whether there is a time-dependent effect. An additional objective was to determine whether this method could induce the penetration of nerve growth factor (NGF) through the BBB. A middle cerebral artery occlusion (MCAO) model was first established. We chose different stimulation time courses and observed the effects of EA treatment (100 Hz frequency; 2 mA intensity) at GV20 and GV26 on the BBB in rats recovering from MCAO 3 weeks after modelling. The rats were injected with 2% Evans blue (EB) saline. The brain water content was measured using a wet/dry weighing method. The degree of penetration of EB was detected using spectrophotometry and laser confocal microscopy. The rats were then injected with NGF, and the concentration of NGF in the brain tissues was measured using ELISA. The increase in the BBB permeability was most notable following the 8 min EA stimulation (P<0.05), which may be advantageous for the targeted delivery of drugs (such as NGF) into the brain. Additionally, this effect did not appear to cause brain oedema (P>0.05) in healthy or MCAO rats. EA treatment for a certain stimulation time at GV20 and GV26 in MCAO rats can increase BBB permeability. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Pretreatment with 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-D-pyranoside Attenuates Cerebral Ischemia/Reperfusion-Induced Injury In Vitro and In Vivo

PubMed Central

Chen, Xia; Deng, Aiqing; Zhou, Tianqiu; Ding, Fei

2014-01-01

Salidroside, extracted from the root of Rhodiola rosea L, is known for its pharmacological properties, in particular its neuroprotective effects. 2-(4-Methoxyphenyl) ethyl-2-acetamido-2-deoxy-β-D- pyranoside (GlcNAc-Sal), an analog of salidroside, was recently synthesized and shown to possess neuroprotective properties. The purpose of the current study was to investigate the neuroprotective effects of GlcNAc-Sal against oxygen–glucose deprivation-reperfusion (OGD-R)-induced neurotoxicity in vitro and global cerebral ischemia-reperfusion (GCI-R) injury in vivo. Cell viability tests and Hoechst 33342 staining confirmed that GlcNAc-Sal pretreatment markedly attenuated OGD-R induced apoptotic cell death in immortalized mouse hippocampal HT22 cells. Western blot, immunofluorescence and PCR analyses revealed that GlcNAc-Sal pretreatment restored the balance of pro- and anti-apoptotic proteins and inhibited the activation of caspase-3 and PARP induced by OGD-R treatment. Further analyses showed that GlcNAc-Sal pretreatment antagonized reactive oxygen species (ROS) generation, iNOS-derived NO production and NO-related apoptotic cell death during OGD-R stimulation. GCI-R was induced by bilateral common carotid artery occlusion (BCCAO) and reperfusion in mice in vivo. Western blot analysis showed that GlcNAc-Sal pretreatment decreased the expression of caspase-3 and increased the expression of Bcl-2 (B-cell lymphoma 2)/Bax (Bcl-2-associated X protein) induced by GCI-R treatment. Our findings suggest that GlcNAc-Sal pretreatment prevents brain ischemia reperfusion injury by the direct or indirect suppression of cell apoptosis and GlcNAc-Sal could be developed as a broad-spectrum agent for the prevention and/or treatment of cerebral ischemic injury. PMID:24991917

Initial experience of a novel sheath guide for transbrachial coil embolization of cerebral aneurysms in the anterior cerebral circulation.

PubMed

Iwata, Tomonori; Mori, Takahisa; Tajiri, Hiroyuki; Miyazaki, Yuichi; Nakazaki, Masahito; Mizokami, Koji

2013-03-01

The transfemoral approach is a common technique for coil embolization of cerebral aneurysms in the anterior cerebral circulation. However, it is difficult to advance a guiding catheter into the carotid artery via the femoral route in patients with a tortuous aortic arch, an unfavorable supra-aortic takeoff, aortic diseases, or occlusion of the femoral artery. To report our initial experiences of coil embolization of cerebral aneurysms in the anterior cerebral circulation with a novel sheath guide for transbrachial carotid cannulation. A sheath guide designed specifically for transbrachial carotid cannulation was developed; transbrachial coil embolization for cerebral aneurysms began in May 2011. Included for analysis were patients who underwent transbrachial coil embolization for cerebral aneurysms in the anterior cerebral circulation from May 2011 to January 2012. Adjuvant techniques, angiographic results, procedural success, and periprocedural complications were investigated. Ten patients underwent transbrachial coil embolization of cerebral aneurysms in the anterior cerebral circulation. All procedures were successful using the brachial route. No periprocedural complications occurred. Patients were permitted to get seated immediately after coil embolization even during hemostasis. The sheath guide specifically designed for transbrachial carotid cannulation was useful for coil embolization of cerebral aneurysms in the anterior cerebral circulation.

The Role of Glutamate Release on Voltage-Dependent Anion Channels (VDAC)-Mediated Apoptosis in an Eleven Vessel Occlusion Model in Rats

PubMed Central

Park, Eunkuk; Lee, Gi-Ja; Choi, Samjin; Choi, Seok-Keun; Chae, Su-Jin; Kang, Sung-Wook; Pak, Youngmi Kim; Park, Hun-Kuk

2010-01-01

Voltage-dependent anion channel (VDAC) is the main protein in mitochondria-mediated apoptosis, and the modulation of VDAC may be induced by the excessive release of extracellular glutamate. This study examined the role of glutamate release on VDAC-mediated apoptosis in an eleven vessel occlusion model in rats. Male Sprague-Dawley rats (250–350 g) were used for the 11 vessel occlusion ischemic model, which were induced for a 10-min transient occlusion. During the ischemic and initial reperfusion episode, the real-time monitoring of the extracellular glutamate concentration was measured using an amperometric microdialysis biosensor and the cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry. To confirm neuronal apoptosis, the brains were removed 72 h after ischemia to detect the neuron-specific nuclear protein and pro-apoptotic proteins (cleaved caspase-3, VDAC, p53 and BAX). The changes in the mitochondrial morphology were measured by atomic force microscopy. A decrease in the % of CBF was observed, and an increase in glutamate release was detected after the onset of ischemia, which continued to increase during the ischemic period. A significantly higher level of glutamate release was observed in the ischemia group. The increased glutamate levels in the ischemia group resulted in the activation of VDAC and pro-apoptotic proteins in the hippocampus with morphological alterations to the mitochondria. This study suggests that an increase in glutamate release promotes VDAC-mediated apoptosis in an 11 vessel occlusion ischemic model. PMID:21203570

Ischemic stroke assessment with near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

Chen, Weiguo; Li, Pengcheng; Zeng, Shaoqun; Luo, Qingming; Hu, Bo

1999-09-01

Many authors have elucidated the theory about oxygenated hemoglobin, deoxygenated hemoglobin absorption in near-infrared spectrum. And the theory has opened a window to measure the hemodynamic changes caused by stroke. However, no proper animal model still has established to confirm the theory. The aim of this study was to validate near-infrared cerebral topography (NCT) as a practical tool and to try to trace the focal hemodynamic changes of ischemic stroke. In the present study, middle cerebral artery occlusion model and the photosensitizer induced intracranial infarct model had been established. NCT and functional magnetic resonance image (fMRI) were obtained during pre- and post-operation. The geometric shape and infarct area of NCT image was compared with the fMRI images and anatomical samples of each rat. The results of two occlusion models in different intervene factors showed the NCT for infarct focus matched well with fMRI and anatomic sample of each rats. The instrument might become a practical tool for short-term prediction of stroke and predicting the rehabilitation after stroke in real time.

Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction

PubMed Central

Chang, Jennifer; Fedinec, Alexander L.; Kuntamallappanavar, Guruprasad; Leffler, Charles W.; Bukiya, Anna N.

2016-01-01

Despite preventive education, the combined consumption of alcohol and caffeine (particularly from “energy drinks”) continues to rise. Physiologic perturbations by separate intake of ethanol and caffeine have been widely documented. However, the biologic actions of the alcohol-caffeine combination and their underlying subcellular mechanisms have been scarcely studied. Using intravital microscopy on a closed-cranial window and isolated, pressurized vessels, we investigated the in vivo and in vitro action of ethanol-caffeine mixtures on cerebral arteries from rats and mice, widely recognized models to address cerebrovascular pathophysiology and pharmacology. Caffeine at concentrations found in human circulation after ingestion of one to two cups of coffee (10 µM) antagonized the endothelium-independent constriction of cerebral arteries evoked by ethanol concentrations found in blood during moderate-heavy alcohol intoxication (40–70 mM). Caffeine antagonism against alcohol was similar whether evaluated in vivo or in vitro, suggesting independence of systemic factors and drug metabolism, but required a functional endothelium. Moreover, caffeine protection against alcohol increased nitric oxide (NO•) levels over those found in the presence of ethanol alone, disappeared upon blocking NO• synthase, and could not be detected in pressurized cerebral arteries from endothelial nitric-oxide synthase knockout (eNOS−/−) mice. Finally, incubation of de-endothelialized cerebral arteries with the NO• donor sodium nitroprusside (10 µM) fully restored the protective effect of caffeine. This study demonstrates for the first time that caffeine antagonizes ethanol-induced cerebral artery constriction and identifies endothelial NO• as the critical caffeine effector on smooth muscle targets. Conceivably, situations that perturb endothelial function and/or NO• availability will critically alter caffeine antagonism of alcohol-induced cerebrovascular constriction without

Effectiveness of sugammadex for cerebral ischemia/reperfusion injury.

PubMed

Ozbilgin, Sule; Yılmaz, Osman; Ergur, Bekir Ugur; Hancı, Volkan; Ozbal, Seda; Yurtlu, Serhan; Gunenc, Sakize Ferim; Kuvaki, Bahar; Kucuk, Burcu Ataseven; Sisman, Ali Rıza

2016-06-01

Cerebral ischemia may cause permanent brain damage and behavioral dysfunction. The efficacy and mechanisms of pharmacological treatments administered immediately after cerebral damage are not fully known. Sugammadex is a licensed medication. As other cyclodextrins have not passed the necessary phase tests, trade preparations are not available, whereas sugammadex is frequently used in clinical anesthetic practice. Previous studies have not clearly described the effects of the cyclodextrin family on cerebral ischemia/reperfusion (I/R) damage. The aim of this study was to determine whether sugammadex had a neuroprotective effect against transient global cerebral ischemia. Animals were assigned to control, sham-operated, S 16 and S 100 groups. Transient global cerebral ischemia was induced by 10-minute occlusion of the bilateral common carotid artery, followed by 24-hour reperfusion. At the end of the experiment, neurological behavior scoring was performed on the rats, followed by evaluation of histomorphological and biochemical measurements. Sugammadex 16 mg/kg and 100 mg/kg improved neurological outcome, which was associated with reductions in both histological and neurological scores. The hippocampus TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and caspase results in the S 16 and S 100 treatment groups were significantly lower than those of the I/R group. Neurological scores in the treated groups were significantly higher than those of the I/R group. The study showed that treatment with 16 mg/kg and 100 mg/kg sugammadex had a neuroprotective effect in a transient global cerebral I/R rat model. However, 100 mg/kg sugammadex was more neuroprotective in rats. Copyright © 2016. Published by Elsevier Taiwan.

Retinal protective effects of topically administered agmatine on ischemic ocular injury caused by transient occlusion of the ophthalmic artery

PubMed Central

Hong, S.; Hara, H.; Shimazawa, M.; Hyakkoku, K.; Kim, C.Y.; Seong, G.J.

2012-01-01

Agmatine, an endogenous polyamine and putative neuromodulator, is known to have neuroprotective effects on various neurons in the central nervous system. We determined whether or not topically administered agmatine could reduce ischemic retinal injury. Transient ocular ischemia was achieved by intraluminal occlusion of the middle cerebral artery of ddY mice (30-35 g) for 2 h, which is known to also induce occlusion of the ophthalmic artery. In the agmatine group (N = 6), a 1.0 mM agmatine-containing ophthalmic solution was administered four times daily for 2 weeks before occlusion. In the control group (N = 6), a 0.1% hyaluronic acid ophthalmic solution was instilled at the same times. At 22 h after reperfusion, the eyeballs were enucleated and the retinal sections were stained by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Transient ocular ischemia induced apoptosis of retinal cells in the entire retinal layer, and topically administered agmatine can significantly reduce this ischemic retinal injury. The proportion of apoptotic cells was definitely decreased (P < 0.001; Kruskal-Wallis test). Overall, we determined that topical agmatine application effectively decreases retinal damage in an in vivo ocular ischemic injury model. This implies that agmatine is a good candidate as a direct neuroprotective agent for eyes with ocular ischemic diseases. PMID:22331138

Retinal artery occlusion during carotid artery stenting with distal embolic protection device.

PubMed

Kohara, Kotaro; Ishikawa, Tatsuya; Kobayashi, Tomonori; Kawamata, Takakazu

2018-01-01

Retinal artery occlusion associated with carotid artery stenosis is well known. Although it can also occur at the time of carotid artery stenting, retinal artery occlusion via the collateral circulation of the external carotid artery is rare. We encountered two cases of retinal artery occlusion that were thought to be caused by an embolus from the external carotid artery during carotid artery stenting with a distal embolic protection device for the internal carotid artery. A 71-year-old man presented with central retinal artery occlusion after carotid artery stenting using the Carotid Guardwire PS and a 77-year-old man presented with branch retinal artery occlusion after carotid artery stenting using the FilterWire EZ. Because additional new cerebral ischaemic lesions were not detected in either case by postoperative diffusion-weighted magnetic resonance imaging, it was highly likely that the debris that caused retinal artery occlusion passed through not the internal carotid artery but collaterals to retinal arteries from the external carotid artery, which was not protected by a distal embolic protection device. It is suggested that a distal protection device for the internal carotid artery alone cannot prevent retinal artery embolisation during carotid artery stenting and protection of the external carotid artery is important to avoid retinal artery occlusion.

Long-term survival and regeneration of neuronal and vasculature cells inside the core region after ischemic stroke in adult mice.

PubMed

Jiang, Michael Qize; Zhao, Ying-Ying; Cao, Wenyuan; Wei, Zheng Zachory; Gu, Xiaohuan; Wei, Ling; Yu, Shan Ping

2017-07-01

Focal cerebral ischemia results in an ischemic core surrounded by the peri-infarct region (penumbra). Most research attention has been focused on penumbra while the pattern of cell fates inside the ischemic core is poorly defined. In the present investigation, we tested the hypothesis that, inside the ischemic core, some neuronal and vascular cells could survive the initial ischemic insult while regenerative niches might exist many days after stroke in the adult brain. Adult mice were subjected to focal cerebral ischemia induced by permanent occlusion of distal branches of the middle cerebral artery (MCA) plus transient ligations of bilateral common carotid artery (CCA). The ischemic insult uniformly reduced the local cerebral blood flow (LCBF) by 90%. Massive cell death occurred due to multiple mechanisms and a significant infarction was cultivated in the ischemic cortex 24 h later. Nevertheless, normal or even higher levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) persistently remained in the core tissue, some NeuN-positive and Glut-1/College IV-positive cells with intact ultrastructural features resided in the core 7-14 days post stroke. BrdU-positive but TUNEL-negative neuronal and endothelial cells were detected in the core where extensive extracellular matrix infrastructure developed. Meanwhile, GFAP-positive astrocytes accumulated in the penumbra and Iba-1-positive microglial/macrophages invaded the core several days after stroke. The long term survival of neuronal and vascular cells inside the ischemic core was also seen after a severe ischemic stroke induced by permanent embolic occlusion of the MCA. We demonstrate that a therapeutic intervention of pharmacological hypothermia could save neurons/endothelial cells inside the core. These data suggest that the ischemic core is an actively regulated brain region with residual and newly formed viable neuronal and vascular cells acutely and chronically after at

Clinical significance of the coexistence of carotid artery plaque and white matter disease in patients with symptomatic cerebral infarction.

PubMed

Ishikawa, Mami; Sugawara, Hitoshi; Tsuji, Toshiyuki; Nagai, Mutsumi; Kusaka, Gen; Naritaka, Heiji

2017-12-01

Symptomatic cerebral infarction (CI) can occur in patients without main cerebral artery stenosis or occlusion. This study investigated the unique features of carotid artery plaque and white matter disease (WMD) in patients with symptomatic CI and transient ischemic attack (TIA) but without stenosis or occlusion of a main cerebral artery. We studied 647 patients who underwent both carotid ultrasound examination and brain magnetic resonance images. Plaque score (PS), plaque number, maximal plaque intima-media thickness and grades of WMD were examined. Subjects were divided into four groups, the CI group, TIA group, myocardial infarction (MI) group and risk factor (RF) group. Plaque and WMD were analyzed in cerebral ischemia group (CI and TIA), compared to non-cerebral ischemia groups and to a high PS group and a high WMD grade group from the RF group. Both of each value of plaque and grades of WMD in the cerebral ischemia group were significantly higher than those in other groups. Grades of WMD in the cerebral ischemia group were significantly higher than those in the high PS group, although there was no significant difference of the each value of plaque between the two groups. The each value of plaque in the cerebral ischemia group was also significantly higher than those in the high WMD grade group, although there was no significant difference of grade of WMD between the two groups. Simultaneous increases in carotid artery plaque and WMD are associated with symptomatic CI, which is not caused by stenosis or occlusion of a main cerebral artery. Copyright © 2017 Elsevier B.V. All rights reserved.