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Sample records for lipiodol induced cerebral

  1. Cerebral Lipiodol Embolism after Lymphatic Embolization for Plastic Bronchitis

    PubMed Central

    Kirschen, Matthew P.; Dori, Yoav; Itkin, Maxim; Licht, Daniel J.; Ichord, Rebecca; Vossough, Arastoo

    2016-01-01

    An adolescent with plastic bronchitis due to congenital heart disease had altered mental status after an interventional lymphatic procedure in which lipiodol contrast was used. Neuroimaging revealed cerebral lipiodol embolization due to direct shunting between lymphatic channels and pulmonary veins. Cerebral lipiodol embolization is a potential neurologic morbidity associated with interventional lymphatic procedures. PMID:27297208

  2. Cerebral Lipiodol Embolism after Lymphatic Embolization for Plastic Bronchitis.

    PubMed

    Kirschen, Matthew P; Dori, Yoav; Itkin, Maxim; Licht, Daniel J; Ichord, Rebecca; Vossough, Arastoo

    2016-09-01

    An adolescent with plastic bronchitis due to congenital heart disease had altered mental status after an interventional lymphatic procedure in which lipiodol contrast was used. Neuroimaging revealed cerebral lipiodol embolization due to direct shunting between lymphatic channels and pulmonary veins. Cerebral lipiodol embolization is a potential neurologic morbidity associated with interventional lymphatic procedures. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Cerebral Lipiodol Embolism: A Complication of Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma

    SciTech Connect

    Matsumoto, Koichi Nojiri, Junichi; Takase, Yukinori; Egashira, Yoshikazu; Azama, Shinichi; Kato, Akira; Kitahara, Kenji; Miyazaki, Koji; Kudo, Sho

    2007-06-15

    We report a case of cerebral lipiodol embolism following transcatheter chemoembolization (TACE) for hepatocellular carcinoma. A 70-year-old woman with a large unresectable hepatocellular carcinoma underwent TACE. Her level of consciousness deteriorated after the procedure, and magnetic resonance imaging and non-contrast computed tomography revealed a cerebral lipiodol embolism. Despite intensive care, the patient died 2 weeks later. The complication might have been due to systemic-pulmonary shunts caused by previous surgeries and/or direct invasion of the recurrent tumor.

  4. Caffeine induced changes in cerebral circulation

    SciTech Connect

    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 differences between the three sets of cerebral blood flow values.

  5. Lipiodol enhanced CT scanning of malignant hepatic tumors.

    PubMed

    Eurvilaichit, C

    2000-04-01

    From August 1984 to March 1991, 41 patients with malignant liver tumors, 30 males and 11 females, aged 30-75 years were treated at Ramathibodi Hospital with injection of mitomycin-C lipiodol emulsion into the tumor via the feeding artery followed by embolization of the feeding artery with gelfoam particles. The patients comprised 30 cases of hepatocellular carcinoma, 4 cases of cholangiocarcinoma and 7 cases of metastatic tumors of which one was from CA stomach, three were from CA breast, and three from CA colon. The vascularity of the tumor was assessed in angiogram obtained prior to treatment and retention pattern of lipiodol in the tumor was evaluated in lipiodol-enhanced CT scan images taken 2-4 weeks following therapy. The results showed that lipiodol CT scan images exhibited four patterns of lipiodol retention in the tumor appearing as opacity as follows (1) homogenous (2) heterogeneous (3) ring-like and (4) none. Lipiodol retention pattern appeared to be somewhat related to vascularity of the tumor. Most of the hypervascular tumors such as hepatocellular carcinoma had homogeneous lipiodol accumulation pattern if the tumor size was less than 5 cm. Metastatic tumors and cholangiocarcinoma showed heterogeneous or ring-like pattern of lipiodol accumulation because they were relatively hypovascular. Hypervascular hepatocellular carcinoma may exhibit heterogeneous or ring-like pattern if they are larger than 5 cms, and have multiple feeding arteries, necrosis or AV shunting. Hepatocellular carcinoma with AV shunting may not show any lipiodol accumulation at all.

  6. Venous malformations: Sclerotherapy with a mixture of ethanol and lipiodol

    SciTech Connect

    Suh, Jin-Suck; Shin, Kyoo-Ho; Na, Jae-Bum; Won, Jong-Yun; Hahn, Soo-Bong

    1997-07-15

    Purpose. To evaluate the usefulness of a mixture of absolute ethanol and lipiodol in the management of venous malformations. Methods. Percutaneous sclerotherapy was performed with a mixture of absolute ethanol and lipiodol (9:1) in 17 patients with venous malformations, once in 12 patients, twice in 5. The therapeutic efficacy was evaluated by pain reduction. Conventional radiographs (n=15) and posttreatment magnetic resonance imaging (n=5) were obtained for the follow-up evaluation. Results. Sclerotherapy was successful in all but two patients. The therapeutic effect was excellent in two patients, good in seven, fair in five, and poor in one. Radiopacity of lipiodol was beneficial for monitoring the procedure rather than for follow-up evaluations. Areas with low signal-intensity strands were increased on T2-weighted images obtained after the sclerotherapy. Conclusion. Sclerotherapy with a mixture of ethanol and lipiodol is effective in treating venous malformations.

  7. Adjuvant Iodine131 Lipiodol after Resection of Hepatocellular Carcinoma

    PubMed Central

    Furtado, Ruelan V.; Ha, Leo; Clarke, Stephen; Sandroussi, Charbel

    2015-01-01

    Background. Survival after liver resection for HCC is compromised by a high rate of intrahepatic recurrence. Adjuvant treatment with a single, postoperative dose of intra-arterial I131 lipiodol has shown promise, as a means of prolonging disease-free survival (DFS). Methodology. DFS and overall survival (OS) after a single dose of postoperative I131 lipiodol were compared to liver resection alone, for treatment of hepatocellular carcinoma (HCC). Data were collected retrospectively for patients who had a curative resection for HCC between December 1993 and September 2011. Seventy-two patients were given I131 lipiodol after surgery and 70 patients had surgery alone. Results. The DFS at 1, 3, and 5 years was 72%, 43%, and 26% in the surgery group and 70%, 39%, and 29% in the adjuvant I131 lipiodol group (p = 0.75). The 1-, 3-, and 5-year OS was 83%, 64%, and 52% in the surgery group and 96%, 72%, and 61% in the adjuvant I131 lipiodol group (p = 0.16). Conclusion. This retrospective study has found no significant benefit to survival, after adjuvant treatment with I131 lipiodol. PMID:26713092

  8. Cerebral ischemia induces transcription of inflammatory and extracellular-matrix-related genes in rat cerebral arteries.

    PubMed

    Vikman, Petter; Ansar, Saema; Henriksson, Marie; Stenman, Emelie; Edvinsson, Lars

    2007-12-01

    Cerebral ischemia results in a local inflammatory response that contributes to the size of the lesion, however, the involvement of the cerebral vasculature is unknown. We hypothesise that the expression of inflammatory genes (Il6, iNOS, cxcl2, TNF-alpha and Il-1beta) and extracellular-matrix-related genes (MMP9, MMP13) is induced in cerebral arteries following cerebral ischemia via activation of mitogen activated kinases (MAPKs). This hypothesis was tested in vivo by experimental subarachnoid haemorrhage (SAH) and temporal middle cerebral artery occlusion (MCAO), and by organ culture of isolated cerebral arteries with quantitative real time PCR (mRNA expression) and immunohistochemistry (localization of protein expression). The gene promoters were investigated in silica with computer analysis. The mRNA analysis revealed that the ischemic models, SAH and MCAO, as well as organ culture of isolated cerebral arteries resulted in transcriptional upregulation of the abovementioned genes. The protein expression involved phosphorylation of three different MAPKs signalling pathways (p38, ERK 1/2 and SAPK/JNK) and the downstream transcription factors (ATF-2, Elk-1, c-Jun) shown by immunohistochemistry and quantified by image analysis. All three models revealed the same pattern of activation in the cerebrovascular smooth muscle cells. The in silica analysis demonstrated binding sites for said transcription factors. The results suggest that cerebral ischemia and organ culture induce activation of p38, ERK 1/2 and SAPK/JNK in cerebral arteries which in turn activate the transcription factors ATF-2, Elk-1 and c-Jun and the expression of inflammatory and extracellular-matrix-related genes in the wall of cerebral arteries.

  9. Reversible cerebral vasoconstriction syndrome induced by adrenaline.

    PubMed

    Palma, Jose-Alberto; Fontes-Villalba, Ariadna; Irimia, Pablo; Garcia-Eulate, Reyes; Martinez-Vila, Eduardo

    2012-04-01

    Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by acute severe thunderclap headaches and evidence of multifocal, segmental, reversible vasoconstrictions of the cerebral arteries. Several precipitating factors have been identified and reported, including the use of recreational substances or sympathomimetic drugs and the postpartum state. Here we present the case of a woman who developed RCVS after the administration of adrenaline (epinephrine) in the setting of an anaphylactic reaction during antibiotic allergy testing. To our knowledge, this is the first reported case of RCVS following the administration of exogenous adrenaline. This case contributes to the understanding of the physiopathological mechanisms underlying reversible cerebral vasoconstriction.

  10. [Subarachnoid hemorrhage induced by cerebral venous thrombosis].

    PubMed

    El Otmani, H; Moutaouakil, F; Fadel, H; Slassi, I

    2012-12-01

    Nontraumatic subarachnoid hemorrhage is a relatively rare disease, typically secondary to a ruptured aneurysm. We report the case of a 23-year-old patient who developed a subarachnoid hemorrhage caused by extensive cerebral venous thrombosis due to a factor V Leiden mutation. Cerebral venous thrombosis is an uncommon etiology of subarachnoid hemorrhage. This raises diagnostic difficulties and a therapeutic dilemma regarding the use of anticoagulants. Copyright © 2012. Published by Elsevier Masson SAS.

  11. Diet-induced ketosis does not cause cerebral acidosis.

    PubMed

    Al-Mudallal, A S; LaManna, J C; Lust, W D; Harik, S I

    1996-03-01

    Ketosis is beneficial for seizure control, possibly through induction of cerebral acidosis. However, cerebral intracellular pH has not previously been measured in ketotic humans and the animal data are sparse. We describe a high-fat diet, avidly consumed by rats, that induced consistent and moderate ketosis. Adult male rats were fed either the high-fat ketogenic diet, a high-carbohydrate diet with the same protein content as the ketogenic diet, or regular laboratory chow. Five to 6 weeks later, the rats were anesthetized, paralyzed, and injected with neutral red; their brains were frozen in situ. Intracellular pH of the cerebral cortex and cerebral glucose, lactate, ATP, phosphocreatine, and gama-aminobutyric acid (GABA) levels were measured. Rats fed the ketogenic diet had > 10-fold increase in their plasma ketones, but we noted no significant differences in cerebral pH or in cerebral metabolites and GABA levels among the three groups. Therefore, the antiepileptic effect of the ketogenic diet probably is not mediated by cerebral acidosis or changes in total cerebral GABA levels.

  12. Mechanisms of magnesium-induced vasodilation in cerebral penetrating arterioles.

    PubMed

    Murata, Takahiro; Dietrich, Hans H; Horiuchi, Tetsuyoshi; Hongo, Kazuhiro; Dacey, Ralph G

    2016-06-01

    We investigated in cerebral penetrating arterioles the signaling mechanisms and dose-dependency of extracellular magnesium-induced vasodilation and also its vasodilatory effects in vessels preconstricted with agonists associated with delayed cerebral vasospasm following SAH. Male rat penetrating arterioles were cannulated. Their internal diameters were monitored. To investigate mechanisms of magnesium-induced vasodilation, inhibitors of endothelial function, potassium channels and endothelial impairment were tested. To simulate cerebral vasospasm we applied several spasmogenic agonists. Increased extracellular magnesium concentration produced concentration-dependent vasodilation, which was partially attenuated by non-specific calcium-sensitive potassium channel inhibitor tetraethylammonium, but not by other potassium channel inhibitors. Neither the nitric oxide synthase inhibitor L-NNA nor endothelial impairment induced by air embolism reduced the dilation. Although the magnesium-induced vasodilation was slightly attenuated by the spasmogen ET-1, neither application of PF2α nor TXA2 analog effect the vasodilation. Magnesium induced a concentration- and smooth muscle cell-dependent dilation in cerebral penetrating arterioles. Calcium-sensitive potassium channels of smooth muscle cells may play a key role in magnesium-induced vasodilation. Magnesium also dilated endothelium-impaired vessels as well as vessels preconstricted with spasmogenic agonists. These results provide a fundamental background for the clinical use of magnesium, especially in treatment against delayed cerebral ischemia or vasospasm following SAH. Copyright © 2015 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  13. [Effect of lipiodol emulsion and local hyperthermia on hepatic tissue blood flow in rabbits with VX-2 liver tumor].

    PubMed

    Suzuki, K; Tada, I; Okada, K; Kim, Y I; Kobayashi, M

    1988-08-01

    The effect of intra-arterial infusion of lipiodol-emulsion and local hyperthermia on tissue blood flow was examined in experimental hepatic tumor and normal liver of rabbits. VX-2 tumor was implanted in liver of rabbit. The tissue blood flow was estimated by hydrogen gas clearance method when the tumor grew to about 2 cm. Tissue blood flow in tumor (64.5 ml/min/100 g) was significantly less than in normal liver (90.8 ml/min/100 g) (p less than 0.005). The intra-arterial infusion of lipiodol-emulsion did not alter the flow in either tissue. However, the addition of hyperthermia induced a substantial rise of tissue blood flow in normal liver (35% increase, from 93.8 to 127 ml/min/100 g) when compared with in VX-2 tumor (8.9% increase, from 65.1 to 71.8 ml/min/100 g). These were accompanied by a selective heating of liver tumor; the tumor temperature rose to 43 degrees C, although that of normal liver remained at 38 degrees C. Our results suggested that a specific temperature rise of liver tumor after infusion of lipiodol-emulsion and local heating might be related to a different response of microcirculation in tumor and normal liver to the hyperthermia.

  14. Arterial Embolization of Unresectable Hepatocellular Carcinoma with Use of Microspheres, Lipiodol, and Cyanoacrylate

    SciTech Connect

    Rand, Thomas Loewe, Christian; Schoder, Maria; Schmook, Maria Theresa; Peck-Radosavljevic, Markus; Kettenbach, Joachim; Wolf, Florian; Schneider, Barbara; Lammer, Johannes

    2005-04-15

    We performed a retrospective analysis of 46 patients with histologically confirmed hepatocellular carcinoma (HCC) who were treated with transarterial embolization (TAE) of the hepatic arteries. To induce permanent embolization, microspheres (Embosphere; 100 to 700{mu}) and a mixture of ethiodized oil (Lipiodol Ultrafluide) with cyanoacrylate (Glubran) was injected. A total of 106 TAE procedures were performed. Cumulative survival rates were calculated. No patient died during embolization or within the first 24 hours. Severe procedure-related complications were observed in 2 patients. At the time of analysis, 38 of 46 patients were alive. The 180-, 360-, 520-, and 700-day cumulative survival rates for the total study population were 80.6%, 70.7%, 70.7%, and 47.1%, respectively, with a median survival of 666 days. TAE with the use of microspheres and Lipiodol and cyanoacrylate for unresectable HCC is a feasible treatment modality. Bland embolization with the use of microspheres can be used in patients for whom chemoembolization is not desired.

  15. Escin attenuates cerebral edema induced by acute omethoate poisoning.

    PubMed

    Wang, Tian; Jiang, Na; Han, Bing; Liu, Wenbo; Liu, Tongshen; Fu, Fenghua; Zhao, Delu

    2011-06-01

    Organophosphorus exposure affects different organs such as skeletal muscles, the gastrointestinal tract, liver, lung, and brain. The present experiment aimed to evaluate the effect of escin on cerebral edema induced by acute omethoate poisoning. Sprague-Dawley rats were administered subcutaneously with omethoate at a single dose of 60 mg/kg followed by escin treatment. The results showed that escin reduced the brain water content and the amount of Evans blue in omethoate-poisoned animals. Treatment with escin decreased the levels of tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2), and prostaglandin E₂ (PGE₂) in the brain. Escin also alleviated the histopathological change induced by acute omethoate poisoning. The findings demonstrated that escin can attenuate cerebral edema induced by acute omethoate poisoning, and the underlying mechanism was associated with ameliorating the permeability of the blood-brain barrier.

  16. Sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia.

    PubMed

    Pinto, M C X; Simão, F; da Costa, F L P; Rosa, D V; de Paiva, M J N; Resende, R R; Romano-Silva, M A; Gomez, M V; Gomez, R S

    2014-06-20

    Brain ischemic tolerance is an endogenous protective mechanism activated by a preconditioning stimulus that is closely related to N-methyl-d-aspartate receptor (NMDAR). Glycine transporter type 1 (GlyT-1) inhibitors potentiate NMDAR and suggest an alternative strategy for brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by sarcosine, a GlyT-1 inhibitor, against global cerebral ischemia and its relation to NMDAR. Sarcosine was administered over 7 days (300 or 500 mg/kg/day, ip) before the induction of a global cerebral ischemia model in Wistar rats (male, 8-week-old). It was observed that sarcosine preconditioning reduced cell death in rat hippocampi submitted to cerebral ischemia. Hippocampal levels of glycine were decreased in sarcosine-treated animals, which was associated with a reduction of [(3)H] glycine uptake and a decrease in glycine transporter expression (GlyT-1 and GlyT-2). The expression of glycine receptors and the NR1 and NR2A subunits of NMDAR were not affected by sarcosine preconditioning. However, sarcosine preconditioning reduced the expression of the NR2B subunits of NMDAR. In conclusion, these data demonstrate that sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia and this neuroprotective state is associated with changes in glycine transport and reduction of NR2B-containing NMDAR expression. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Ketogenic diet prevents cardiac arrest-induced cerebral ischemic neurodegeneration.

    PubMed

    Tai, K-K; Nguyen, N; Pham, L; Truong, D D

    2008-07-01

    Ketogenic diet (KD) is an effective treatment for intractable epilepsies. We recently found that KD can prevent seizure and myoclonic jerk in a rat model of post-hypoxic myoclonus. In the present study, we tested the hypothesis that KD can prevent the cerebral ischemic neurodegeneration in this animal model. Rats fed a standard diet or KD for 25 days were being subjected to mechanically induced cardiac arrest brain ischemia for 8 min 30 s. Nine days after cardiac arrest, frozen rat brains were sectioned for evaluation of ischemia-induced neurodegeneration using fluoro-jade (FJ) staining. The FJ positive degenerating neurons were counted manually. Cardiac arrest-induced cerebral ischemia in rats fed the standard diet exhibited extensive neurodegeneration in the CA1 region of the hippocampus, the number of FJ positive neurons was 822+/-80 (n=4). They also showed signs of neurodegeneration in the Purkinje cells of the cerebellum and in the thalamic reticular nucleus, the number of FJ positive neurons in the cerebellum was 55+/-27 (n=4), the number of FJ positive neurons in the thalamic reticular nucleus was 22+/-5 (n=4). In contrast, rats fed KD showed no evidence of neurodegeneration, the number of FJ positive neurons in these areas were zero. The results demonstrate that KD can prevent cardiac arrest-induced cerebral ischemic neurodegeneration in selected brain regions.

  18. Treatment of Liver Tumors with Lipiodol TACE: Technical Recommendations from Experts Opinion

    SciTech Connect

    Baere, Thierry de; Arai, Yasuaki; Lencioni, Riccardo; Geschwind, Jean-Francois; Rilling, William; Salem, Riad; Matsui, Osamu; Soulen, Michael C.

    2016-03-15

    Transarterial chemoembolization with Lipiodol (Lipiodol TACE), also called conventional TACE, was developed in the early 1980s and widely adopted worldwide after randomized control trials and meta-analysis demonstrated superiority of Lipiodol TACE to best supportive care. Presently, there is no level one evidence that other TACE techniques are superior to Lipiodol TACE for intermediate stage hepatocellular carcinoma (HCC), which includes patients with preserved liver function and nonsurgical large or multinodular HCC without distant metastases. In addition, TACE is part of the treatment for progressive or symptomatic liver metastases from gastroenteropancreatic neuroendocrine tumors. When injected into the hepatic artery, Lipiodol has the unique property of selective uptake and retention in hyperarterialyzed liver tumors. Lipiodol/drug emulsion followed by particle embolization has been demonstrated to improve the pharmacokinetic of the drug and tumor response. Radio opacity of Lipiodol helps to monitor treatment delivery, with retention of Lipiodol serving as an imaging biomarker for tumor response. For 30 years, Lipiodol TACE has been inconsistently referenced in many publications with various levels of details for the method of preparation and administration, with reported progressive outcomes following improvements in the technique and the devices used to deliver the treatment and better patient selection. Consequently, there is no consensus on the standard method of TACE regarding the use of anticancer agents, embolic material, technical details, and the treatment schedule. In order to develop an internationally validated technical recommendation to standardize the Lipiodol TACE procedure, a worldwide panel of experts participated in a consensus meeting held on May 10, 2014.

  19. Holmium-lipiodol-alginate microspheres for fluoroscopy-guided embolotherapy and multimodality imaging.

    PubMed

    Oerlemans, Chris; Seevinck, Peter R; Smits, Maarten L; Hennink, Wim E; Bakker, Chris J G; van den Bosch, Maurice A A J; Nijsen, J Frank W

    2015-03-30

    Embolotherapy is a minimally invasive transcatheter technique aiming at reduction or complete obstruction of the blood flow by infusion of micro-sized particles in order to induce tumor regression. A major drawback of the current commercially available and clinically used microspheres is that they cannot be detected in vivo with medical imaging techniques, impeding intra- and post-procedural feedback. It can be expected that real-time monitoring of microsphere infusion and post-procedural imaging will result in better predictability and higher efficacy of the treatment. In this study, a novel microsphere formulation has been developed that can be visualized with fluoroscopy, X-ray computed tomography (CT) and magnetic resonance imaging (MRI). The microspheres were prepared with the JetCutter technique and consist of alginate (matrix-forming polymer), holmium (cross-linking and MRI contrast agent), lipiodol (radiopaque contrast agent) and Pluronic F-68 (surfactant). The mean size (±SEM) of the hydrated holmium-lipiodol-alginate microspheres (Ho-lip-ams) was 570±12 μm with a holmium content of 0.38±0.01% (w/w). Stability studies showed that the microspheres remained intact during incubation for two weeks in fetal calf serum (FCS) at 37 °C. The inclusion of lipiodol in the microspheres rendered excellent visualization capabilities for fluoroscopy and CT, whereas the holmium ions, which keep the alginate network together, also allow MR imaging. In this study it was shown that single sphere detection was possible by fluoroscopy, CT and MRI. The Ho-lip-ams were visualized in real-time, during infusion in a porcine kidney using fluoroscopy, and post-procedural, the deposition of the microspheres was examined with fluoroscopy, (cone beam rotational) CT and MRI. The different imaging modalities showed similar deposition patterns of the microspheres within the organ. The combination of intra-procedural visualization, multimodality imaging for patient follow-up and the

  20. Polymerization kinetics of a mixture of Lipiodol and Glubran 2 cyanoacrylate glue upon contact with a proteinaceous solution.

    PubMed

    Li, Y J; Barthès-Biesel, D; Salsac, A-V

    2017-10-01

    The Glubran 2 cyanoacrylate glue is a liquid embolic agent used to block blood vessels endovascularly. Typically mixed with an iodized oil (Lipiodol) for visualization under X-ray, it polymerizes when in contact with blood and tissues owing to the presence of ions and proteins. The objective of the study is to determine the influence of plasma proteins in the polymerization reaction. A triggering solution containing bovine serum albumin (BSA) and the main blood ions is used as a model of plasma. The polymerization kinetics of Glubran 2-Lipiodol mixtures is measured upon aspiration in a capillary tube and contact with the proteinaceous solution. Having varied the glue and protein concentrations, we show that glue-Lipiodol mixtures with concentrations larger or equal to 25% polymerize when put in contact with an ionic solution containing at least 4% of BSA. The reaction is decomposed into two phases: a fast zwitterionic polymerization induced by the BSA molecules followed by a slower polymerization phase. The reaction speed and extent of the solidification region mostly depend on the glue concentration. The time for the glue solution to polymerize over a 1mm thickness varies from 5s for pure glue to about 1min for a 50% glue concentration, and 10min for a 25% glue mixture. It is the first time that the kinetics of the two polymerization reactions is quantified for Glubran 2, which will provide the information needed by interventional radiologists to optimize the planning of endovascular glue injection. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Patient dosimetry for 131I-lipiodol therapy.

    PubMed

    Monsieurs, Myriam A; Bacher, Klaus; Brans, Boudewijn; Vral, Anne; De Ridder, Leo; Dierckx, Rudi A; Thierens, Hubert M

    2003-04-01

    Patient dosimetry data for intra-arterial()iodine-131 lipiodol therapy for hepatocellular carcinoma (HCC) are scarce. The aim of this study was to determine the absorbed dose (D) to the tumour and healthy tissues, as well as the effective dose (E), by different methods for 17 therapies in 15 patients who received a mean activity of 1.9 GBq (SD 0.2) (131)I-lipiodol. Eight patients received thyroid blocking by potassium iodide (KI). Patient dosimetry was performed based on bi-planar total body scans using the Monte Carlo simulation program MCNP-4B and the MIRDOSE-3 standard software program. CT images of each patient were used to determine liver and tumour volume and position. The total body dose to the patient was also determined by biological dosimetry with the in vitro micronucleus (MN) assay. From the increase in micronucleus yield after therapy, the equivalent total body dose (ETBD) was calculated. Results for D and E were comparable between MCNP and MIRDOSE (liver: mean 7.8 Gy, SD 1.8, lungs: 6.8 Gy, SD 2.9, E: 2.01 Gy, SD 0.58). MIRDOSE gave a systematic overestimation for the tumour dose, especially for tumours <3 cm (15%). The MCNP method is more accurate since the dose contributions from tumour to organs and vice versa can be accounted for. The absorbed dose to the thyroid was significantly lower for patients who received KI (7.2 Gy, SD 2.2) than for the other patients (13.8 Gy, SD 5.0). MN yields could be obtained for only 12 of the 17 therapies due to hypersplenism. A mean ETBD of 1.66 Gy (SD 0.73) was obtained, but the MN results showed no correlation between the ETBD and the total body dose values of the physical dosimetry. Also, in all except one of the patients, no further reduction in the number of thrombocytes was observed after therapy, probably due to the existing hypersplenism. It is concluded that in view of the high E values, patient dosimetry is necessary for patients receiving (131)I-lipiodol therapy. Except in the case of the smaller tumours

  2. SU-D-BRB-07: Lipiodol Impact On Dose Distribution in Liver SBRT After TACE

    SciTech Connect

    Kawahara, D; Ozawa, S; Hioki, K; Suzuki, T; Lin, Y; Okumura, T; Ochi, Y; Nakashima, T; Ohno, Y; Kimura, T; Murakami, Y; Nagata, Y

    2015-06-15

    Purpose: Stereotactic body radiotherapy (SBRT) combining transarterial chemoembolization (TACE) with Lipiodol is expected to improve local control. This study aims to evaluate the impact of Lipiodol on dose distribution by comparing the dosimetric performance of the Acuros XB (AXB) algorithm, anisotropic analytical algorithm (AAA), and Monte Carlo (MC) method using a virtual heterogeneous phantom and a treatment plan for liver SBRT after TACE. Methods: The dose distributions calculated using AAA and AXB algorithm, both in Eclipse (ver. 11; Varian Medical Systems, Palo Alto, CA), and EGSnrc-MC were compared. First, the inhomogeneity correction accuracy of the AXB algorithm and AAA was evaluated by comparing the percent depth dose (PDD) obtained from the algorithms with that from the MC calculations using a virtual inhomogeneity phantom, which included water and Lipiodol. Second, the dose distribution of a liver SBRT patient treatment plan was compared between the calculation algorithms. Results In the virtual phantom, compared with the MC calculations, AAA underestimated the doses just before and in the Lipiodol region by 5.1% and 9.5%, respectively, and overestimated the doses behind the region by 6.0%. Furthermore, compared with the MC calculations, the AXB algorithm underestimated the doses just before and in the Lipiodol region by 4.5% and 10.5%, respectively, and overestimated the doses behind the region by 4.2%. In the SBRT plan, the AAA and AXB algorithm underestimated the maximum doses in the Lipiodol region by 9.0% in comparison with the MC calculations. In clinical cases, the dose enhancement in the Lipiodol region can approximately 10% increases in tumor dose without increase of dose to normal tissue. Conclusion: The MC method demonstrated a larger increase in the dose in the Lipiodol region than the AAA and AXB algorithm. Notably, dose enhancement were observed in the tumor area; this may lead to a clinical benefit.

  3. A Comparison of Three Transarterial Lipiodol-Based Formulations for Hepatocellular Carcinoma: In Vivo Biodistribution Study in Humans

    SciTech Connect

    Yu, Simon Chun Ho Leung, Thomas Wai Tong; Lau, Wan Yee; Lee, Nelson; Hui, Edwin Pun; Yeo, Winnie; Lai, Paul Bo San; Mok, Tony Shu Kam

    2008-03-15

    This study aimed to evaluate and compare the biodistribution properties of three transarterial Lipiodol-based therapeutic regimens in human hepatocellular carcinoma (HCC). In this prospective study with 13 patients randomly allocated to one of three study groups, each of the patients received transcatheter intra-arterial administration into a solitary HCC with one of three different Lipiodol-based formulations: Lipiodol-ethanol mixture (LEM; Group A), Lipiodol alone (Group B), and Lipiodol and gelatin pledgets (Group C). With the use of radioactive iodine-131-labeled Lipiodol, each group was assessed for (1) pattern of Lipiodol accumulation in the lungs within the first 2 weeks as evaluated by single-photon emission computed tomography and (2) decomposition of Lipiodol formulation within the first 2 weeks as evaluated by radioactivity detected in peripheral blood and urine. The degree of Lipiodol retention in the tumor within the first 4 weeks was evaluated with CT. No statistically significant difference in Lipiodol accumulation in the lungs was detected among the three groups. However, the peak accumulation in the lungs was delayed 3 days for Group A compared to Groups B and C. The degree of Lipiodol retention within the tumor in Group A was significantly greater than that in Groups B and C on day 14 (p = 0.014) and day 28 (p = 0.013). This study showed that LEM is associated with a greater embolic effect in intrahepatic HCC at 4 weeks, and a comparable degree of lung shunting and decomposition rates, compared with ethanol-free Lipiodol formulations.

  4. Effects of ketamine on isoflurane- and sevoflurane-induced cerebral vasodilation in rabbits.

    PubMed

    Nagase, Kiyoshi; Iida, Hiroki; Dohi, Shuji

    2003-04-01

    Although ketamine has been reported to have little effect on the cerebral circulation when used with other anesthetics, its effect on the cerebral vascular response to volatile anesthetics, which increase cerebral blood flow in a concentration-dependent manner, remains obscure. A closed cranial window was prepared in 15 pentobarbital-anesthetized adult rabbits. The cerebral pial arteriolar alteration induced by either isoflurane (n = 8) or sevoflurane (n = 7) at 0 (before volatile anesthetic), 0.33, 0.67, and 1.0 minimum alveolar concentration (MAC) was measured under three consecutive conditions: intravenous infusion with saline, with ketamine, and with ketamine plus l-arginine. Ketamine reduced the vasodilation induced by 0.67 (120 +/- 9% versus 113 +/- 9%; P <.05) and 1.0 MAC isoflurane (136 +/- 11% versus 118 +/- 10%; P <.05), but l-arginine did not restore the isoflurane-induced cerebral vasodilation. In rabbits inhaling sevoflurane, the degree of cerebral vasodilator response was smaller than that by isoflurane, and the cerebral vasodilation was comparable whether in the presence or absence of ketamine (with or without l-arginine). In conclusion, ketamine reduces isoflurane-induced cerebral vasodilation, apparently independently of nitric oxide formation, while sevoflurane-induced cerebral vasodilation is not significantly affected by ketamine.

  5. Cocaine induces apoptosis in cerebral vascular muscle cells: potential roles in strokes and brain damage.

    PubMed

    Su, Jialin; Li, Jianfeng; Li, Wenyan; Altura, Bella T; Altura, Burton M

    2003-12-15

    Cocaine abuse is known to induce different types of brain-microvascular damage and many adverse cerebrovascular effects, including cerebral vasculitis, intracranial hemorrhage, cerebral infarction and stroke. A major physiological event leading to these pathophysiological actions of cocaine could be apoptosis. Whether cocaine can cause brain-microvascular pathology and vascular toxicity by inducing apoptosis of cerebral vascular smooth muscle cells is not known. This study, using several different methods to discern apoptosis, was designed to investigate if primary cultured canine cerebral vascular smooth muscle cells can undergo apoptosis when treated with cocaine. After treatment with cocaine (10(-6)-10(-3) M) for 12-24 h, the death rates of cerebral vascular smooth muscle cells increased in a concentration-dependent manner compared with controls. Morphological analysis of cerebral vascular smooth muscle cells using confocal fluoresence microscopy showed that the percentage of apoptotic cerebral vascular smooth muscle cells increased after cocaine (10(-6)-10(-3) M) treatment in a concentration-dependent manner. TUNEL assays also showed positive results for cerebral vascular smooth muscle cells treated with cocaine. These results clearly demonstrate that cerebral vascular smooth muscle cells can undergo rapid apoptosis in response to cocaine in a concentration-dependent manner. Cocaine-induced apoptosis may thus play a major role in brain-microvascular damage, cerebral vascular toxicity and strokes.

  6. Physical analysis on laser-induced cerebral damage

    NASA Astrophysics Data System (ADS)

    Luo, Xiaosen; Liu, Jiangang; Tao, Chunkan; Lan, Xiufeng; Cao, Lingyan; Pan, Weimin; Shen, Zhonghua; Lu, Jian; Ni, Xiaowu

    2005-01-01

    Experimental investigation on cerebral damage of adult SD rats induced by 532nm CW laser was performed. Tissue heat conductive equation was set up based on two-layered structure model. Finite difference algorithm was utilized to numerically simulate the temperature distribution in the brain tissue. Allowing for tissue response to temperature variation, free boundary model was used to discuss tissue thermal coagulation formation in brain. Experimental observations show that thermal coagulation and necrosis can be caused due to laser light absorption. The result of the calculation shows that the process of the thermal coagulation of the given mode comprises two stages: fast and slow. At the first stage, necrosis domain grows fast. Then necrosis domain growth becomes slower because of the competition between the heat diffusion into the surrounding undamaged tissue and the heat dissipation caused by blood perfusion. At the center of coagulation area no neuron was observed and at the transitional zone few nervous cells were seen by microscope. The research can provide reference data for developing clinical therapy of some kind of encephalic diseases by using 532nm laser, and for making cerebral infarction models in animal experiment.

  7. [Comparative evaluation of ultrasonography, computerized tomography, angiography and lipiodol CT in defining extent of hepatocarcinoma. A multicenter study].

    PubMed

    Dalla Palma, L; Pozzi Mucelli, R; Sponza, M; Bartolozzi, C; De Santis, M; Gandini, G; Mannella, P; Matricardi, L; Rossi, C; Simonetti, G

    1995-03-01

    The authors report the results of a multicentric trial on hepatocellular carcinoma (HCC) patients, whose lesions were confirmed with biopsy or by high (> 400 ng/ml) alpha-fetoprotein levels. The series consisted of 149 patients examined in 8 different centers and submitted to ultrasonography (US), Computed Tomography (CT) before and after contrast agent administration, angiography and Lipiodol CT. According to lesion size and number, the patients were divided with each imaging modality into three groups: a) group 1: unifocal HCC < 5 cm diameter; b) group 2: multifocal HCC with 2-3 nodules and/or tumor mass < 80 ml; c) multifocal HCC with more than 3 nodules (with total tumor mass not exceeding 40% of liver volume) or with total tumor mass > 80 ml. In 77 patients all the examinations were available for comparison. US and CT diagnosed more patients as belonging to group 1 than angiography and Lipiodol CT, while more patients were classified as groups 2 and 3 with angiography and Lipiodol CT, meaning that US and CT may understage some HCC cases (about 15%) because they show a lower number of nodules. This observation was confirmed by the direct comparison between US and Lipiodol CT (in 114 patients), CT and Lipiodol CT (in 103 patients) and angiography and Lipiodol CT (in 116 patients). US and Lipiodol CT were in disagreement in 18 cases, CT and Lipiodol CT in 16 cases and angiography and Lipiodol CT in 13 cases. In most of these cases, Lipiodol CT showed more lesions than the other techniques. The size of the undetected lesions was small, ranging few mm to 2 cm in nearly all cases. To conclude, the results of this multicentric trial show that Lipiodol CT is a fundamental tool to evaluate HCC extent. In contrast, conventional CT appeared not to add any significant piece of information and can therefore be excluded from the diagnostic protocol of HCC.

  8. Lipiodol: A Potential Direct Surrogate for Cone-Beam Computed Tomography Image Guidance in Radiotherapy of Liver Tumor

    SciTech Connect

    Yue Jinbo; Sun Xindong; Cai Jing; Yin Fangfang; Yin Yong; Zhu Jian; Lu Jie; Liu Tonghai; Yu Jinming; Shi Xuetao; Song Jinlong

    2012-02-01

    Purpose: To investigate the feasibility of using lipiodol as a direct surrogate for target localization using cone-beam CT (CBCT) image guidance in radiotherapy (RT) of patients with unresectable liver tumors after transarterial chemoembolization. Methods and Materials: Forty-six patients with an unresectable solitary liver tumor were enrolled for RT using active breathing control (ABC) and CBCT image guidance after transarterial chemoembolization. Each patient had pre- and posttreatment CBCT in the first 10 fractions of treatment. Lipiodol retention was evaluated using daily CBCT scans, and volume of lipiodol retention in the liver was calculated and compared between planning CT and post-RT CT. Influence of lipiodol on dosimetry was evaluated by measuring doses using an ion chamber with and without the presence of lipiodol. Margin analysis was performed on the basis of both inter- and intrafractional target localization errors. Results: Twenty-eight patients successfully completed the study. The shape and size of lipiodol retention did not vary substantially during the course of treatment. The mean Dice similarity coefficient for the lipiodol volume in pretreatment CT and that in posttreatment CT was 0.836 (range, 0.817-0.885). The maximum change (ratio of the lipiodol volume in pretreatment CT to that in posttreatment CT) was 1.045. The mean dose changes with the presence of <10 mL lipiodol were -1.44% and 0.13% for 6 MV and 15 MV, respectively. With ABC and online CBCT image guidance, clinical target volume-planning target volume margins were determined to be 2.5 mm in the mediolateral direction, 2.9 mm in the anteroposterior direction, and 4.0 mm in the craniocaudal direction. Conclusions: Lipiodol could be used as a direct surrogate for CBCT image guidance to improve the localization accuracy for RT of liver tumors. Combination of ABC and CBCT image guidance with lipiodol can potentially reduce the clinical target volume-planning target volume margin.

  9. 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.

  10. Aqueous extract of Cordyceps alleviates cerebral ischemia-induced short-term memory impairment in gerbils

    PubMed Central

    Lee, Sang-Hak; Ko, Il-Gyu; Kim, Sung-Eun; Hwang, Lakkyong; Jin, Jun-Jang; Choi, Hyun-Hee; Kim, Chang-Ju

    2016-01-01

    Cerebral ischemia is caused by reduced cerebral blood flow due to a transient or permanent cerebral artery occlusion. Ischemic injury in the brain leads to neuronal cell death, and eventually causes neurological impairments. Cordyceps, the name given to the fungi on insects, has abundant useful natural products with various biological activities. Cordyceps is known to have nephroprotective, hepatoprotective, anti-inflammatory, antioxidative, and antiapoptotic effects. We investigated the effects of Cordyceps on short-term memory, neuronal apoptosis, and cell proliferation in the hippocampal dentate gyrus following transient global ischemia in gerbils. For this study, a step-down avoidance test, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunohistochemistry for caspase-3 and 5-bromo-2′-de-oxyuridine, and western blot for Bax, Bcl-2, brain-derived neurotrophic factor (BDNF), and tyrosin kinase B were performed. In the present study, Cordyceps alleviated cerebral ischemia-induced short-term memory impairment. Cordyceps showed therapeutic effects through inhibiting cerebral ischemia-induced apoptosis in the hippocampus. Cordyceps suppressed cerebral ischemia-induced cell proliferation in the hippocampal dentate gyrus due to the reduced apoptotic neuronal cell death. Cordyceps treatment also enhanced BDNF and TrkB expressions in the hippocampus of ischemic gerbils. It can be suggested that Cordyceps overcomes cerebral ischemia-induced neuronal apoptosis, thus facilitates recovery following cerebral ischemia injury. PMID:27162767

  11. Aqueous extract of Cordyceps alleviates cerebral ischemia-induced short-term memory impairment in gerbils.

    PubMed

    Lee, Sang-Hak; Ko, Il-Gyu; Kim, Sung-Eun; Hwang, Lakkyong; Jin, Jun-Jang; Choi, Hyun-Hee; Kim, Chang-Ju

    2016-04-01

    Cerebral ischemia is caused by reduced cerebral blood flow due to a transient or permanent cerebral artery occlusion. Ischemic injury in the brain leads to neuronal cell death, and eventually causes neurological impairments. Cordyceps, the name given to the fungi on insects, has abundant useful natural products with various biological activities. Cordyceps is known to have nephroprotective, hepatoprotective, anti-inflammatory, antioxidative, and antiapoptotic effects. We investigated the effects of Cordyceps on short-term memory, neuronal apoptosis, and cell proliferation in the hippocampal dentate gyrus following transient global ischemia in gerbils. For this study, a step-down avoidance test, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunohistochemistry for caspase-3 and 5-bromo-2'-de-oxyuridine, and western blot for Bax, Bcl-2, brain-derived neurotrophic factor (BDNF), and tyrosin kinase B were performed. In the present study, Cordyceps alleviated cerebral ischemia-induced short-term memory impairment. Cordyceps showed therapeutic effects through inhibiting cerebral ischemia-induced apoptosis in the hippocampus. Cordyceps suppressed cerebral ischemia-induced cell proliferation in the hippocampal dentate gyrus due to the reduced apoptotic neuronal cell death. Cordyceps treatment also enhanced BDNF and TrkB expressions in the hippocampus of ischemic gerbils. It can be suggested that Cordyceps overcomes cerebral ischemia-induced neuronal apoptosis, thus facilitates recovery following cerebral ischemia injury.

  12. Ischemic Effects of Transcatheter Arterial Embolization with N-Butyl Cyanoacrylate-Lipiodol on the Colon in a Swine Model

    SciTech Connect

    Ikoma, Akira; Kawai, Nobuyuki; Sato, Morio Sonomura, Tetsuo; Minamiguchi, Hiroki; Nakai, Motoki; Takasaka, Isao; Nakata, Kouhei; Sahara, Shinya; Sawa, Naohisa; Shirai, Shintaro; Mori, Ichiro

    2010-10-15

    This study was designed to assess the safety of transcatheter arterial embolization (TAE) with n-butyl cyanoacrylate-lipiodol (NBCA-Lp) for the large bowel and to investigate the vital response to NBCA-Lp in a swine model. In nine swine, nine arteries nourishing the colon were embolized with NBCA-Lp (1 ml of NBCA mixed with 4 ml of lipiodol): sigmoid-rectal branch artery in six swine, right colic branch artery in two, and middle colic branch artery in one. The amount of NBCA-Lp was 0.1-0.4 ml. Sacrifice was conducted 3 days after TAE to identify histological infarction. Classification was conducted retrospectively: group A, vasa recta without NBCA-Lp embolization despite TAE; group B, three or fewer vasa recta with NBCA-Lp embolization; and group C, five or more vasa recta with NBCA-Lp embolization. In one swine in group A, no necrotic focus was observed. In group B, three of four swine experienced no ischemic damage. The remaining one swine experienced necrosis of mucosal and submucosal layers in one-fourth of the circumference. In group C, all four swine with marginal artery and five vasa recta or more embolized experienced total necrosis of mucosa, submucosa, and smooth muscle layers of the whole colonic circumference. Significant difference on the extent of ischemic damage was observed between groups B and C (P < 0.05). Microscopically, NBCA-Lp induced acute vasculitis. Embolization of three or fewer vasa recta with NBCA-Lp induced no ischemic damage or limited necrosis, whereas embolization of five or more vasa recta with NBCA-Lp induced extensive necrosis.

  13. Quantitative assessment of lipiodol deposition after Chemoembolization: Comparison between cone-beam CT and multi-detector CT

    PubMed Central

    Chen, Rongxin; Geschwind, Jean-François; Wang, Zhijun; Tacher, Vania; Lin, MingDe

    2013-01-01

    Purpose To evaluate the ability of cone-beam computed tomography (CBCT) acquired directly after TACE to assess lipiodol deposition in hepatocellular carcinoma (HCC) and compare it to unenhanced MDCT. Materials and methods Fifteen HCC patients were treated with conventional TACE, and CBCT was used to assess the lipiodol deposition directly after TACE. Unenhanced MDCT was performed 24 hours after TACE. Four patients were excluded because the margin of tumor or area of lipiodol deposition was not clear. The image enhancement density of the entire tumor (T) and liver parenchyma (L) was measured by ImageJ software, and tumor-to-liver contrast (TLC) was calculated. In addition, volumetric measurement of tumor and lipiodol was performed by semiautomatic 3D volume segmentation and compared using linear regression to evaluate consistency between two imaging modalities. Results The mean value of TLC on CBCT was not significantly different from that on MDCT (337.7±233.5 HU versus 283.0±152.1 HU, P=0.103). The average volume of the whole tumor and of only the lipiodol deposited regions, and the calculated average percentage of lipiodol retention on CBCT were not significantly different when compared to MDCT (tumor volume: 9.6±11.8 cm3 versus 10.8±14.2 cm3, P=0.142; lipiodol volume: 6.3±7.7 cm3 versus 7.0±8.1 cm3, P=0.214; percentage of lipiodol retention: 68.9%±24.0% versus 72.2%±23.1%, P=0.578). Additionally, there was a high correlation in the volume of tumor and lipiodol between CBCT and MDCT (R2=0.919 and 0.903, respectively). Conclusions The quantitative image enhancement and volume analyses demonstrate that CBCT is similar to MDCT in assessing the lipiodol deposition in HCC after TACE. PMID:24094672

  14. Detection of hypervascular hepatocellular carcinoma: Comparison of multi-detector CT with digital subtraction angiography and Lipiodol CT

    PubMed Central

    Zheng, Xiao-Hua; Guan, Yong-Song; Zhou, Xiang-Ping; Huang, Juan; Sun, Long; Li, Xiao; Liu, Yuan

    2005-01-01

    AIM: The purpose of this study was to compare the diagnostic accuracy of biphasic multi-detector row helical computed tomography (MDCT), digital subtraction angiography (DSA) and Lipiodol computed tomography (CT) in detection of hypervascular hepatocellular carcinoma (HCC). METHODS: Twenty-eight patients with nodular HCC underwent biphasic MDCT examination: hepatic arterial phase (HAP) 25 s and portal venous phase (PVP) 70 s after injection of the contrast medium (1.5 mL/kg). They also underwent hepatic angiography and intra-arterial infusion of iodized oil. Lipiodol CT was performed 3-4 wk after infusion. MDCT images were compared with DSA and Lipiodol CT images for detection of hepatic nodules. RESULTS: The three imaging techniques had the same sensitivity in detecting nodules >20 mm in diameter. There was no significant difference in the sensitivity among HAP-MDCT, Lipiodol CT and DSA for nodules of 10-20 mm in diameter. For the nodules <10 mm in diameter, HAP-MDCT identified 47, Lipiodol CT detected 27 (χ2 = 11.3, P = 0.005<0.01, HAP-MDCT vs Lipiodol CT) and DSA detected 16 (χ2 = 9.09, P = 0.005<0.01 vs Lipiodol CT and χ2 = 29.03, P = 0.005<0.01vs HAP-MDCT). However, six nodules <10 mm in diameter were detected only by Lipiodol CT. CONCLUSION: MDCT and Lipiodol CT are two complementary modalities. At present, MDCT does not obviate the need for DSA and subsequent Lipiodol CT as a preoperative examination for HCC. PMID:15633215

  15. Utilizing a cranial window to visualize the middle cerebral artery during endothelin-1 induced middle cerebral artery occlusion.

    PubMed

    Regenhardt, Robert W; Ansari, Saeed; Azari, Hassan; Caldwell, Kenneth J; Mecca, Adam P

    2013-02-22

    Creation of a cranial window is a method that allows direct visualization of structures on the cortical surface of the brain(1-3). This technique can be performed in many locations overlying the rat cerebrum, but is most easily carried out by creating a craniectomy over the readily accessible frontal or parietal bones. Most frequently, we have used this technique in combination with the endothelin-1 middle cerebral artery occlusion model of ischemic stroke to quantify the changes in middle cerebral artery vessel diameter that occur with injection of endothelin-1 into the brain parenchyma adjacent to the proximal MCA(4, 5). In order to visualize the proximal portion of the MCA during endothelin -1 induced MCAO, we use a technique to create a cranial window through the temporal bone on the lateral aspect of the rat skull (Figure 1). Cerebral arteries can be visualized either with the dura intact or with the dura incised and retracted. Most commonly, we leave the dura intact during visualization since endothelin-1 induced MCAO involves delivery of the vasoconstricting peptide into the brain parenchyma. This bypasses the need to incise the dura directly over the visualized vessels for drug delivery. This protocol will describe how to create a cranial window to visualize cerebral arteries in a step-wise fashion, as well as how to avoid many of the potential pitfalls pertaining to this method.

  16. Spaceflight-induced alterations in cerebral artery vasoconstrictor, mechanical, and structural properties: implications for elevated cerebral perfusion and intracranial pressure

    PubMed Central

    Taylor, Curtis R.; Hanna, Mina; Behnke, Bradley J.; Stabley, John N.; McCullough, Danielle J.; Davis, Robert T.; Ghosh, Payal; Papadopoulos, Anthony; Muller-Delp, Judy M.; Delp, Michael D.

    2013-01-01

    Evidence indicates that cerebral blood flow is both increased and diminished in astronauts on return to Earth. Data from ground-based animal models simulating the effects of microgravity have shown that decrements in cerebral perfusion are associated with enhanced vasoconstriction and structural remodeling of cerebral arteries. Based on these results, the purpose of this study was to test the hypothesis that 13 d of spaceflight [Space Transportation System (STS)-135 shuttle mission] enhances myogenic vasoconstriction, increases medial wall thickness, and elicits no change in the mechanical properties of mouse cerebral arteries. Basilar and posterior communicating arteries (PCAs) were isolated from 9-wk-old female C57BL/6 mice for in vitro vascular and mechanical testing. Contrary to that hypothesized, myogenic vasoconstrictor responses were lower and vascular distensibility greater in arteries from spaceflight group (SF) mice (n=7) relative to ground-based control group (GC) mice (n=12). Basilar artery maximal diameter was greater in SF mice (SF: 236±9 μm and GC: 215±5 μm) with no difference in medial wall thickness (SF: 12.4±1.6 μm; GC: 12.2±1.2 μm). Stiffness of the PCA, as characterized via nanoindentation, was lower in SF mice (SF: 3.4±0.3 N/m; GC: 5.4±0.8 N/m). Collectively, spaceflight-induced reductions in myogenic vasoconstriction and stiffness and increases in maximal diameter of cerebral arteries signify that elevations in brain blood flow may occur during spaceflight. Such changes in cerebral vascular control of perfusion could contribute to increases in intracranial pressure and an associated impairment of visual acuity in astronauts during spaceflight.—Taylor, C. R., Hanna, M., Behnke, B. J., Stabley, J. N., McCullough, D. J., Davis III, R. T., Ghosh, P., Papadopoulos, A., Muller-Delp, J. M., Delp, M. D. Spaceflight-induced alterations in cerebral artery vasoconstrictor, mechanical, and structural properties: implications for elevated

  17. [131-I-lipiodol in therapy of liver carcinoma--methods and case report].

    PubMed

    Stefanović, L; Nikolić, V; Obradović, M; Selir, Z; Mihoci, Z; Mihailović, J; Malesević, M

    2001-01-01

    Primary malignant liver tumors are successfully treated only by means of surgery, but no more than 10% of patients are candidates for surgical intervention. The rest receive only palliative treatment which is, as a rule, unsuccessful. 131I-Lipiodol therapy (commercial label LIPIOCISTM) applied to the hepatic artery through a catheter has been used since 1984, primarily for treatment of hepatocellular carcinoma (HCC). The aim of this paper is to review the methodology of 131J-Lipiodol treatment of primary liver carcinomas. This treatment was applied for the first time in Yugoslavia. A female patient, 46 years of age had an inoperable primary liver carcinoma. Since progression of the disease couldn't be controlled by chemotherapy, treatment with 131I-Lipiodol was indicated. After blocking the thyroid with Lugol, Sol. 2.22 GBq of 131I-Lipiodol was injected into hepatic artery via catheter, and the patient was isolated in a designated facility until discharged. Around 5 months later, second therapeutic dose of 1.11 GBq was administered. Early post-therapy complications were severe, but transient. After 131I-Lipiodol therapy, the tumor growth was stopped, but the patient's general condition slowly deteriorated. The patient died 7 months after receiving the first therapeutic dose. In the reported patient, 131I-Lipiodol therapy stopped the tumor growth within the liver and significantly prolonged survival compared to the expected, but no improvement in quality of life was achieved. This treatment methodology is very complex. Medical staff providing care for these patients is exposed to substantial irradiation.

  18. Music-induced changes in functional cerebral asymmetries.

    PubMed

    Hausmann, Markus; Hodgetts, Sophie; Eerola, Tuomas

    2016-04-01

    After decades of research, it remains unclear whether emotion lateralization occurs because one hemisphere is dominant for processing the emotional content of the stimuli, or whether emotional stimuli activate lateralised networks associated with the subjective emotional experience. By using emotion-induction procedures, we investigated the effect of listening to happy and sad music on three well-established lateralization tasks. In a prestudy, Mozart's piano sonata (K. 448) and Beethoven's Moonlight Sonata were rated as the most happy and sad excerpts, respectively. Participants listened to either one emotional excerpt, or sat in silence before completing an emotional chimeric faces task (Experiment 1), visual line bisection task (Experiment 2) and a dichotic listening task (Experiment 3 and 4). Listening to happy music resulted in a reduced right hemispheric bias in facial emotion recognition (Experiment 1) and visuospatial attention (Experiment 2) and increased left hemispheric bias in language lateralization (Experiments 3 and 4). Although Experiments 1-3 revealed an increased positive emotional state after listening to happy music, mediation analyses revealed that the effect on hemispheric asymmetries was not mediated by music-induced emotional changes. The direct effect of music listening on lateralization was investigated in Experiment 4 in which tempo of the happy excerpt was manipulated by controlling for other acoustic features. However, the results of Experiment 4 made it rather unlikely that tempo is the critical cue accounting for the effects. We conclude that listening to music can affect functional cerebral asymmetries in well-established emotional and cognitive laterality tasks, independent of music-induced changes in the emotion state.

  19. Chronic nicotine exposure exacerbates transient focal cerebral ischemia-induced brain injury.

    PubMed

    Li, Chun; Sun, Hong; Arrick, Denise M; Mayhan, William G

    2016-02-01

    Tobacco smoking is a risk factor contributing to the development and progression of ischemic stroke. Among many chemicals in tobacco, nicotine may be a key contributor. We hypothesized that nicotine alters the balance between oxidant and antioxidant networks leading to an increase in brain injury following transient focal cerebral ischemia. Male Sprague-Dawley were treated with nicotine (2 or 4 mg·kg(-1)·day(-1)) for 4 wk via an implanted subcutaneous osmotic minipump and subjected to a 2-h middle cerebral artery occlusion (MCAO). Infarct size and neurological deficits were evaluated at 24 h of reperfusion. Superoxide levels were determined by lucigenin-enhanced chemiluminescence. Expression of oxidant and antioxidant proteins was measured using Western blot analysis. We found that chronic nicotine exposure significantly increased infarct size and worsened neurological deficits. In addition, nicotine significantly elevated superoxide levels of cerebral cortex under basal conditions. Transient focal cerebral ischemia produced an increase in superoxide levels of cerebral cortex in control group, but no further increase was found in the nicotine group. Furthermore, chronic nicotine exposure did not alter protein expression of NADPH oxidase but significantly decreased MnSOD and uncoupling protein-2 (UCP-2) in the cerebral cortex and cerebral arteries. Our findings suggest that nicotine-induced exacerbation in brain damage following transient focal cerebral ischemia may be related to a preexisting oxidative stress via decreasing of MnSOD and UCP-2. Copyright © 2016 the American Physiological Society.

  20. Hypersensitivity reactions to transcatheter chemoembolization with cisplatin and Lipiodol suspension for unresectable hepatocellular carcinoma.

    PubMed

    Kawaoka, Tomokazu; Aikata, Hiroshi; Katamura, Yoshio; Takaki, Shintaro; Waki, Koji; Hiramatsu, Akira; Takahashi, Shoichi; Hieda, Masashi; Kakizawa, Hideaki; Chayama, Kazuaki

    2010-08-01

    To assess the predictors of hypersensitivity reaction to chemoembolization procedures with cisplatin and Lipiodol suspension for the treatment of hepatocellular carcinoma (HCC). Between February 2005 and December 2008, 434 patients with HCC were treated with chemoembolization with a cisplatin and Lipiodol suspension. This retrospective cohort study analyzed the incidence of hypersensitivity reactions as an adverse effect and their predictors by multivariate logistic regression analyses. In total, 847 chemoembolization procedures were carried out in 434 patients. The median number of procedures per patient was 2 (range, 1-12). Mean dose of cisplatin per chemoembolization session was 27 mg (range, 15.0-80.0 mg), and the median total dose of cisplatin per patient was 55 mg (range, 5.0-560.0 mg). Hypersensitivity reactions occurred in 14 patients (1.7%). The median number of chemoembolization procedures in these patients was 7 (range, 3-10). Mean dose of cisplatin per session was 22 mg (range, 9.2-35.7 mg), and the median total dose of cisplatin was 134 mg (range, 37-286 mg). On multivariate analysis, the only parameter that showed an independent association with hypersensitivity reactions was the performance of 3 or more than three chemoembolization procedures. Performance of more than three chemoembolization procedures with a cisplatin and Lipiodol suspension was found to be independently associated with hypersensitivity reactions. Patients undergoing repeated chemoembolization procedures with cisplatin and Lipiodol suspension may experience hypersensitivity reactions as an adverse effect. Copyright (c) 2010 SIR. Published by Elsevier Inc. All rights reserved.

  1. 3D Volumetric Evaluation of Lipiodol Retention in HCC after Chemoembolization: A Quantitative Comparison between CBCT and MDCT

    PubMed Central

    Wang, Zhijun; Lin, MingDe; Lesage, David; Chen, Rongxin; Chapiro, Julius; Gu, Tara; Tacher, Vania; Duran, Rafael; Geschwind, Jean-François

    2014-01-01

    Rationale and Objectives To evaluate the capability of cone-beam computed tomography (CBCT) acquired immediately after transcatheter arterial chemoembolization (TACE) in determining Lipiodol retention quantitatively and volumetrically when compared to 1-day post-procedure unenhanced MDCT. Materials and methods From June to December, 2012, fifteen patients met the inclusion criteria of unresectable hepatocellular carcinoma (HCC) that was treated with conventional TACE (cTACE), and had intra-procedural CBCT and 1-day post-TACE MDCT. Four patients were excluded because the Lipiodol was diffuse throughout the entire liver or Lipiodol deposition was not clear on both CBCT and MDCT. Eleven patients with a total of 31 target lesions were included in the analysis. A quantitative and 3D software was used to assess complete, localized and diffuse lipiodol deposition. Tumor volume, Lipiodol volume in the tumor, % Lipiodol retention, and Lipiodol enhancement in Hounsfield Unit (HU) were calculated and compared between CBCT and MDCT using two-tailed student’s t-test and Bland-Altman plots. Results The mean value of tumor volume, Lipiodol deposited regions, calculated average % Lipiodol retention, and HU value of CBCT were not significantly different from those of MDCT (tumor volume: 9.37±11.35cm3 vs. 9.34±11.44cm3, P=0.991; Lipiodol volume: 7.84±9.34cm3 vs. 7.84±9.60 cm3, P=0.998; % Lipiodol retention: 89.3%±14.7% vs. 90.2% ± 14.9%, P=0.811; HU value: 307.7±160.1 HU vs. 257.2±120.0 HU, P=0.139). Bland-Altman plots showed only minimal difference and high agreement when comparing CBCT to MDCT. Conclusion CBCT has a similar capability, intraprocedurally, to assess Lipiodol deposition in 3D for patients with HCC treated with cTACE when compared to MDCT. PMID:24507426

  2. Diffuse cerebrovascular dilation: Case report of amezinium metilsulfate-induced reversible cerebral vasoconstriction syndrome.

    PubMed

    Kobayashi, Makoto

    2016-03-01

    Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with reversible cerebral vasoconstriction, and often precipitated by the postpartum state and vasoactive medications. We describe a case of a patient with RCVS induced by amezinium metilsulfate, a sympathomimetic drug, in whom magnetic resonance angiography (MRA) initially revealed diffusely dilated cerebral arteries. A 34-year-old woman was prescribed amezinium metilsulfate for hypotension. Twelve days later, she suffered from abrupt severe headaches and was referred to our department. She had no neurological deficits; however, MRA revealed diffusely dilated anterior, middle, and posterior cerebral arteries with vasoconstriction. She was tentatively diagnosed with RCVS and successfully treated with verapamil for headache. Nevertheless, follow-up MRAs disclosed widespread segmental vasoconstriction that resolved in two months. Diffuse cerebrovascular dilation has not been addressed but may be associated with RCVS pathophysiology. In addition, physicians should bear in mind that amezinium metilsulfate can potentially induce RCVS. © International Headache Society 2015.

  3. [Changes in the cerebral flow velocity induced in the middle cerebral artery by acute stress studied by transcranial Doppler ultrasonography].

    PubMed

    Martín, R; González, M J; Ruiz, C; Montiel, I; Alberdi, M; Matías-Guiu, J

    1994-10-29

    The behavior of brain flow on acute stress has not been previously evaluated. Transcranial Doppler ultrasonography (TD) is a bloodless method to evaluate the speed of cerebral flow in the arteries of the Willis polygon. The present study was designed to analyze the changes which occur in the same during two situations of acute stress. The mean speed of cerebral flow (MS) and the pulsation rate (PR) of the right and left middle cerebral artery (MCA) were measured basally and following a mental stress test (calculation) and physical stress (cold test) by TD and through the temporal window. Twenty-five healthy volunteers (18 women and 8 men) with a mean age of 27.8 +/- 7.3 years were studied. In response to mental stress an increase was observed in MS in both the right MCA (10 +/- 8.6 cm/sec) and the left MCA (10.4 +/- 8.7 cm/sec) with a decrease in the MCA (0.14 +/- 0.23 in the right MCA, 0.14 +/- 0.18 cm/sec in the left MCA). In response to the cold test an increase in MS (7.3 +/- 7.5 cm/sec in the right MCA, 14.8 +/- 14.7 cm/sec in the left MCA) was also observed with a decrease in the PR (0.2 +/- 0.2 in the right MCA and 0.2 +/- 0.16 in the left MCA). No significant differences were observed in the changes induced in the right or left artery or in those induced by the mental or cold tests. These results suggest that the acute stress produces an increase in cerebral flow in the arteries of the Willis polygon.

  4. Changes of hypoxia-inducible factor-1 signaling and the effect of cilostazol in chronic cerebral ischemia

    PubMed Central

    Chen, Han; Wei, Aixuan; He, Jinting; Yu, Ming; Mang, Jing; Xu, Zhongxin

    2013-01-01

    Hypoxia-inducible factor-1 and its specific target gene heme oxygenase-1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol (30 mg/kg) for 9 weeks. Morris water maze results showed that cognitive impairment gradually worsened as the cerebral ischemia proceeded. Immunohistochemistry, semi-quantitative PCR and western blot analysis showed that hypoxia-inducible factor-1α and heme oxygenase-1 expression levels increased after chronic cerebral ischemia, with hypoxia-inducible factor-1α expression peaking at 3 weeks and heme oxygenase-1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxia-inducible factor-1α may upregulate heme oxygenase-1 expression following chronic cerebral ischemia and that the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, decreased hypoxia-inducible factor-1α and heme oxygenase-1 expression levels, and reduced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an anti-apoptotic mechanism. PMID:25206477

  5. Effect of Inducible Co-Stimulatory Molecule siRNA in Cerebral Infarction Rat Models

    PubMed Central

    Luo, Yingquan; Yang, Yu; Zhang, Hui; Zhang, Ting; Wang, Yina; Tan, Shengyu; Xu, Yan; Li, Dan; Ye, Ling; Chen, Ping

    2015-01-01

    Background T cell-induced inflammatory response and related cytokine secretion at the injury site may participate in the pathogenesis of cerebral infarction. Recent studies established inducible co-stimulatory molecule (ICOS) as a novel T cell-related factor for its activation and functions. We thus investigate the role of ICOS in cerebral infarction. Material/Methods The siRNA of ICOS was first used to suppress the gene expression in cultured lymphocytes. An in vivo study was then performed by intravenous application of ICOS siRNA in cerebral infarction rats. Survival rates, neurological scores, serum tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-17 levels were observed. Results The expression of ICOS in cultured lymphocytes was significantly suppressed by siRNA. In the in vivo study, the application of siRNA effectively lowered mortality rates of rats, in addition to the improvement of neurological behaviors and amelioration of cerebral tissue damage. Serum levels of TNF-α, IL-1 and IL-17 were all significantly suppressed after siRNA injection. Conclusions ICOS siRNA can protect brain tissues from ischemia injuries after cerebral infarction, improve limb movement and coordination, lower the mortality rate of rats, and inhibit T cell-induced cytokines. These results collectively suggest the potential treatment efficacy of ICOS siRNA against cerebral infarction. PMID:26436531

  6. PUMA is invovled in ischemia/reperfusion-induced apoptosis of mouse cerebral astrocytes.

    PubMed

    Chen, H; Tian, M; Jin, L; Jia, H; Jin, Y

    2015-01-22

    PUMA (p53-upregulated modulator of apoptosis), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and p53-independent forms of apoptosis. PUMA has been invovled in the onset and progress of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease. Although many studies have shown that ischemia and reperfusion (I/R) can induce the apoptosis of astrocytes, the role of PUMA in I/R-mediated apoptosis of cerebral astrocyte apoptosis remains unclear. To mimic in vivo I/R conditions, primary mouse cerebral astrocytes were incubated in a combinational cultural condition of oxygen, glucose, and serum deprivation (OSGD) for 1 h followed by reperfusion (OSGD/R). Cell death determination assays and cell viability assays indicated that OSGD and OSGD/R induce the apoptosis of primary cerebral astrocytes. The expression of PUMA was significantly elevated in primary cerebral astrocytes during OSGD/R. Moreover, targeted down-regulation of PUMA by siRNA transfection significantly decreased the OSGD/R-induced apoptosis of primary cerebral astrocytes. We also found that OSGD and OSGD/R triggered the release of cytochrome c in astrocytes, indicating the dependence on a mitochondrial apoptotic pathway. Reactive oxygen species (ROS) was extremely generated during OSGD and OSGD/R, and the elimination of ROS by treated with N-acetyl-L-cysteine (NAC) remarkably inhibited the expression of PUMA and the apoptosis of primary cerebral astrocytes. The activation of Caspase 3 and Caspase 9 was extremely elevated in primary cerebral astrocytes during OSGD. In addition, we found that knockdown of PUMA led to the depressed expression of Bax, cleaved caspase-9 and caspase-3 during OSGD/R. These results indicate that PUMA is invovled in the apoptosis of cerebral astrocytes upon I/R injury.

  7. Influence of Lipiodol Agent on Proton Beam Range in Radiotherapy Planning Using Computed Tomography for Hepatocellular Carcinoma

    SciTech Connect

    Shin, Dongho; Kim, Tae Hyun; Park, Sung Yong Kwak, Jungwon; Moon, Sung Ho; Yoon, Myonggeun; Lee, Se Byeong; Park, Soah; Shin, Kyung Hwan; Kim, Dae Yong; Cho, Kwan Ho; Park, Joong-Won; Kim, Chang-Min

    2008-11-01

    Purpose: To evaluate the influence of lipiodol on the proton beam range, which has not yet been determined. Methods and Materials: Two computed tomography (CT) data sets were obtained with a T25-flask containing lipiodol and water that was placed above a water phantom. The plan with the lipiodol CT images was performed, and then a verification plan was applied to the water CT images. The actual proton beam ranges in the lipiodol and water were measured under same conditions, and we compared the calculated proton beam range in the treatment planning system with measured values. Results: The calculated distal range in the treatment planning system was 12 cm in water, which was 3.87 cm longer than that in lipiodol (8.13 cm). In contrast, the measured distal range was 12 {+-} 0.01 cm in water, which was 0.21 {+-} 0.01 cm longer than that of lipiodol (11.78 {+-} 0.01 cm). A 3.65 {+-} 0.01-cm range shift was found in the calculated range compared with the measured range. For 10 hepatocellular carcinoma patients, the distal range in the verification plan with the corrected CT images in which the Hounsfield unit (HU) value of lipiodolized lesion was replaced with the average HU value of the surrounding tissue was 0.61 {+-} 0.26 cm (range, 0.26-0.99) longer than that in the plan with uncorrected CT images. Conclusions: It could be relevant for the purposes of range calculation of proton beams in the treatment planning system that the HU value of a lipiodolized lesion is replaced by the average HU value of the surrounding normal tiss0008.

  8. Parameters for Stable Water-in-Oil Lipiodol Emulsion for Liver Trans-Arterial Chemo-Eembolization.

    PubMed

    Deschamps, F; Moine, L; Isoardo, T; Tselikas, L; Paci, A; Mir, L M; Huang, N; Fattal, E; de Baère, T

    2017-08-02

    Water-in-oil type and stability are important properties for Lipiodol emulsions during conventional trans-arterial chemo-embolization. Our purpose is to evaluate the influence of 3 technical parameters on those properties. The Lipiodol emulsions have been formulated by repetitive back-and-forth pumping of two 10-ml syringes through a 3-way stopcock. Three parameters were compared: Lipiodol/doxorubicin ratio (2/1 vs. 3/1), doxorubicin concentration (10 vs. 20 mg/ml) and speed of incorporation of doxorubicin in Lipiodol (bolus vs. incremental vs. continuous). The percentage of water-in-oil emulsion obtained and the duration until complete coalescence (stability) for water-in-oil emulsions were, respectively, evaluated with the drop-test and static light scattering technique (Turbiscan). Among the 48 emulsions formulated, 32 emulsions (67%) were water-in-oil. The percentage of water-in-oil emulsions obtained was significantly higher for incremental (94%) and for continuous (100%) injections compared to bolus injection (6%) of doxorubicin. Emulsion type was neither influenced by Lipiodol/doxorubicin ratio nor by doxorubicin concentration. The mean stability of water-in-oil emulsions was 215 ± 257 min. The emulsions stability was significantly longer when formulated using continuous compared to incremental injection (326 ± 309 vs. 96 ± 101 min, p = 0.018) and using 3/1 compared to 2/1 ratio of Lipiodol/doxorubicin (372 ± 276 vs. 47 ± 43 min, p = <0.0001). Stability was not influenced by the doxorubicin concentration. The continuous and incremental injections of doxorubicin in the Lipiodol result in highly predictable water-in-oil emulsion type. It also demonstrates a significant increase in stability compared to bolus injection. Higher ratio of Lipiodol/doxorubicin is a critical parameter for emulsion stability too.

  9. [Perspectives in the treatment of subarachnoid-hemorrhage-induced cerebral vasospasm].

    PubMed

    Fandino, J; Fathi, A R; Graupner, T; Jacob, S; Landolt, H

    2007-02-01

    Cerebral vasospasm is still the most important cause of death and disability after rupture of intracranial aneurysms. The therapeutic strategies in the treatment of subarachnoid hemorrhage induced vasospasm vasospasm include four groups: 1) prevention of vasospasm; 2) reversion of vasospasm; 3) improvement of cerebral perfusion; and 4) neuroprotection and rescue therapies. Recent experimental studies allowed the design of phase II clinical studies which demonstrated positive results with medications and compounds such as statins (simvastatin and pravastatin) and endothelin-1 receptor antagonists (clasozentan). Moreover, experimental and clinical evidences showed the advantages of early cerebrospinal fluid drainage, intrathecal administration of NO-donors, effects of Ca2+ protein kinase inhibitor (Fasudil) and catecholamines on the cerebral vessels. This review article summarizes the stage of investigation of these medications and therapeutic strategies which will be relevant in the treatment of cerebral vasospasm.

  10. Multiple cerebral infarctions in a young patient with heroin-induced hypereosinophilic syndrome.

    PubMed

    Bolz, Jan; Meves, Saskia H; Kara, Kaffer; Reinacher-Schick, Anke; Gold, Ralf; Krogias, Christos

    2015-09-15

    Hypereosinophilic syndrome represents a rare cause for cerebral infarctions and inflammatory neurological disorders. Various possible pathogenic mechanisms for cerebral infarctions have already been discussed. Complex mechanisms including a local hypercoagulability by eosinophilic granules as well as a direct damage to endothelial cells, leading to alterations of the microcirculation seem to be involved. The changing pattern of heroin use to inhalation/sniffing leading to an increasing abuse may cause a rise in the prevalence of Heroin induced eosinophilia, as it has been reported in a case of eosinophilic pneumonia associated with heroin inhalation. To our knowledge, the present case report displays the first description of stroke in the setting of heroin induced hypereosinophilia. Thus, besides usual vasoconstriction, HES should be considered in drug-induced cerebral infarctions.

  11. Glycopyrrolate abolishes the exercise-induced increase in cerebral perfusion in humans.

    PubMed

    Seifert, Thomas; Fisher, James P; Young, Colin N; Hartwich, Doreen; Ogoh, Shigehiko; Raven, Peter B; Fadel, Paul J; Secher, Niels H

    2010-10-01

    Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise-induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebral metabolism (from arterial and internal jugular venous O(2), glucose and lactate differences), as well as the middle cerebral artery mean blood velocity (MCA V(mean); transcranial Doppler ultrasound) during a sustained static handgrip contraction at 40% of maximal voluntary contraction (n = 9) and the MCA V(mean) during ergometer cycling (n = 8). Separate, randomized and counterbalanced trials were performed in control (no drug) conditions and following muscarinic cholinergic receptor blockade by glycopyrrolate. Glycopyrrolate increased resting heart rate from approximately 60 to approximately 110 beats min(-1) (P < 0.01) and cardiac output by approximately 40% (P < 0.05), but did not affect mean arterial pressure. The central cardiovascular responses to exercise with glycopyrrolate were similar to the control responses, except that cardiac output did not increase during static handgrip with glycopyrrolate. Glycopyrrolate did not significantly affect cerebral metabolism during static handgrip, but a parallel increase in MCA V(mean) (approximately 16%; P < 0.01) and CBF (approximately 12%; P < 0.01) during static handgrip, as well as the increase in MCA V(mean) during cycling (approximately 15%; P < 0.01), were abolished by glycopyrrolate (P < 0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise-induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen.

  12. Cerebral iodized lipid embolization via a pulmonary arteriovenous shunt: rare complication of transcatheter arterial embolization for hepatocellular carcinoma

    PubMed Central

    2013-01-01

    We report the first European case of cerebral iodized lipid embolism post transcatheter arterial embolization for hepatocellular carcinoma. Lipiodol emboli and corresponding multifocal brain ischemia were documented with computed tomography (CT) and magnetic resonance (MR) in the acutely symptomatic patient. Transcranial Doppler sonography with contrast indicated a right-to-left shunt, while on a follow-up CT scan lipiodol embolization was detected in both lungs. Dilated pulmonary vessels and thick vascular channels were seen in the vicinity of the right diaphragm suggestive of pulmonary arteriovenous shunt. The patient symptoms regressed with supportive care alone, but he died 5 months later due to hepatic failure unrelated to the procedure. PMID:23721061

  13. Coenzyme Q10 Abrogated the 28 Days Aluminium Chloride Induced Oxidative Changes in Rat Cerebral Cortex

    PubMed Central

    Majumdar, Anuradha S.; Nirwane, Abhijit; Kamble, Rahul

    2014-01-01

    Objective: The present study was designed to elucidate the impact of oral administration of aluminium chloride for 28 days with respect to oxidative stress in the cerebral cortex of female rats. Further, to investigate the potentials of Coenzyme (Co) Q10 (4, 8, and 12 mg/kg, i.p.) in mitigating the detrimental changes. Materials and Methods: Biochemical estimations of cerebral lipid peroxidation (LPO), reduced glutathione (GSH), vitamin E and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were carried out after 28 days of aluminium chloride (AlCl3) and Co Q10 exposures along with histopathological examination of cerebral cortex of the rats. Results: Subacute exposure to AlCl3(5 mg/kg) led to significant decrease in levels of GSH, vitamin E and activities of SOD, CAT, GPx, and an increase in LPO of cerebral cortex. These aberrations were restored by Co Q10 (12 mg/kg, i.p.). This protection offered was comparable to that of L-deprenyl (1 mg/kg, i.p.) which served as a reference standard. Histopathological evaluations confirmed that the normal cerebral morphology was maintained by Co Q10. Conclusion: Thus, AlCl3 exposure hampers the activities of various antioxidant enzymes and induces oxidative stress in cerebral cortex of female Wistar rats. Supplementation with intraperitoneal Co Q10 abrogated these deleterious effects of AlCl3. PMID:25253934

  14. Coenzyme q10 abrogated the 28 days aluminium chloride induced oxidative changes in rat cerebral cortex.

    PubMed

    Majumdar, Anuradha S; Nirwane, Abhijit; Kamble, Rahul

    2014-05-01

    The present study was designed to elucidate the impact of oral administration of aluminium chloride for 28 days with respect to oxidative stress in the cerebral cortex of female rats. Further, to investigate the potentials of Coenzyme (Co) Q10 (4, 8, and 12 mg/kg, i.p.) in mitigating the detrimental changes. Biochemical estimations of cerebral lipid peroxidation (LPO), reduced glutathione (GSH), vitamin E and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were carried out after 28 days of aluminium chloride (AlCl3) and Co Q10 exposures along with histopathological examination of cerebral cortex of the rats. Subacute exposure to AlCl3(5 mg/kg) led to significant decrease in levels of GSH, vitamin E and activities of SOD, CAT, GPx, and an increase in LPO of cerebral cortex. These aberrations were restored by Co Q10 (12 mg/kg, i.p.). This protection offered was comparable to that of L-deprenyl (1 mg/kg, i.p.) which served as a reference standard. Histopathological evaluations confirmed that the normal cerebral morphology was maintained by Co Q10. Thus, AlCl3 exposure hampers the activities of various antioxidant enzymes and induces oxidative stress in cerebral cortex of female Wistar rats. Supplementation with intraperitoneal Co Q10 abrogated these deleterious effects of AlCl3.

  15. Lipiodol Trans-arterial Chemoembolization of Hepatocellular Carcinoma with Idarubicin: First Experience

    SciTech Connect

    Favelier, Sylvain; Boulin, Mathieu; Hamza, Samia; Cercueil, Jean-Pierre; Cherblanc, Violaine; Lepage, Come; Hillon, Patrick; Chauffert, Bruno; Krause, Denis; Guiu, Boris

    2013-08-01

    BackgroundThere is still no consensus about the best chemotherapeutic agent for transarterial chemoembolization (TACE). A recent in vitro study demonstrated that idarubicin, an anthracycline, was by far the most cytotoxic drug on human hepatocellular carcinoma (HCC) cell lines. Idarubicin is much more lipophilic than doxorubicin, leading to higher cell penetration through lipidic membranes and greater accumulation of the drug in the lipiodol. Furthermore, idarubicin has the ability to overcome multidrug resistance. Therefore, we designed this pilot human study to evaluate the safety and efficacy of lipiodol TACE using idarubicin.MethodsIn 21 consecutive patients treated by lipiodol TACE with idarubicin (10 mg) for HCC, safety data, tumor response (Response Evaluation Criteria in Solid Tumors, mRECIST), time to treatment failure (TTTF), and overall survival were evaluated.ResultsPostembolization syndrome was observed after 30.9 % (17 of 55) of sessions. No patient died from a TACE-related complication. No hematological grade 3-5 adverse event was observed. At least one grade 3 or higher adverse event occurred in 19 % (4 of 21) of patients. On imaging, no progression was encountered; four patients (24 %) exhibited stable disease, 12 (57 %) exhibited a partial response, and five (19 %) exhibited a complete response. Median TTTF was 16.7 months (Kaplan-Meier analysis). At 6 months, 94.7 % (95 % confidence interval [CI] 68.1-99.2) of patients did not reach treatment failure, whereas treatment failure was not reached in 50.6 % (95 % CI 21.6-73.9) of patients at 1 year. Overall survival was 83.5 % (95 % CI 57-94.4) at 1 year.ConclusionIdarubicin seems safe and effective in lipiodol TACE of HCC. This warrants further study to determine the potential of this drug to replace doxorubicin for TACE.

  16. Radiation exposure and radiation protection of the physician in iodine-131 Lipiodol therapy of liver tumours.

    PubMed

    Risse, J H; Ponath, C; Palmedo, H; Menzel, C; Grünwald, F; Biersack, H J

    2001-07-01

    Intra-arterial iodine-131 labelled Lipiodol therapy for liver cancer has been investigated for safety and efficacy over a number of years, but data on radiation exposure of personnel have remained unavailable to date. The aim of this study was to assess the radiation exposure of the physician during intra-arterial 131I-Lipiodol therapy for liver malignancies and to develop appropriate radiation protection measures and equipment. During 20 intra-arterial administrations of 131I-Lipiodol (1110-1924 MBq), radiation dose equivalents (RDE) to the whole body, fingers and eyes of the physician were determined for (a) conventional manual administration through a shielded syringe, (b) administration with an automatic injector and (c) administration with a lead container developed in-house. Administration by syringe resulted in a finger RDE of 19.5 mSv, an eye RDE of 130-140 microSv, and a whole-body RDE of 108-119 microSv. The injector reduced the finger RDE to 5 mSv. With both technique (a) and technique (b), contamination of angiography materials was observed. The container allowed safe transport and administration of the radiopharmaceutical from 4 m distance and reduced the finger RDE to <3 microSv and the eye RDE to <1 microSv during injection. During femoral artery compression, radiation exposure to the fingers reached 170 microSv, but the whole-body dose could be reduced from a mean RDE of 114 microSv to 14 microSv. No more contamination occurred. In conclusion, radiation exposure was high when 131I-Lipiodol was administered by syringe or injector, but was significantly reduced with the lead container.

  17. Cyclophosphamide-induced agenesis of cerebral aqueduct resulting in hydrocephalus in mice.

    PubMed

    Prakash; Singh, Gajendra; Singh, Sukh Mahendra

    2007-07-01

    The present work was undertaken to reveal the mechanism of cerebral aqueduct agenesis found to result in hydrocephalus following intrauterine exposure to model teratogen, cyclophosphamide, in murine fetuses. A single dose of 10-mg/kg body weight cyclophosphamide was injected intaperitoneally to pregnant mice on day 10, 11 or 12 of gestation. Fetuses were collected through abdominal incision on day 18 and studied for various malformations of brain and cranium including hydrocephalus. Incomplete development and failure of canalization of the cerebral aqueduct were detected when serial sections of brain in coronal and transverse planes were studied under the microscope. Biotechnological investigations such as % DNA fragmentation, % viable cell count and cell proliferation assay were carried out on brain cells for further studies. Agenesis and non-canalization of the cerebral aqueduct resulted in increased pressure of CSF, which led to rupture of the aqueduct complicated by leakage and accumulation of CSF in brain substance forming a cavity containing CSF parallel and lateral to the unopened part of the cerebral aqueduct. Incomplete development along with non-canalization of the cerebral aqueduct resulted in blockage of CSF flow through the ventricles that manifest as internal hydrocephalus. External hydrocephalus on the other hand was detected where the CSF accumulated in the cavity formed inside the brain substance and established communication with the CSF in the subarachnoid space. Cyclophosphamide induced inhibition of mitosis and cell differentiation of ependymal cells reflecting a decreased % viable cell count and cell proliferation assay along with augmentation of apoptosis of brain cells quantified as increased % DNA fragmentation count, which were identified as the contributing factors underlying the agenesis and incomplete development of the cerebral aqueduct. The study also suggests that cell survival, proliferation, migration or differentiation of

  18. Intra-arterial injection of iodine-131-labeled lipiodol for treatment of hepatocellular carcinoma.

    PubMed

    Boucher, Eveline; Garin, Etienne; Guylligomarc'h, Anne; Olivié, Damien; Boudjema, Karim; Raoul, Jean-Luc

    2007-01-01

    The therapeutic effect of intra-arterial injection of 131-iodine-labeled lipiodol for treatment of hepatocellular carcinoma in palliative or adjuvant settings has been promising. We report, the results of an open study of this therapy in cirrhotic patients with small hepatocellular carcinoma. Forty patients with hepatocellular carcinoma were given intra-arterial injections of 131-iodine-labeled lipiodol. These injections were repeated if necessary every 3 months. Tumor response (WHO criteria) was determined on CT scans performed after each treatment and every 3 months during the follow-up. Side effects and the cause of death were recorded. Therapeutic response and survival were analyzed. The median number of treatment was 2 (1-4). There was one complete response, 18 partial responses (47.5% response rate); 19 had stable disease and 2 progressions. Overall survival rates (+/-CI 95%) at 1, 2 and 3 years were: 90+/-4.7%, 60.3+/-8%, and 39+/-8.3%, respectively. Median survival was 27 months; 25 patients have died (4-56 months), 8 of tumor progression with a multifocal spread in the liver. Tolerance was good except for 2 patients who develop a fatal drug-related pulmonary insufficiency. These data suggest that intra-arterial therapeutic injection of 131-iodine-labeled lipiodol for treatment of hepatocellular carcinoma can provide high rate response and long survival for individuals not eligible for surgery or local treatment.

  19. Arterial Hepatic Embolization of Unresectable Hepatocellular Carcinoma Using a Cyanoacrylate/Lipiodol Mixture

    SciTech Connect

    Berghammer, Peter; Pfeffel, Franz; Winkelbauer, Fritz; Wiltschke, Christoph; Schenk, Thomas; Lammer, Johannes; Mueller, Christian; Zielinski, Christoph

    1998-05-15

    Purpose: A survival analysis in 16 patients with unresectable hepatocellular carcinoma (HCC) undergoing transcatheter arterial embolization (TAE) using a combination of lipiodol and N-butyl-2-cyanoacrylate (5 : 1) was performed in a retrospective study. Methods: A combination of lipiodol and N-butyl-2-cyanoacrylate (5 : 1) was used for TAE. All patients had disease compatible with Okuda stages I and II. Results: Twenty-four embolizations were done; five patients had more than one embolization. Median alpha-fetoprotein levels declined from 116 to 48.6 ng/ml. A median of 0.3 ml cyanoacrylate was administered per patient. Median survival was 8.5 months (range 2-49 months). After a median follow-up of 4 years, 12 patients have died (75%). Okuda stage I and II patients had a median survival time of 34.4 and 5.5 months respectively. Few side effects (19%) were seen. Conclusion: We conclude that the TAE procedure used [lipiodol and N-butyl-2-cyanoacrylate (5 : 1)] is safe and produced only few side effects, thus constituting a valuable therapeutic option for patients with Okuda stage I andII HCC.

  20. Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction.

    PubMed

    Chang, Jennifer; Fedinec, Alexander L; Kuntamallappanavar, Guruprasad; Leffler, Charles W; Bukiya, Anna N; Dopico, Alex M

    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

  1. 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

  2. Cerebral blood flow changes during sodium-lactate-induced panic attacks

    SciTech Connect

    Stewart, R.S.; Devous, M.D. Sr.; Rush, A.J.; Lane, L.; Bonte, F.J.

    1988-04-01

    Dynamic single-photon emission computed axial tomography (CAT) with inhaled xenon-133 was used to measure regional cerebral blood flow in 10 drug-free patients with DSM-III-diagnosed panic disorder and in five normal control subjects. All subjects underwent regional cerebral blood flow studies while at rest or during normal saline infusion and during sodium lactate infusion. Six of the 10 patients and none of the control subjects experienced lactate-induced panic attacks. Lactate infusion markedly raised hemispheric blood flow levels in both control subjects and patients who did not panic. Patients who did panic experienced either a minimal increase or a decrease in hemispheric blood flow.

  3. Transarterial Alcohol-Lipiodol Therapy in Patients with Hepatocellular Carcinoma Using Low Alcohol Concentrations.

    PubMed

    Mohné, F; Meyer, C; Kuhl, C K; Pieper, C C; Schild, H H

    2016-07-01

    To evaluate transarterial alcohol-lipiodol therapy (TAL) with low concentrations of alcohol for the treatment of hepatocellular carcinoma (HCC). 17 patients (69.3 ± 10.7a, 13 male, 4 female) with previously untreated HCC (tumor diameter: 7.7 ± 5.8 cm), who underwent 20 transarterial alcohol-lipiodol injections, were evaluated retrospectively. 14 patients had HCC with coexistent cirrhosis (Child-A n = 9, Child-B n = 4, Child-C n = 1). 9 patients presented an Okuda stage I, 7 patients an Okuda stage II and 1 patient an Okuda stage III. Infiltration of the portal vein was seen in 3 patients. 15 patients underwent TAL with an alcohol:lipiodol ratio of 1:2, another one with a ratio of 1:3 and yet another one with a ratio of 1:5. The median survival was 23 months, and the 1-year and 2-year survival rates were 62.7 % and 31.4 %, respectively. The median survival of patients with HCC < 7.5 cm (n = 10) was 25 months and significantly (p = 0.009) higher than for patients with HCC ≥ 7.5 cm (n = 7; 3 months). Tumor diameters ≥ 7.5 cm were associated with worse lipiodol-contrasting of HCC. Intrainterventional side effects were only feelings of slight abdominal pressure in 2 of 20 interventions. Postinterventional, mild side effects were observed after 3 interventions (abdominal pain n = 1, thoracic pain n = 1, fever n = 1). Serious complications were not observed, in particular there was no decompensation of liver cirrhosis. TAL with low concentrations of alcohol was a safe and effective treatment in our cohort in spite of extensive tumors and impaired liver function. TAL could be a treatment option for patients who cannot receive other therapies (e. g. TACE, RFA) because of their advanced tumor disease, liver cirrhosis or other contraindications. • TAL can be performed safely in advanced tumor disease and liver cirrhosis Citation Format: • Mohné F, Meyer C, Kuhl CK et al. Transarterial Alcohol-Lipiodol

  4. Traumatic Brain Injury by a Closed Head Injury Device Induces Cerebral Blood Flow Changes and Microhemorrhages

    PubMed Central

    Kallakuri, Srinivasu; Bandaru, Sharath; Zakaria, Nisrine; Shen, Yimin; Kou, Zhifeng; Zhang, Liying; Haacke, Ewart Mark; Cavanaugh, John M

    2015-01-01

    Objectives: Traumatic brain injury is a poly-pathology characterized by changes in the cerebral blood flow, inflammation, diffuse axonal, cellular, and vascular injuries. However, studies related to understanding the temporal changes in the cerebral blood flow following traumatic brain injury extending to sub-acute periods are limited. In addition, knowledge related to microhemorrhages, such as their detection, localization, and temporal progression, is important in the evaluation of traumatic brain injury. Materials and Methods: Cerebral blood flow changes and microhemorrhages in male Sprague Dawley rats at 4 h, 24 h, 3 days, and 7 days were assessed following a closed head injury induced by the Marmarou impact acceleration device (2 m height, 450 g brass weight). Cerebral blood flow was measured by arterial spin labeling. Microhemorrhages were assessed by susceptibility-weighted imaging and Prussian blue histology. Results: Traumatic brain injury rats showed reduced regional and global cerebral blood flow at 4 h and 7 days post-injury. Injured rats showed hemorrhagic lesions in the cortex, corpus callosum, hippocampus, and brainstem in susceptibility-weighted imaging. Injured rats also showed Prussian blue reaction products in both the white and gray matter regions up to 7 days after the injury. These lesions were observed in various areas of the cortex, corpus callosum, hippocampus, thalamus, and midbrain. Conclusions: These results suggest that changes in cerebral blood flow and hemorrhagic lesions can persist for sub-acute periods after the initial traumatic insult in an animal model. In addition, microhemorrhages otherwise not seen by susceptibility-weighted imaging are present in diverse regions of the brain. The combination of altered cerebral blood flow and microhemorrhages can potentially be a source of secondary injury changes following traumatic brain injury and may need to be taken into consideration in the long-term care of these cases. PMID:26605126

  5. Radiation-Induced Temporary Alopecia After Embolization of Cerebral Aneurysm

    PubMed Central

    Verma, Shyam; Srinivas, CR; Thomas, Maria

    2014-01-01

    A 47-year-old Indian woman with dark hair developed dramatic alopecia of the occipito-vertical area two weeks after a fluoroscopically-guided endovascular procedure for treatment of cerebral aneurysm. There was spontaneous repopulation of hair in 14 weeks. Neuro-radiological intervention procedures are becoming commoner by the day in India, and the rare but documented possibility of such reactions occurring in patients should be kept in mind by the treating surgeon as well as dermatologist. Necessary counseling regarding this uncommon side-effect is of essence, especially when the radiation dose exceeds 3 Gy. We believe this is the first case ever reported in Indian dermatology literature. PMID:25484428

  6. Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage

    PubMed Central

    Hou, Sheng Tao; Nilchi, Ladan; Li, Xuesheng; Gangaraju, Sandhya; Jiang, Susan X.; Aylsworth, Amy; Monette, Robert; Slinn, Jacqueline

    2015-01-01

    Semaphorin 3A (Sema3A) increased significantly in mouse brain following cerebral ischemia. However, the role of Sema3A in stroke brain remains unknown. Our aim was to determine wether Sema3A functions as a vascular permeability factor and contributes to ischemic brain damage. Recombinant Sema3A injected intradermally to mouse skin, or stereotactically into the cerebral cortex, caused dose- and time-dependent increases in vascular permeability, with a degree comparable to that caused by injection of a known vascular permeability factor vascular endothelial growth factor receptors (VEGF). Application of Sema3A to cultured endothelial cells caused disorganization of F-actin stress fibre bundles and increased endothelial monolayer permeability, confirming Sema3A as a permeability factor. Sema3A-mediated F-actin changes in endothelial cells were through binding to the neuropilin2/VEGFR1 receptor complex, which in turn directly activates Mical2, a F-actin modulator. Down-regulation of Mical2, using specific siRNA, alleviated Sema3A-induced F-actin disorganization, cellular morphology changes and endothelial permeability. Importantly, ablation of Sema3A expression, cerebrovascular permeability and brain damage were significantly reduced in response to transient middle cerebral artery occlusion (tMCAO) and in a mouse model of cerebral ischemia/haemorrhagic transformation. Together, these studies demonstrated that Sema3A is a key mediator of cerebrovascular permeability and contributes to brain damage caused by cerebral ischemia. PMID:25601765

  7. Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage.

    PubMed

    Hou, Sheng Tao; Nilchi, Ladan; Li, Xuesheng; Gangaraju, Sandhya; Jiang, Susan X; Aylsworth, Amy; Monette, Robert; Slinn, Jacqueline

    2015-01-20

    Semaphorin 3A (Sema3A) increased significantly in mouse brain following cerebral ischemia. However, the role of Sema3A in stroke brain remains unknown. Our aim was to determine wether Sema3A functions as a vascular permeability factor and contributes to ischemic brain damage. Recombinant Sema3A injected intradermally to mouse skin, or stereotactically into the cerebral cortex, caused dose- and time-dependent increases in vascular permeability, with a degree comparable to that caused by injection of a known vascular permeability factor vascular endothelial growth factor receptors (VEGF). Application of Sema3A to cultured endothelial cells caused disorganization of F-actin stress fibre bundles and increased endothelial monolayer permeability, confirming Sema3A as a permeability factor. Sema3A-mediated F-actin changes in endothelial cells were through binding to the neuropilin2/VEGFR1 receptor complex, which in turn directly activates Mical2, a F-actin modulator. Down-regulation of Mical2, using specific siRNA, alleviated Sema3A-induced F-actin disorganization, cellular morphology changes and endothelial permeability. Importantly, ablation of Sema3A expression, cerebrovascular permeability and brain damage were significantly reduced in response to transient middle cerebral artery occlusion (tMCAO) and in a mouse model of cerebral ischemia/haemorrhagic transformation. Together, these studies demonstrated that Sema3A is a key mediator of cerebrovascular permeability and contributes to brain damage caused by cerebral ischemia.

  8. Acute volume expansion attenuates hyperthermia-induced reductions in cerebral perfusion during simulated hemorrhage

    PubMed Central

    Schlader, Zachary J.; Seifert, Thomas; Wilson, Thad E.; Bundgaard-Nielsen, Morten; Secher, Niels H.

    2013-01-01

    Hyperthermia reduces the capacity to withstand a simulated hemorrhagic challenge, but volume loading preserves this capacity. This study tested the hypotheses that acute volume expansion during hyperthermia increases cerebral perfusion and attenuates reductions in cerebral perfusion during a simulated hemorrhagic challenge induced by lower-body negative pressure (LBNP). Eight healthy young male subjects underwent a supine baseline period (pre-LBNP), followed by 15- and 30-mmHg LBNP while normothermic, hyperthermic (increased pulmonary artery blood temperature ∼1.1°C), and following acute volume infusion while hyperthermic. Primary dependent variables were mean middle cerebral artery blood velocity (MCAvmean), serving as an index of cerebral perfusion; mean arterial pressure (MAP); and cardiac output (thermodilution). During baseline, hyperthermia reduced MCAvmean (P = 0.001) by 12 ± 9% relative to normothermia. Volume infusion while hyperthermic increased cardiac output by 2.8 ± 1.4 l/min (P < 0.001), but did not alter MCAvmean (P = 0.99) or MAP (P = 0.39) compared with hyperthermia alone. Relative to hyperthermia, at 30-mmHg LBNP acute volume infusion attenuated reductions (P < 0.001) in cardiac output (by 2.5 ± 0.9 l/min; P < 0.001), MAP (by 5 ± 6 mmHg; P = 0.004), and MCAvmean (by 12 ± 13%; P = 0.002). These data indicate that acute volume expansion does not reverse hyperthermia-induced reductions in cerebral perfusion pre-LBNP, but that it does attenuate reductions in cerebral perfusion during simulated hemorrhage in hyperthermic humans. PMID:23580601

  9. Long Non-coding RNA H19 Induces Cerebral Ischemia Reperfusion Injury via Activation of Autophagy.

    PubMed

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

    2017-02-01

    Long non-coding RNA H19 (lncRNA H19) was found to be upregulated by hypoxia, its expression and function have never been tested in cerebral ischemia and reperfusion (I/R) injury. This study intended to investigate the role of lncRNA H19 and H19 gene variation in cerebral I/R injury with focusing on its relationship with autophagy activation. Cerebral I/R was induced in rats by middle cerebral artery occlusion followed by reperfusion. SH-SY5Y cells were subjected to oxygen and glucose deprivation and reperfusion (OGD/R) to simulate I/R injury. Real-time PCR, flow cytometry, immunofluorescence and Western blot were used to evaluate the level of lncRNA H19, apoptosis, autophagy and some related proteins. The modified multiple ligase reaction was used to analyze the gene polymorphism of six SNPs in H19, rs217727, rs2067051, rs2251375, rs492994, rs2839698 and rs10732516 in ischemic stroke patients. We found that the expression of lncRNA H19 was upregulated by cerebral I/R in rats, as well as by OGD/R in vitro in the cells. Inhibition of lncRNA H19 and autophagy protected cells from OGD/R-induced death, respectively. Autophagy activation induced by OGD/R was prevented by H19 siRNA. Autophagy inducer, rapamycin, abolished lncRNA H19 effect. Furthermore, we found that lncRNA H19 inhibited autophagy through DUSP5-ERK1/2 axis. The result from blood samples of ischemic patients revealed that the variation of H19 gene increased the risk of ischemic stroke. Taken together, the results of present study suggest that LncRNA H19 could be a new therapeutic target of ischemic stroke.

  10. Long Non-coding RNA H19 Induces Cerebral Ischemia Reperfusion Injury via Activation of Autophagy

    PubMed Central

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

    2017-01-01

    Long non-coding RNA H19 (lncRNA H19) was found to be upregulated by hypoxia, its expression and function have never been tested in cerebral ischemia and reperfusion (I/R) injury. This study intended to investigate the role of lncRNA H19 and H19 gene variation in cerebral I/R injury with focusing on its relationship with autophagy activation. Cerebral I/R was induced in rats by middle cerebral artery occlusion followed by reperfusion. SH-SY5Y cells were subjected to oxygen and glucose deprivation and reperfusion (OGD/R) to simulate I/R injury. Real-time PCR, flow cytometry, immunofluorescence and Western blot were used to evaluate the level of lncRNA H19, apoptosis, autophagy and some related proteins. The modified multiple ligase reaction was used to analyze the gene polymorphism of six SNPs in H19, rs217727, rs2067051, rs2251375, rs492994, rs2839698 and rs10732516 in ischemic stroke patients. We found that the expression of lncRNA H19 was upregulated by cerebral I/R in rats, as well as by OGD/R in vitro in the cells. Inhibition of lncRNA H19 and autophagy protected cells from OGD/R-induced death, respectively. Autophagy activation induced by OGD/R was prevented by H19 siRNA. Autophagy inducer, rapamycin, abolished lncRNA H19 effect. Furthermore, we found that lncRNA H19 inhibited autophagy through DUSP5-ERK1/2 axis. The result from blood samples of ischemic patients revealed that the variation of H19 gene increased the risk of ischemic stroke. Taken together, the results of present study suggest that LncRNA H19 could be a new therapeutic target of ischemic stroke. PMID:28203482

  11. Electroacupuncture induces acute changes in cerebral cortical miRNA profile, improves cerebral blood flow and alleviates neurological deficits in a rat model of stroke

    PubMed Central

    Zheng, Hai-zhen; Jiang, Wei; Zhao, Xiao-feng; Du, Jing; Liu, Pan-gong; Chang, Li-dan; Li, Wen-bo; Hu, Han-tong; Shi, Xue-min

    2016-01-01

    Electroacupuncture has been shown to improve cerebral blood flow in animal models of stroke. However, it is unclear whether electroacupuncture alters miRNA expression in the cortex. In this study, we examined changes in the cerebral cortical miRNA profile, cerebral blood flow and neurological function induced by electroacupuncture in a rat model of stroke. Electroacupuncture was performed at Renzhong (GV26) and Neiguan (PC6), with a frequency of 2 Hz, continuous wave, current intensity of 3.0 mA, and stimulation time of 1 minute. Electroacupuncture increased cerebral blood flow and alleviated neurological impairment in the rats. miRNA microarray profiling revealed that the vascular endothelial growth factor signaling pathway, which links cell proliferation with stroke, was most significantly affected by electroacupuncture. Electroacupuncture induced changes in expression of rno-miR-206-3p, rno-miR-3473, rno-miR-6216 and rno-miR-494-3p, and these changes were confirmed by quantitative real-time polymerase chain reaction. Our findings suggest that changes in cell proliferation-associated miRNA expression induced by electroacupuncture might be associated with the improved cerebral blood supply and functional recovery following stroke. PMID:28197190

  12. Salidroside prevents cognitive impairment induced by chronic cerebral hypoperfusion in rats.

    PubMed

    Yan, Zhi-Qiang; Chen, Jun; Xing, Guo-Xiang; Huang, Jian-Guo; Hou, Xiang-Hong; Zhang, Yong

    2015-06-01

    To investigate the effects of salidroside on cognitive dysfunction induced by chronic cerebral hypoperfusion in rats. Male Sprague-Dawley rats (n = 36) were divided into three groups (n = 12 per group): sham operation; bilateral permanent occlusion of the common carotid arteries (2-VO); 2-VO + salidroside. Rats received 20 mg/kg per day salidroside or vehicle intraperitoneal injection beginning the day before surgery and continuing until 34 days postoperatively. Cognitive function was evaluated by Morris water maze test and hippocampal long-term potentiation (LTP) measurement. Hippocampal neuronal apoptosis was evaluated via immunofluorescence. Chronic cerebral hypoperfusion caused marked cognitive deficit and LTP inhibition. These effects were largely ameliorated by salidroside administration. Salidroside prevented caspase-3 activation, increased the ratio of Bax/Bcl-2, and reversed hippocampal neuronal loss induced by chronic cerebral hypoperfusion. Salidroside prevents cognitive deficits caused by chronic cerebral hypoperfusion in rats, and alleviates apoptosis in the hippocampal CA1 area. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  13. Cerebral oxygenation and haemodynamic effects induced by nimodipine in healthy subjects

    PubMed Central

    Canova, Daniela; Roatta, Silvestro; Micieli, Giuseppe; Bosone, Daniele

    2012-01-01

    Summary The cerebrovascular effects of nimodipine are still poorly understood even in the healthy condition; in particular, its effects on tissue oxygenation have never been investigated. The aim of the present study was to investigate changes in cerebral oxygenation and blood volume upon oral administration of nimodipine (90 mg) in the healthy condition. In eight subjects, changes in cerebral tissue oxygenation and blood volume were determined simultaneously with changes in blood velocity of the middle cerebral artery (VMCA) by using, respectively, near infrared spectroscopy (NIRS) and transcranial Doppler ultrasonography (TCD). The subjects also underwent non-invasive assessment of arterial blood pressure (ABP) and end-tidal CO2. TCD and NIRS CO2 reactivity indices were also extracted. Nimodipine significantly reduced ABP (11±13%) and increased heart rate, as well as NIRS oxygenation (6.0±4.8%) and blood volume indices (9.4±10.1%), while VMCA was not significantly decreased (2.0±3.5%). Nimodipine slightly but significantly reduced the VMCA response to changes in pCO2 whereas the CO2 reactivity of NIRS parameters was improved. The observed changes in cerebral tissue oxygenation and blood volume indicate nimodipine-induced cerebrovascular dilation and increased perfusion, while the effect on VMCA possibly results from dilation of the insonated artery. The present results cast doubt on the putative nimodipine-induced impairment of CO2 reactivity. PMID:23402678

  14. Cerebral oxygenation and haemodynamic effects induced by nimodipine in healthy subjects.

    PubMed

    Canova, Daniela; Roatta, Silvestro; Micieli, Giuseppe; Bosone, Daniele

    2012-01-01

    The cerebrovascular effects of nimodipine are still poorly understood even in the healthy condition; in particular, its effects on tissue oxygenation have never been investigated. The aim of the present study was to investigate changes in cerebral oxygenation and blood volume upon oral administration of nimodipine (90 mg) in the healthy condition. In eight subjects, changes in cerebral tissue oxygenation and blood volume were determined simultaneously with changes in blood velocity of the middle cerebral artery (VMCA) by using, respectively, near infrared spectroscopy (NIRS) and transcranial Doppler ultrasonography (TCD). The subjects also underwent noninvasive assessment of arterial blood pressure (ABP) and end-tidal CO2. TCD and NIRS CO2 reactivity indices were al-so extracted. Nimodipine significantly reduced ABP (11±13%) and increased heart rate, as well as NIRS oxygenation(6.0±4.8%) and blood volume indices (9.4±10.1%), while V(MCA) was not significantly decreased (2.0±3.5%). Nimodipine slightly but significantly reduced the V(MCA) response to changes in pCO2 whereas the CO2 reactivity of NIRS parameters was improved. The observed changes in cerebral tissue oxygenation and blood volume indicate nimodipine-induced cerebrovascular dilation and increased perfusion, while the effect on V(MCA)possibly results from dilation of the insonated artery. The present results cast doubt on the putative nimodipine-induced impairment of CO2 reactivity.

  15. Antioxidants prevent ethanol-induced contractions of canine cerebral vascular smooth muscle: relation to alcohol-induced brain injury.

    PubMed

    Li, W; Zheng, T; Altura, B T; Altura, B M

    2001-03-30

    The present study was designed to test the hypothesis that alpha-tocopherol (Vit. E) and pyrrolidine dithiocarbamate (PDTC) might exert direct effects on alcohol-induced contractions of canine basilar cerebral arteries. After precontraction of arterial ring segments with ethanol, PDTC (10(-8)-10(-6) M) and Vit. E (10(-6)-10(-4) M) induced concentration-dependent relaxations of cerebral arteries, compared to untreated controls. The effective concentrations producing approximately 50% of the maximal relaxation responses (EC(50) values) were about 2.48+/-0.09 x 10(-7) M for PDTC, and 1.87+/-0.10 x 10(-5) mM for Vit. E, respectively. Preincubation of these arterial rings with EC(50)'s of PDTC or Vit. E for 40 min attenuate markedly the contractions produced by alcohol, at concentrations of 1-400 mM. However, both PDTC and Vit.E do not relax equi-potent precontractions induced by either KCl or prostaglandin F(2alpha) (PGF(2alpha)) or inhibit their contractions. These data suggest that alcohol-induced contractions of cerebral arteries are mediated via excitation-contraction coupling pathways different from those used by KCl or receptor-mediated agonists such as PGF(2alpha). The present results, when viewed in light of other recently published data, suggest that antioxidants may prove useful in the amelioration and treatment of alcohol-induced brain damage and strokes.

  16. Triptan-induced Reversible Cerebral Vasoconstriction Syndrome: Two Case Reports with a Literature Review.

    PubMed

    Kato, Yuji; Hayashi, Takeshi; Mizuno, Satoko; Horiuchi, Yohsuke; Ohira, Masayuki; Tanahashi, Norio; Takao, Masaki

    We encountered two patients with sumatriptan-induced reversible cerebral vasoconstriction syndrome (RCVS). The present patients were taking sumatriptan for the first time because they had been tentatively diagnosed with a migraine. On reviewing the literature, we found nine other cases of triptan-induced RCVS, predominantly among women aged 30 to 40 years. RCVS has been precipitated by triptan at the first ever use, after daily use, and even with long-term use at a normal dose. Patients with acute onset of severe headache should be thoroughly evaluated, and triptan should be administered appropriately. If triptan-induced RCVS is suspected, vascular imaging should be repeated after several days.

  17. Triptan-induced Reversible Cerebral Vasoconstriction Syndrome: Two Case Reports with a Literature Review

    PubMed Central

    Kato, Yuji; Hayashi, Takeshi; Mizuno, Satoko; Horiuchi, Yohsuke; Ohira, Masayuki; Tanahashi, Norio; Takao, Masaki

    2016-01-01

    We encountered two patients with sumatriptan-induced reversible cerebral vasoconstriction syndrome (RCVS). The present patients were taking sumatriptan for the first time because they had been tentatively diagnosed with a migraine. On reviewing the literature, we found nine other cases of triptan-induced RCVS, predominantly among women aged 30 to 40 years. RCVS has been precipitated by triptan at the first ever use, after daily use, and even with long-term use at a normal dose. Patients with acute onset of severe headache should be thoroughly evaluated, and triptan should be administered appropriately. If triptan-induced RCVS is suspected, vascular imaging should be repeated after several days. PMID:27904122

  18. Cerebral blood oxygenation changes induced by visual stimulation in humans

    NASA Astrophysics Data System (ADS)

    Wenzel, Rudiger; Obrig, Hellmuth; Ruben, Jan; Villringer, Kersten; Thiel, Andreas; Bernarding, Johannes; Dirnagl, Ulrich; Villringer, Arno

    1996-10-01

    We examined local changes of cerebral oxygenation in response to visual stimuli by means of near infrared spectroscopy. A sharply outlined colored moving stimulus which is expected to evoke a broad activation of the striate and prestriate cortex was presented to sixteen healthy subjects. Six of these subjects were also exposed to a colored stationary and a gray stationary stimulus. In two subjects the colored moving stimulus was tested against the colored stationary with an optode position presumably over area V5/MT. As a control condition, subjects performed a simple finger opposition task. Since the calcarine fissure varies greatly with respect to bony landmarks, optodes were positioned individually according to 3D reconstructed magnetic resonance imaging (MRI). Concentration changes in oxyhemoglobin (oxy-Hb) and deoxyhemoglobin (deoxy-Hb) were continuously monitored with a temporal resolution of 1 s, using an NIRO 500. In response to the visual stimulus, the grand average across all sixteen subjects resulted in a significant increase in oxy-Hb of 0.33 +/- 0.09 arbitrary units mirrored by a significant decrease in deoxy-Hb of -0.18 +/- 0.02 arbitrary units, while the motor control condition elicited no significant changes in any parameters. When the near infrared spectroscopy probes were positioned over area V5/MT, the drop of deoxy-Hb associated with the moving stimulus was significantly more pronounced than with the stationary stimulus in both subjects examined. No significant differences between the visual stimuli were observed at the optode position close to the calcarine fissure. The oxygenation changes observed in this study are consistent with the pattern we have reported for motor activation. They are in line with physiological considerations and functional MRI studies relying on blood oxygenation level-dependent contrast.

  19. Induced and spontaneous hemodynamic oscillations in cerebral and extracerebral tissue for coherent hemodynamics spectroscopy

    NASA Astrophysics Data System (ADS)

    Sassaroli, Angelo; Zang, Xuan; Tgavalekos, Kristen T.; Fantini, Sergio

    2017-02-01

    We report preliminary results of a study for investigating the spatial homogeneity of induced and spontaneous oscillations in the concentration of oxyhemoglobin on the scalp/skull layer of two human subjects. Hemodynamic oscillations were induced by modulation of arterial blood pressure, which triggers the cerebral autoregulation mechanism. Induced hemodynamic oscillations are used in coherent hemodynamics spectroscopy to derive physiological parameters of interest for medical diagnostics. For example, our dedicated mathematical model translates typical near-infrared spectroscopy observables, like the amplitude and phase relationship of the oscillations of oxy- and deoxyhemoglobin concentrations into capillary and venous blood transit times, cutoff frequency of the autoregulation process, and other parameters related to microvascular blood volume. In this study, we focused on the phase relationship between the oscillations of oxyhemoglobin concentrations in three optical channels, two of which feature a short (5 mm) source-detector separation (sampling the scalp/skull only) and the third one features a long (30 mm) source-detector separation (sampling both extracerebral and cerebral tissues). The two main goals of the study were: a) to compare the coherence of induced and spontaneous oscillations; b) to assess if induced and spontaneous oscillations may be assumed to be uniform in the extracerebral layer. This was assessed by studying the phase relationship of oscillations in oxyhemoglobin concentration at the two short source-detector separations. About point a) we verified that induced oscillations have a higher incidence of coherence than spontaneous oscillations: 74% for induced oscillations, and 30% for spontaneous oscillations. About point b) the results show an overall trend for both spontaneous and induced oscillations to be homogeneous or "quasi-homogeneous" in the extracerebral tissue; however, we observed cases where a significant non-zero phase

  20. Behavior of Lipiodol Markers During Image Guided Radiotherapy of Bladder Cancer

    SciTech Connect

    Chai Xiangfei; Herk, Marcel van; Kamer, Jeroen B. van de; Remeijer, Peter; Bex, Axel; Betgen, Anja; De Reijke, Theo M.; Hulshof, Maarten C.C.M.; Pos, Floris J.; Bel, Arjan

    2010-05-01

    Purpose: To investigate the stability of a novel type of markers used in partial bladder tumor irradiation and tumor deformation as indicated by the markers. Materials and Methods: In 15 patients with solitary bladder cancer, lipiodol was injected in the bladder wall during flexible cystoscopy to identify the tumor. A planning CT scan was made, followed by daily cone-beam CT (CBCT) scans during treatment. To study the accuracy of using these markers for image guidance, uncertainties U1 and U2 were calculated, which were defined as the difference between submask registration (covering single marker) and the average of all submask registrations and the difference between the submask registration and the general mask registration (including all markers), respectively. Finally, to study tumor deformation, the relative movement of each marker pair was correlated with the relative bladder volume (RBV). Results: The analyzed patients had 2.3 marker injections on average. The lipiodol spot size was 0.72 +- 1.1 cm{sup 3}. The intensity of spots in both CT and CBCT was significantly higher than the surrounding bladder tissue. The uncertainties U1 and U2 were comparable, and the uncertainties in left-right direction (0.14-0.19 cm) were smaller than those in cranial-caudal and anterior-posterior directions (0.19-0.32 cm). The relative marker movement of within-zone marker pairs was much smaller (and has less dependence on the RBV) than across-zones marker pairs. Conclusions: Lipiodol markers are a feasible method to track bladder tumor by using online CBCT. Tumor deformation is observed, especially for tumors that cross the defined bladder zones.

  1. Alleviation of Brain Injury-Induced Cerebral Metabolic Depression by Amphetamine: A Cytochrome Oxidase Histochemistry Study

    PubMed Central

    Sutton, Richard L.; Hovda, David A.; Chen, Michael J.; Feeney, Dennis M.

    2000-01-01

    Measurements of oxidative metabolic capacity following the ablation of rat sensorimotor cortex and ,he administration of amphetamine were examined to determine their effects on the metabolic dysfunction that follows brain injury. Twenty-four hours after surgery, rats sustaining either sham operations or unilateral cortical ablation were administered a single injection of D-amphetamine (2 mg/kg; i.p.) or saline and then sacrificed 24 h later. Brain tissue was processed for cytochrome oxidase histochemistry, and 12 bilateral cerebral areas were measured, using optical density as an index of the relative amounts of the enzyme. Compared with that of the control groups, cytochrome oxidase in the injured animals was significantly reduced throughout the cerebral cortex and in 5 of II subcortical structures. This injury-induced depression of oxidative capacity was most pronounced in regions of the hemisphere ipsilateral to the ablation. Animals given D-amphetamine had less depression of oxidative capacity, which was most pronounced bilaterally in the cerebral cortex, red nucleus, and superior colliculus; and in the nucleus accumbens, caudateputamen, and globus pallidus ipsilaterai to the ablation. The ability of D-amphetamine to alleviate depressed cerebral oxidative metabolism following cortical injury may be one mechanism by which drugs increasing noradrenaline release accelerate functional recovery in both animals and humans. PMID:10709218

  2. Left Lobe Recurrent Hepatocellular Carcinoma Treated with Lipiodol-TAE via the Left Internal Mammary Artery

    SciTech Connect

    Kanetsuki, Ichiro; Hori, Akira; Ohshiro, Kiyoshi; Nishi, Hirokazu; Yasutani, Tadashi; Sueyoshi, Takeshi; Tanaka, Hitoshi

    1997-09-15

    A multinodular hepatocellular carcinoma (HCC) was treated with seven transarterial interventions via the hepatic artery over a 2-year, 5-month period before the eighth angiography showed a recurrent HCC in the anterior portion of the left hepatic lobe. The left internal mammary artery (IMA) was feeding the tumor. This was successfully treated with Lipiodol-transcatheter arterial embolization using a coaxial system via a branch of the left IMA. No complications resulted from the procedure. The left IMA should be considered as a possible feeding artery to an HCC occurring in the anterior portion of the left hepatic lobe.

  3. Neuroprotective activity of Wedelia calendulacea on cerebral ischemia/reperfusion induced oxidative stress in rats

    PubMed Central

    Prakash, Tigari; Kotresha, Dupadahalli; Nedendla, Rama Rao

    2011-01-01

    Objective: This study was undertaken to evaluate the neuroprotective activity of Wedelia calendulacea against cerebral ischemia/reperfusion induced oxidative stress in the rats. Materials and Methods: The global cerebral ischemia was induced in male albino Wistar rats by occluding the bilateral carotid arteries for 30 min followed by 1 h and 4 h reperfusion. At various times of reperfusion, the histopathological changes and the levels of malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione–s–transferase (GST), and hydrogen peroxide (H2O2) activity and brain water content were measured. Results: The ischemic changes were preceded by increase in concentration of MDA, hydrogen peroxide and followed by decreased GPx, GR, and GST activity. Treatment with W. calendulacea significantly attenuated ischemia–induced oxidative stress. W. calendulacea administration markedly reversed and restored to near normal level in the groups pre-treated with methanolic extract (250 and 500 mg/kg, given orally in single and double dose/day for 10 days) in dose-dependent way. Similarly, W. calendulacea reversed the brain water content in the ischemia reperfusion animals. The neurodegenaration also conformed by the histopathological changes in the cerebral-ischemic animals. Conclusion: The findings from the present investigation reveal that W. calendulacea protects neurons from global cerebral–ischemic injury in rat by attenuating oxidative stress. PMID:22144773

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

    PubMed Central

    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. PMID:28250754

  5. Telmisartan ameliorates oxidative stress and subarachnoid haemorrhage-induced cerebral vasospasm.

    PubMed

    Erdi, Fatih; Keskin, Fatih; Esen, Hasan; Kaya, Bulent; Feyzioglu, Bahadir; Kilinc, Ibrahim; Karatas, Yasar; Cuce, Gokhan; Kalkan, Erdal

    2016-03-01

    Growing evidence suggests that oxidative stress is one of the factors contributing to subarachnoid haemorrhage (SAH)-induced cerebral vasospasm. SAH-induced cerebral vasospam alters thioredoxin (Trx) cycle enzymes and thioredoxin-interacting protein (TXNIP) as an important endogenous antioxidant system. In this study, we have explored the effects of telmisartan on the vascular morphological changes, endothelial apoptosis, tissue oxidative stress status and the level of Trx cycle enzymes/ TXNIP in a rabbit SAH model. Forty male New Zealand rabbits were randomly divided into five groups of eight rabbits each: control group, sham group, SAH group, SAH + vehicle group and SAH + telmisartan group. SAH was created by a single cisterna magna blood injection. SAH + telmisartan group received telmisartan treatment (5 mg/kg intraperitoneal, once daily) for 72 h. The brainstem tissue Trx1, Trx2, Trx reductase (TrxR), TrxR1and TXNIP levels were investigated. Total oxidant status (TOS), total antioxidant status (TAS), malondialdehyde (MDA) levels and tumour necrosis factor alpha (TNF alpha) levels were investigated. Basilar artery segments were investigated for cross-sectional area, wall thickness measurements and endothelial apoptosis. Telmisartan treatment restored the lowered level of Trx1, TrxR, TAS and the expression of TrxR1 seen in SAH. Telmisartan treatment also decreased TXNIP expression, TOS, MDA and TNF alpha levels. Morphological changes of cerebral vasospasm were attenuated after treatment. Endothelial apoptosis significantly reduced. Treatment with telmisartan ameliorates oxidative stress and SAH-induced cerebral vasospasm in rabbits. These effects of telmisartan may be associated with downregulation of TXNIP and upregulation of Trx/TrxR.

  6. Ganzfeld-induced hallucinatory experience, its phenomenology and cerebral electrophysiology.

    PubMed

    Wackermann, Jirí; Pütz, Peter; Allefeld, Carsten

    2008-01-01

    Ganzfeld, i.e., exposure to an unstructured, uniform stimulation field, elicits in most observers pseudo-hallucinatory percepts, and may even induce global functional state changes ('altered states of consciousness'). The present paper gives a comprehensive overview of the phenomenology of subjective experience in the ganzfeld and its electrophysiological correlates. Laboratory techniques for visual or multi-modal ganzfeld induction are explained. The spectrum of ganzfeld-induced phenomena, ranging from elementary percepts to complex, vivid, dream-like imagery is described, and the latter illustrated by transcripts of subjects' reports. Similarities and differences to related sensory/perceptual phenomena are also discussed. Earlier findings on electrophysiological correlates of the ganzfeld are reviewed. Our own studies of electroencephalographic (EEG) activity in the ganzfeld are presented in some detail, and a re-analysis of data on EEG correlates of hallucinatory percepts in statu nascendi is reported. The results do not support the hypothesis of the hypnagogic origin of the percepts; the ganzfeld-induced steady-state is an activated state, and the spectral EEG dynamics in the alpha frequency range reveals processes of attention shifts and percept formation. The final section is devoted to the controversial topic of allegedly anomalous communication between human subjects ('ganzfeld telepathy'). It is shown that the use of ganzfeld in this research field relies partly on unsupported hypotheses concerning ganzfeld-induced states, partly on a weak conceptual background of the experimental procedure. The rôle of a particular belief system shared by the participants and experimenters is critically discussed.

  7. Effect of siRNA‑induced inhibition of IL‑6 expression in rat cerebral gliocytes on cerebral edema following traumatic brain injury.

    PubMed

    Xu, Bin; Yu, Dong-Ming; Liu, Fu-Sheng

    2014-10-01

    The present study aimed to investigate the effect of RNA interference (RNAi) on the inhibition of interleukin (IL)‑6 expression in rat cerebral gliocytes in vitro and rat cerebral traumatic tissues in vivo, as well as the effect of RNAi on cerebral edema. pSUPER vectors containing IL‑6 small hairpin RNA (pSUPER‑IL‑6 1‑5) were designed, constructed and transfected into C6 rat glioma cells using cationic liposomes. ELISA was used to select the plasmid with the strongest interference effect. A freefall method was used to generate a rat brain injury model and rats were randomly divided into treatment, empty plasmid and control groups (n=14/group). IL‑6 levels, water content and sodium content were determined in the brain tissues at 24 and 72 h post‑injury. pSUPER‑IL‑6 was effectively transfected into C6 cells and was found to inhibit the expression of IL‑6 rather than IL‑8. The pSUPER‑IL‑6 1 vector was most effective in inducing RNAi. In vivo, IL‑6 levels were observed to be lowest in the interference group and there were statistically significant differences in water and sodium content among the experimental groups (P<0.05). RNAi was found to inhibit IL‑6 expression in vivo and in vitro in rat cerebral gliocytes, and the reduction of the IL‑6 levels was found to reduce post‑traumatic cerebral edema.

  8. Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats

    PubMed Central

    2010-01-01

    Background Ischemic hypoxic brain injury often causes irreversible brain damage. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines. From the point of view of "self-medication" or "preventive medicine," Cordyceps sinensis was used in the prevention of cerebral ischemia in this paper. Methods The right middle cerebral artery occlusion model was used in the study. The effects of Cordyceps sinensis (Caterpillar fungus) extract on mortality rate, neurobehavior, grip strength, lactate dehydrogenase, glutathione content, Lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na+K+ATPase activity and glutathione S transferase activity in a rat model were studied respectively. Results Cordyceps sinensis extract significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. At the same time, supplementation of Cordyceps sinensis extract significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. Conclusions These experimental results suggest that complement Cordyceps sinensis extract is protective after cerebral ischemia in specific way. The administration of Cordyceps sinensis extract significantly reduced focal cerebral ischemic/reperfusion injury. The defense mechanism against cerebral ischemia was by increasing antioxidants activity related to lesion pathogenesis. PMID:20955613

  9. Protective effects of natrii sulfas on cerebral focal ischemia induced by MCAO in rats.

    PubMed

    Sohn, Youngjoo; Kang, Ho Chang; Kim, Kon Sik; Park, Sun-Min; Sohn, Nak-Won; Jung, Hyuk-Sang; Kim, Sung-Hoon

    2009-01-01

    This study examined the effect of Natrii sulfas, a treatment for stroke patients suffering constipation in Oriental medicine, on the physiological indices and brain edema of rats. Brain edema was induced by a middle cerebral artery occlusion (MCAO), Natrii sulfas was administered after the MCAO. At 3, 6, 15, 24, and 48 hours after reperfusion, the physiological indices such as the fecal weight, urine volume and water content in the stools were assessed. The edema index was measured 48 hours after reperfusion. At 48 hours, the expressions of iNOS, MMP9, VEGF, GFAP, Bax, Bcl-2, c-Fos, and HSP72 positive astrocytes were observed on the brain tissues by immunohistochemistry. Natrii sulfas significantly improved the decrease in fecal weight, urine volume and water content in the stool caused by the ischemic insult (p < 0.05) and attenuated the brain edema caused by the ischemia insult (p < 0.05). Natrii sulfas significantly down-regulated iNOS and MMP9 expressions and attenuated the astrocyte swelling due to brain edema in the penumbra of the cerebral cortex of MCAO rats. Natrii sulfas reduced the excess Bax and HSP72 expressions in ischemic brain, which was statistically significant in the penumbra of the cerebral cortex but not in the caudate putamen. These results suggest Natrii sulfas has a protective effect on ischemia-induced brain edema and improves the physiological symptoms.

  10. Prolactin protects against the methamphetamine-induced cerebral vascular toxicity.

    PubMed

    Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M; Ali, Syed F; Gonzalez, Carmen

    2013-11-01

    Methamphetamine (Meth) is a highly addictive drug of abuse which alters the dopaminergic system and damages the blood-brain barrier (BBB), structure that protects the brain tissue from the circulating substances in the blood, keeping a low permeability through the presence of tight junctions (TJs) between endothelial cells. Meth increases BBB permeability by decreasing the TJs proteins claudin-5 and occludin and by decreasing the viability of endothelial cells. Individuals abused of Meth have increased blood concentrations of prolactin (PRL); hormone related with milk production, but able to increase the expression of TJs proteins and to decrease permeability on the mammary epithelium and brain endothelial cells. However, the effects of PRL on the permeability of the BBB in the presence of Meth have not been studied. Here, we report Meth-induced apoptosis and decreased cellular proliferation as well as the trans-endothelial electrical resistance (TEER), related to a decrease of claudin-5 and occludin in primary cultured bovine brain microvessel endothelial cells. The expression of the PRL receptor was not altered. Administration of PRL prevented a decrease in cellular proliferation, an increase in apoptosis and restored the TEER and TJs proteins to basal levels. This protection was absent at high Meth concentrations. These data suggest that PRL protects brain endothelial cells against the Meth-induced toxicity. Further investigation is required to study the mechanisms involved and to confirm these effects in vivo.

  11. H2S induces vasoconstriction of rat cerebral arteries via cAMP/adenylyl cyclase pathway.

    PubMed

    Li, Sen; Ping, Na-Na; Cao, Lei; Mi, Yan-Ni; Cao, Yong-Xiao

    2015-12-15

    Hydrogen sulfide (H2S), traditionally known for its toxic effects, is now involved in regulating vascular tone. Here we investigated the vasoconstrictive effect of H2S on cerebral artery and the underlying mechanism. Sodium hydrosulfide (NaHS), a donor of H2S, concentration-dependently induced vasoconstriction on basilar artery, which was enhanced in the presence of isoprenaline, a β-adrenoceptor agonist or forskolin, an adenylyl cyclase activator. Administration of NaHS attenuated the vasorelaxant effects of isoprenaline or forskolin. Meanwhile, the NaHS-induced vasoconstriction was diminished in the presence of 8B-cAMP, an analog of cAMP, but was not affected by Bay K-8644, a selective L-type Ca(2+) channel agonist. These results could be explained by the revised effects of NaHS on isoprenaline-induced cAMP elevation and forskolin-stimulated adenylyl cyclase activity. Additionally, NaHS-induced vasoconstriction was enhanced by removing the endothelium or in the presence of L-NAME, an inhibitor of nitric oxide synthase. L-NAME only partially attenuated the effect of NaHS which was given together with forskolin on the pre-contracted artery. In conclusion, H2S induces vasoconstriction of cerebral artery via, at least in part, cAMP/adenylyl cyclase pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Radiation-induced cerebral meningioma: a recognizable entity.

    PubMed

    Rubinstein, A B; Shalit, M N; Cohen, M L; Zandbank, U; Reichenthal, E

    1984-11-01

    The authors retrospectively analyzed the clinical and histopathological findings in 201 patients with intracranial meningiomas operated on in the period 1978 to 1982. Forty-three of the patients (21.4%) had at some previous time received radiation treatment to their scalp, the majority for tinea capitis. The findings in these 43 irradiated patients were compared with those in the 158 non-irradiated patients. Several distinctive clinical and histological features were identified in the irradiated group, which suggest that radiation-induced meningiomas can be defined as a separate nosological subgroup. The use of irradiation in large numbers of children with tinea capitis in the era prior to the availability of griseofulvin may be responsible for a significantly increased incidence of intracranial meningiomas.

  13. Fulminant hepatic failure in rats induces oxidative stress differentially in cerebral cortex, cerebellum and pons medulla.

    PubMed

    Sathyasaikumar, K V; Swapna, I; Reddy, P V B; Murthy, Ch R K; Dutta Gupta, A; Senthilkumaran, B; Reddanna, P

    2007-03-01

    Hepatic Encephalopathy (HE) is one of the most common complications of acute liver diseases and is known to have profound influence on the brain. Most of the studies, available from the literature are pertaining to whole brain homogenates or mitochondria. Since brain is highly heterogeneous with functions localized in specific areas, the present study was aimed to assess the oxidative stress in different regions of brain-cerebral cortex, cerebellum and pons medulla during acute HE. Acute liver failure was induced in 3-month old adult male Wistar rats by intraperitoneal injection of thioacetamide (300 mg/kg body weight for two days), a well known hepatotoxin. Oxidative stress conditions were assessed by free radical production, lipid peroxidation, nitric oxide levels, GSH/GSSG ratio and antioxidant enzyme machinery in three distinct structures of rat braincerebral cortex, cerebellum and pons medulla. Results of the present study indicate a significant increase in malondialdehyde (MDA) levels, reactive oxygen species (ROS), total nitric oxide levels [(NO) estimated by measuring (nitrites + nitrates)] and a decrease in GSH/GSSG ratio in all the regions of brain. There was also a marked decrease in the activity of the antioxidant enzymes-glutathione peroxidase, glutathione reductase and catalase while the super oxide dismutase activity (SOD) increased. However, the present study also revealed that pons medulla and cerebral cortex were more susceptible to oxidative stress than cerebellum. The increased vulnerability to oxidative stress in pons medulla could be due to the increased NO levels and increased activity of SOD and decreased glutathione peroxidase and glutathione reductase activities. In summary, the present study revealed that oxidative stress prevails in different cerebral regions analyzed during thioacetamide-induced acute liver failure with more pronounced effects on pons medulla and cerebral cortex.

  14. Intra-arterial injection of 131I-labeled Lipiodol for advanced hepatocellular carcinoma: a 7 years' experience.

    PubMed

    Lintia-Gaultier, Alina; Perret, Christophe; Ansquer, Catherine; Eugène, Thomas; Kraeber-Bodéré, Françoise; Frampas, Eric

    2013-07-01

    Internal irradiation with iodine-131 (I)-labeled Lipiodol is one of the currently available forms of palliative therapy for patients with advanced hepatocellular carcinoma (HCC). Despite a cumulative experience of more than 10 years with this treatment, only a few studies have reported on its efficacy and safety. The aim of this study was to retrospectively evaluate the efficacy of intra-arterial I-labeled Lipiodol injection for treatment against advanced HCC. Fifty patients (47 men and three women; mean age 64 years) given an intra-arterial injection of I-Lipiodol (5 ml of 2.2 GBq Lipiodol labeled with I; number of mean sessions per patient, 1.3; range 1-4) were retrospectively compared with 36 patients (31 men and five women; mean age 64 years) who were given only medical support. Portal vein thrombosis was present in 86 and 100% of patients, respectively. Efficacy was determined on the basis of overall survival as the endpoint using the Kaplan-Meier method. Tumor response was evaluated with computed tomography according to Response Evaluation Criteria In Solid Tumors (RECIST 1.1) and European Association for the Study of the Liver (EASL) criteria. For patients treated with I-Lipiodol, median survival was 32 weeks, compared with 8 weeks for the untreated group (P=0.007). Survival at 6 months and at 1 and 2 years was 65, 35, and 22%, respectively, for patients treated with I-Lipiodol compared with 28, 8, and 0% for the untreated group. At 1 month, more than 80% of patients were responders (complete response, partial response, and stable disease) on the basis of the RECIST and EASL criteria, and at 6 months 39% were responders. No radiotoxic effect was observed, especially with respect to interstitial pneumonia. No significant difference was observed between survival and α-fetoprotein levels, Barcelona Clinic Liver Cancer clinical score, and portal vein thrombosis. Intra-arterial injection of I-Lipiodol is safe and provides significant survival benefit in terms of

  15. An Experimental Model of Vasovagal Syncope Induces Cerebral Hypoperfusion and Fainting-Like Behavior in Awake Rats

    PubMed Central

    McBride, Devin W.; Reis, Cesar; Frank, Ethan; Klebe, Damon W.; Zhang, John H.; Applegate, Richard

    2016-01-01

    Vasovagal syncope, a contributing factor to elderly falls, is the transient loss of consciousness caused by decreased cerebral perfusion. Vasovagal syncope is characterized by hypotension, bradycardia, and reduced cerebral blood flow, resulting in fatigue, altered coordination, and fainting. The purpose of this study is to develop an animal model which is similar to human vasovagal syncope and establish an awake animal model of vasovagal syncope. Male Sprague-Dawley rats were subjected to sinusoidal galvanic vestibular stimulation (sGVS). Blood pressure, heart rate, and cerebral blood flow were monitored before, during, and post-stimulation. sGVS resulted in hypotension, bradycardia, and decreased cerebral blood flow. One cohort of animals was subjected to sGVS while freely moving. sGVS in awake animals produced vasovagal syncope-like symptoms, including fatigue and uncoordinated movements; two animals experienced spontaneous falling. Another cohort of animals was preconditioned with isoflurane for several days before being subjected to sGVS. Isoflurane preconditioning before sGVS did not prevent sGVS-induced hypotension or bradycardia, yet isoflurane preconditioning attenuated sGVS-induced cerebral blood flow reduction. The sGVS rat model mimics elements of human vasovagal syncope pathophysiology (hypotension, bradycardia, and decreased cerebral perfusion), including behavioral symptoms such as fatigue and altered balance. This study indicates that the sGVS rat model is similar to human vasovagal syncope and that therapies directed at preventing cerebral hypoperfusion may decrease syncopal episodes and reduce injuries from syncopal falls. PMID:27658057

  16. MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury

    PubMed Central

    Deroide, Nicolas; Li, Xuan; Lerouet, Dominique; Van Vré, Emily; Baker, Lauren; Harrison, James; Poittevin, Marine; Masters, Leanne; Nih, Lina; Margaill, Isabelle; Iwakura, Yoichiro; Ryffel, Bernhard; Pocard, Marc; Tedgui, Alain; Kubis, Nathalie; Mallat, Ziad

    2013-01-01

    Milk fat globule-EGF 8 (MFGE8) plays important, nonredundant roles in several biological processes, including apoptotic cell clearance, angiogenesis, and adaptive immunity. Several recent studies have reported a potential role for MFGE8 in regulation of the innate immune response; however, the precise mechanisms underlying this role are poorly understood. Here, we show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1β production. MFGE8 inhibited necrotic cell–induced and ATP-dependent IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions in primed cells. Itgb3 deficiency in macrophages abrogated the inhibitory effect of MFGE8 on ATP-induced IL-1β production. In a setting of postischemic cerebral injury in mice, MFGE8 deficiency was associated with enhanced IL-1β production and larger infarct size; the latter was abolished after treatment with IL-1 receptor antagonist. MFGE8 supplementation significantly dampened caspase-1 activation and IL-1β production and reduced infarct size in wild-type mice, but did not limit cerebral necrosis in Il1b-, Itgb3-, or P2rx7-deficient animals. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1β production. PMID:23454767

  17. Peroxynitrite induces apoptosis in canine cerebral vascular muscle cells: possible relation to neurodegenerative diseases and strokes.

    PubMed

    Li, Jianfeng; Su, Jialin; Li, Wenyan; Liu, Weimin; Altura, Bella T; Altura, Burton M

    2003-10-30

    Considerable evidence is accumulating to suggest that in vivo formation of free radicals in the brain, such as peroxynitrite (ONOO-), and programmed cell death (i.e. apoptosis) play important roles in neurodegeneration and stroke. However, it is not known whether ONOO- can induce apoptosis in cerebral vascular smooth muscle cells (CVSMCs). The present study was designed to determine whether or not canine CVSMCs undergo apoptosis following treatment with ONOO-. Direct exposure of canine CVSMCs to ONOO- induced apoptosis in a concentration-dependent manner, as confirmed by means of fluorescence staining, TdT-mediated dUTP nick-end labeling and comet assays. Peroxynitrite treatment resulted in an elevation of [Ca2+]i in the CVSMCs. Peroxynitrite-induced apoptosis may thus be brought about by activation of Ca2+-dependent endonucleases. Although the precise mechanisms by which peroxynitrite induces apoptosis need to be further investigated, the present findings could be used to suggest that ONOO- formation in the brain may play important roles in neurodegenerative processes and strokes via detrimental actions on cerebral microvessels and blood flow.

  18. Investigation of redox status in chronic cerebral hypoperfusion-induced neurodegeneration in rats

    PubMed Central

    Saxena, Anil Kumar; Abdul-Majeed, Saif Saad; Gurtu, Sunil; Mohamed, Wael M.Y.

    2015-01-01

    Aging related reduction in cerebral blood flow (CBF) has been linked with neurodegenerative disorders including Alzheimer's disease and dementia. Experimentally, a condition of chronic cerebral hypoperfusion due to reduced CBF can be induced by permanent bilateral occlusion of common carotid arteries (2-vessel occlusion, 2VO) in rats. Since oxidative stress, leading to neuronal apoptosis and death, is one of the mechanisms, which is thought to play a significant role in chronic degenerative neurological disorders, the present study was planned to assess the ROS status by measuring the levels of anti-oxidant enzymes that might occur during chronic cerebral hypoperfusion. Antioxidant enzymes namely glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase were measured in the brain tissue at eight weeks of 2VO induction in rats. Results show significantly elevated levels of GPx, SOD, and catalase enzymes as compared with the control group. It is possible that compensatory rise in antioxidant enzymes occurs in response to increased oxidative stress following ischemic insult. PMID:26937356

  19. Kir6.1 knockdown aggravates cerebral ischemia/reperfusion-induced neural injury in mice.

    PubMed

    Dong, Yin-Feng; Wang, Lin-Xiao; Huang, Xu; Cao, Wen-Jing; Lu, Ming; Ding, Jian-Hua; Sun, Xiu-Lan; Hu, Gang

    2013-08-01

    ATP-sensitive potassium (K-ATP) channels couple energy metabolism with electric activity, which play important roles in brain diseases including stroke. However, the impacts of Kir6.1-containing K-ATP channels that mainly expressed on glia in stroke remain unclear. In this study, we found that expression of Kir6.1 was significantly decreased in the ischemic brain area of C57BL/6J mice after 1-h middle cerebral artery occlusion (MCAO) and 24-h reperfusion. Then, we subjected Kir6.1 heterozygote knockout (Kir6.1(+/-) ) mice to cerebral ischemia/reperfusion (I/R) injury and found that Kir6.1(+/-) mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by glial over-activation and blood-brain barrier (BBB) damages. Furthermore, we showed that Kir6.1 knockdown aggravated endoplasmic reticulum (ER) stress and thereby increased the levels of proinflammatory factors tumor necrosis factor-α and interleukin-1β (TNF-α and IL-1β) in mouse brain. Our findings reveal that Kir6.1 knockdown exacerbates cerebral I/R-induced brain damages via increasing ER stress and inflammatory response, indicating that Kir6.1-containing K-ATP channels may be a potential therapeutic target for stroke. © 2013 John Wiley & Sons Ltd.

  20. Relationship between caffeine-induced changes in resting cerebral perfusion and blood oxygenation level-dependent signal.

    PubMed

    Laurienti, Paul J; Field, Aaron S; Burdette, Jonathan H; Maldjian, Joseph A; Yen, Yi-Fen; Moody, Dixon M

    2003-09-01

    Recent interest has emerged in the use of pharmacologic methods to maximize blood oxygenation level-dependent (BOLD) signal intensity changes in functional MR imaging (fMRI). Adenosine antagonists, such as caffeine and theophylline, have been identified as potential agents for this purpose. The present study was designed to determine whether caffeine-induced decreases in cerebral perfusion result in enhanced BOLD responses to visual and auditory stimuli. MR imaging was used to measure resting cerebral perfusion and stimulus-induced BOLD signal intensity changes in 19 patients. We evaluated the relationship between resting cerebral perfusion and the magnitude of BOLD signal intensity induced by visual and auditory stimulation under caffeine and placebo conditions. The data showed that changes in resting cerebral perfusion produced by caffeine are not a consistent predictor of BOLD signal intensity magnitude. Although all cerebral perfusion was reduced in all study participants in response to caffeine, only 47% of the participants experienced BOLD signal intensity increase. This finding was independent of the participants' usual caffeine consumption. The data presented herein show that the relationship between resting cerebral perfusion and the magnitude of BOLD signal intensity is complex. It is not possible to consistently enhance BOLD signal intensity magnitude by decreasing resting perfusion with caffeine. Future studies aimed at evaluating the relationship between perfusion and BOLD signal intensity changes should seek a means to selectively modulate known components of the neural and vascular responses independently.

  1. Inhibitory effect of vasopressin receptor antagonist OPC-31260 on experimental brain oedema induced by global cerebral ischaemia.

    PubMed

    Molnár, A H; Varga, C; Berkó, A; Rojik, I; Párducz, A; László, F; László, F A

    2008-03-01

    The effects of the non-peptide vasopressin V(2) receptor antagonist 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) on the cerebral oedema induced by general cerebral hypoxia were studied in rats. The general cerebral hypoxia was produced by bilateral common carotid ligation in Sprague-Dawley rats of the CFY strain. By 6 h after the ligation, half of the rats had died, but the survival rate was significantly higher following OPC-31260 administration. Electron microscopic examinations revealed typical ischaemic changes after the carotid ligation. The carotid ligation increased the brain contents of water and Na(+) and enhanced the plasma vasopressin level. The increased brain water and Na(+) accumulation was prevented by OPC-31260 administration, but the plasma vasopressin level was further enhanced by OPC-31260. These results demonstrate the important role of vasopressin in the development of the disturbances in brain water and electrolyte balance in response to general cerebral hypoxia. The carotid ligation-induced cerebral oedema was significantly reduced following oral OPC-31260 administration. The protective mechanism exerted by OPC-31260 stems from its influence on the renal vasopressin V(2) receptors. These observations might suggest an effective approach to the treatment of global hypoxia-induced cerebral oedema in humans.

  2. Curcumin attenuates the middle cerebral artery occlusion-induced reduction in γ-enolase expression in an animal model

    PubMed Central

    Gim, Sang-Ah; Lee, So-Ra; Shah, Fawad-Ali

    2015-01-01

    Curcumin exerts a protective effect in cerebral ischemia through its anti-oxidant and anti-inflammatory activities. γ-enolase is a glycolytic enzyme expressed in neurons that is known to exerts a neuroprotective effect. We investigated whether curcumin regulates γ-enolase expression in focal cerebral ischemic injury in rats. Middle cerebral artery occlusion (MCAO) was performed to induce focal cerebral ischemia. Adult male rats were injected intraperitoneally with either vehicle or curcumin (50 mg/kg) 1 h after MCAO and cerebral cortex tissues were isolated 24 h after MCAO. We found that MCAO-induced injury resulted in a reduction in γ-enolase expression in vehicle-treated animals using a proteomics approach. However, this reduction was attenuated in animals with MCAO treated with curcumin. Reverse-transcription PCR and Western blot analyses also showed that curcumin treatment prevented the MCAO injury-induced reduction in γ-enolase expression. The results of this study suggest that curcumin exerts its neuroprotective function in focal cerebral ischemia by regulating the expression of γ-enolase. PMID:26755923

  3. Dexamethasone exacerbates cerebral edema and brain injury following lithium-pilocarpine induced status epilepticus.

    PubMed

    Duffy, B A; Chun, K P; Ma, D; Lythgoe, M F; Scott, R C

    2014-03-01

    Anti-inflammatory therapies are the current most plausible drug candidates for anti-epileptogenesis and neuroprotection following prolonged seizures. Given that vasogenic edema is widely considered to be detrimental for outcome following status epilepticus, the anti-inflammatory agent dexamethasone is sometimes used in clinic for alleviating cerebral edema. In this study we perform longitudinal magnetic resonance imaging in order to assess the contribution of dexamethasone on cerebral edema and subsequent neuroprotection following status epilepticus. Lithium-pilocarpine was used to induce status epilepticus in rats. Following status epilepticus, rats were either post-treated with saline or with dexamethasone sodium phosphate (10mg/kg or 2mg/kg). Brain edema was assessed by means of magnetic resonance imaging (T2 relaxometry) and hippocampal volumetry was used as a marker of neuronal injury. T2 relaxometry was performed prior to, 48 h and 96 h following status epilepticus. Volume measurements were performed between 18 and 21 days after status epilepticus. Unexpectedly, cerebral edema was worse in rats that were treated with dexamethasone compared to controls. Furthermore, dexamethasone treated rats had lower hippocampal volumes compared to controls 3 weeks after the initial insult. The T2 measurements at 2 days and 4 days in the hippocampus correlated with hippocampal volumes at 3 weeks. Finally, the mortality rate in the first week following status epilepticus increased from 14% in untreated rats to 33% and 46% in rats treated with 2mg/kg and 10mg/kg dexamethasone respectively. These findings suggest that dexamethasone can exacerbate the acute cerebral edema and brain injury associated with status epilepticus.

  4. Hydrogen Sulfide Attenuates Tissue Plasminogen Activator-Induced Cerebral Hemorrhage Following Experimental Stroke.

    PubMed

    Liu, Hui; Wang, Yi; Xiao, Yunqi; Hua, Zichun; Cheng, Jian; Jia, Jia

    2016-06-01

    Tissue plasminogen activator (tPA), the only approved drug for the treatment of ischemic stroke, increases the risk of cerebral hemorrhage. Here, we investigated whether the newly identified gaso-transmitter hydrogen sulfide (H2S), when used in combination with tPA, reduced the hemorrhagic transformation following stroke. In a mouse model of middle cerebral artery occlusion (MCAO), intravenous injection of tPA enhanced cerebral hemorrhage, which was significantly attenuated by the co-administration of two structurally unrelated H2S donors, ADT-OH and NaHS. By assessing extravasation of Evans blue into the ischemic hemisphere as well as brain edema following MCAO, we further showed that a tPA-exacerbated BBB disruption was significantly ameliorated by the co-administration of ADT-OH. In the mouse MCAO model, tPA upregulated Akt activation, vascular endothelial growth factor (VEGF) expression, and metalloproteinase 9 (MMP9) activity in the ischemic brain, which was remarkably attenuated by ADT-OH. In the in vitro glucose-oxygen deprivation (OGD) model, ADT-OH markedly attenuated tPA-enhanced Akt activation and VEGF expression in brain microvascular endothelial cells. Finally, ADT-OH improved functional outcomes in mice subjected to MCAO and tPA infusion. In conclusion, H2S donors reduced tPA-induced cerebral hemorrhage by possibly inhibiting the Akt-VEGF-MMP9 cascade. Administration of H2S donors has potential as a novel modality to improve the safety of tPA following stroke.

  5. Neuroprotective effect of Momordica charantia in global cerebral ischemia and reperfusion induced neuronal damage in diabetic mice.

    PubMed

    Malik, Zafar Ahmad; Singh, Manjeet; Sharma, P L

    2011-01-27

    Momordica charantia L. (Cucurbitaceae) fruits have been used traditionally for centuries, especially for treating diabetes and associated complications. The present study was performed to evaluate neuroprotective effect of lyophilized M. charantia fruit juice against global cerebral ischemia and reperfusion induced neuronal injury in diabetic mice. Global cerebral ischemia induced by occluding both common carotid arteries for 10 min followed by 24 h reperfusion was used to induce neuronal injury. Ischemia-reperfusion induced neuronal injury was evaluated in terms of cerebral infarct size, generation of free radicals measured as thiobarbaturic acid reactive substances (TBARS), and neurological functions measured as short term memory and motor activity. The cerebral oxidative stress and damage, and neurological deficits were dose dependently attenuated by pre-treatment with the lyophilized M. charantia juice (200-800 mg/kg, p.o., o.d.). Moreover, M. charantia also exhibited dose dependent antihyperglycemic activity in diabetic mice. These results suggest that M. charantia has potent neuroprotective activity against global cerebral ischemia-reperfusion induced neuronal injury and consequent neurological deficits in diabetic mice. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  6. In vivo photoacoustic tomography of mouse cerebral edema induced by cold injury

    NASA Astrophysics Data System (ADS)

    Xu, Zhun; Zhu, Quing; Wang, Lihong V.

    2011-06-01

    For the first time, we have implemented photoacoustic tomography (PAT) to image the water content of an edema in vivo. We produced and imaged a cold-induced cerebral edema transcranially, then obtained blood vessel and water accumulation images at 610 and 975 nm, respectively. We tracked the changes at 12, 24, and 36 h after the cold injury. The blood volume decreased after the cold injury, and the maximum area of edema was observed 24 h after the cold injury. We validated PAT of the water content of the edema through magnetic Resonance Imaging and the water spectrum from the spectrophotometric measurement.

  7. Neuroprotective activityof Cymbopogon martinii against cerebral ischemia/reperfusion-induced oxidative stress in rats.

    PubMed

    Buch, Prakruti; Patel, Vishal; Ranpariya, Vishavas; Sheth, Navin; Parmar, Sachin

    2012-06-26

    Cymbopogon martinii (Roxb.) Watson (Family: Graminae), commonly known as Palmarosa, is traditionally prescribed for central nervous system (CNS) disorders such as neuralgia, epileptic fits and anorexia. Although the plant possesses diverse pharmacological actions, the neuroprotective action has got little attention. The present study evaluated neuroprotective effect of essential oil of Cymbopogon martinii (EOCM) against global cerebral ischemia/reperfusion (I/R)-induced oxidative stress in rats. Global ischemic brain damage was induced by bilateral common carotid artery (BCCA) occlusion for 30 min, followed by 60 min reperfusion on Wistar albino rats. The biochemical levels of lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), total thiols and glutathione (GSH) were estimated and brain coronal sections and histopathological studies were performed. BCCA occlusion, followed by reperfusion caused varied biochemical/enzymatic alterations viz. increase in LPO and decrease in SOD, CAT, total thiols and GSH. The prior treatment of EOCM (50 mg/kg and 100 mg/kg, p.o. for 10 days) markedly reversed these changes and restored to normal levels as compared to I/R groups. Moreover, brain coronal sections and histopathological studies revealed protection against ischemic brain damage in the EOCM-treated groups. This study, for the first time, shows potent neuroprotective effect of EOCM against global cerebral I/R-induced oxidative stress in rats, suggesting its therapeutic potential in cerebrovascular diseases (CVD) including stroke.

  8. TRPC Channels Mediate a Muscarinic Receptor-Induced Afterdepolarization in Cerebral Cortex

    PubMed Central

    Yan, Hai-Dun; Villalobos, Claudio; Andrade, Rodrigo

    2009-01-01

    Activation of muscarinic cholinergic receptors on pyramidal cells of the cerebral cortex induces the appearance of a slow afterdepolarization that can sustain autonomous spiking after a brief excitatory stimulus. Accordingly, this phenomenon has been hypothesized to allow for the transient storage of memory traces in neuronal networks. Here we investigated the molecular basis underlying the muscarinic receptor-induced afterdepolarization using molecular biological and electrophysiological strategies. We find that the ability of muscarinic receptors to induce the inward aftercurrent underlying the slow afterdepolarization is inhibited by expression of a Gαq-11 dominant negative and is also markedly reduced in a phospholipase C β1 (PLCβ1) knock-out mouse. Furthermore, we show, using a genetically encoded biosensor, that activation of muscarinic receptor induces the breakdown of phosphatidylinositol 4,5-bisphosphate in pyramidal cells. These results indicate that the Gαq-11/PLCβ1 cascade plays a key role in the ability of muscarinic receptors to signal the inward aftercurrent. We have shown previously that the muscarinic afterdepolarization is mediated by a calcium-activated nonselective cation current, suggesting the possible involvement of TRPC channels. We find that expression of a TRPC dominant negative inhibits, and overexpression of wild-type TRPC5 or TRPC6 enhances, the amplitude of the muscarinic receptor-induced inward aftercurrent. Furthermore, we find that coexpression of TRPC5 and T-type calcium channels is sufficient to reconstitute a muscarinic receptor-activated inward aftercurrent in human embryonic kidney HEK-293 cells. These results indicate that TRPC channels mediate the muscarinic receptor-induced slow afterdepolarization seen in pyramidal cells of the cerebral cortex and suggest a possible role for TRPC channels in mnemonic processes. PMID:19675237

  9. Dynamic cerebral autoregulation to induced blood pressure changes in human experimental and clinical sepsis.

    PubMed

    Berg, Ronan M G; Plovsing, Ronni R; Bailey, Damian M; Holstein-Rathlou, Niels-Henrik; Møller, Kirsten

    2016-11-01

    Previous studies have demonstrated that dynamic cerebral autoregulation to spontaneous fluctuations in blood pressure is enhanced following lipopolysaccharide (LPS) infusion, a human experimental model of early sepsis, whereas by contrast it is impaired in patients with severe sepsis or septic shock. In this study, we hypothesized that this pattern of response would be identical during induced changes in blood pressure. Dynamic cerebral autoregulation was assessed in nine healthy volunteers and six septic patients. The healthy volunteers underwent a 4-h intravenous infusion of LPS (total dose: 2 ng kg(-1) ). Mean arterial blood pressure (MAP, arterial transducer) and middle cerebral artery blood flow velocity (MCAv, transcranial Doppler ultrasound) were recorded continuously during thigh-cuff deflation-induced changes in MAP for the determination of a modified rate of regulation (RoR). This was performed before and after LPS infusion in healthy volunteers, and within 72 h following clinical diagnosis of sepsis in patients. In healthy volunteers, thigh-cuff deflation caused a MAP reduction of 16 (13-20) % at baseline and 18 (16-20) % after LPS, while the MAP reduction was 12 (11-13) % in patients (P<0·05 versus volunteers at baseline; P<0·01 versus volunteers after LPS). The corresponding RoR values increased from 0·46 (0·31-0·49) s(-1) at baseline to 0·58 (0·36-0·74) s(-1) after LPS (P<0·05) in healthy volunteers, whereas they were similar to values observed in patients [0·43 (0·36-0·52) s(-1) ; P = 0·91 versus baseline; P = 0·14 versus LPS]. While our findings support the concept that dynamic cerebral autoregulation is enhanced during the very early stages of sepsis, they remain inconclusive with regard to more advanced stages of disease, because thigh-cuff deflation failed to induce sufficient MAP reductions in patients. © 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

  10. Repeated Estradiol Treatment Attenuates Chronic Cerebral Hypoperfusion-Induced Neurodegeneration in Rat Hippocampus.

    PubMed

    Stanojlović, Miloš; Guševac, Ivana; Grković, Ivana; Mitrović, Nataša; Zlatković, Jelena; Horvat, Anica; Drakulić, Dunja

    2016-08-01

    Although a substantial number of pre-clinical and experimental studies have investigated effects of 17β-estradiol, its precise molecular mechanism of action in the early state of chronic cerebral hypoperfusion remains controversial. The present study attempted to verify whether post-ischemic estradiol treatment (33.3 μg/kg for seven consecutive days) affects previously reported number of hippocampal apoptotic cells and amount of DNA fragmentation characteristic for apoptosis as well as the expression of key elements within synaptosomal Akt and Erk signal transduction pathways (NF-κB, Bax, Bcl-2, cytochrome C, caspase 3, and PARP). Additionally, alterations of aforementioned molecules linked to protection in various neurodegenerative disorders were monitored in the cytosolic, mitochondrial, and nuclear fractions associating investigated kinases and NF-κB with gene expression of their downstream effectors-Bcl-2, Bax, and caspase 3. The results revealed that an initial increase in the number of apoptotic cells and amount of DNA fragmentation induced by chronic cerebral hypoperfusion was significantly reduced by 17β-estradiol. In synaptic regions, an altered profile with respect to the protein expression of Bcl-2 and phosphorylated Akt was detected, although the level of other examined proteins was not modified. In other investigated sub-cellular fractions, 17β-estradiol elicited phosphorylation and translocation of Akt and Erk along with modulation of the expression of their subsequent effectors. Our findings support the concept that repeated post-ischemic 17β-estradiol treatment attenuates neurodegeneration induced by chronic cerebral hypoperfusion in hippocampus through the activation of investigated kinases and regulation of their downstream molecules in sub-cellular manner indicating a time window and regime of its administration as a valid therapeutic intervention.

  11. Anti-oxidative effect of resveratrol on aluminum induced toxicity in rat cerebral tissue.

    PubMed

    Zakaria, M M H; Hajipour, B; Estakhri, R; Saleh, B M

    2017-01-01

    The direct protective effects of resveratrol against oxidative stress have been demonstrated in neuroglial cells, the mechanisms of these effects are not fully understood. The aim of this research was to study the effect of resveratrol on AL induced cerebral injury in rat. We divided the groups as follows with 10 animals each: a) Group I - served as control receiving normal drinking water and diet ad libitum. b) Group II - animals were administered aluminum at a dose level of 100 mg/kg body weight for a period of 6 weeks daily through oral gavage. c) Group III - animals were administered aluminum at a dose level of 100 mg/kg body weight and resveratrol at a dose of 10 mg/kg body weight intraperitoneally for a period of 6 weeks daily. After 6 weeks rats were anesthetized and decapitated. Brains were removed immediately and frozen in liquid nitrogenRESULTS: The levels of SOD and GPx antioxidant enzymes were decreased in all of the groups receiving aluminium, but it was less severe in resveratrol treated group. SOD and GPx levels in aluminium + resveratrol group were higher than in the aluminum group (p < 0.05). MDA level, as an index of lipid peroxidation, increased significantly in all of the groups receiving aluminium. MDA level was lower in aluminium + resveratrol group compared to aluminum group and the difference was significant (p < 0.05). This study suggests that resveratrol is effective in preventing AL induced toxicity by reducing MDA production in cerebral tissue. Resveratrol also attenuated SOD and GPx suppression in cerebral tissue significantly. Our findings provide the rationale for further studies directed to understanding the mechanism of resveratrol in preventing neurodeterioration (Tab. 1, Ref. 35).

  12. The impact of early aerobic exercise on brain microvascular alterations induced by cerebral hypoperfusion.

    PubMed

    Leardini-Tristão, Marina; Borges, Juliana Pereira; Freitas, Felipe; Rangel, Raquel; Daliry, Anissa; Tibiriçá, Eduardo; Estato, Vanessa

    2017-02-15

    The therapeutic potential of early exercise training following cerebral hypoperfusion was investigated on brain perfusion and inflammation in rats with permanent bilateral occlusion of the common carotid arteries (2VO). Wistar rats were subjected to 2VO or sham surgery and each group was then subdivided randomly into sedentary or exercise groups. Early exercise training was initiated after three days of 2VO or sham surgery and consisted of seven days of treadmill training (30min/day at ∼60% of maximal exercise test), composing four groups: 1) Sham sedentary (Sham-Sed), 2) Sham exercised (Sham-Ex), 3) 2VO sedentary (2VO-Sed) and 4) 2VO exercised (2VO-Ex). Microvascular cerebral blood flow (MCBF) and NADPH oxidase and eNOS gene expression were evaluated by laser speckle contrast imaging and RT-PCR, respectively, and brain functional capillary density and endothelial-leukocyte interactions were evaluated by fluorescence intravital video-microscopy. The 2VO-Sed group presented a decrease in MCBF (Sham-Sed: 230.9±12.2 vs. 2VO-Sed: 183.6±10.6 arbitrary perfusion units, P<0.05) and in functional capillary density (Sham-Sed: 336.4±25.3 vs. 2VO-Sed: 225.5±28.1capillaries/mm(2), P<0.05). Early intervention with physical exercise was able to prevent the cerebral microvascular inflammation by decreasing endothelial-leukocyte interactions (2VO-Ex: 0.9±0.3 vs. 2VO-Sed: 5±0.6cells/min/100μm, P<0.0001) and reducing brain NADPH oxidase gene expression (2VO-Ex: 1.7±0.1 arbitrary units, P<0.05). Cerebral microcirculatory and inflammatory alterations appear to be triggered during the first days after 2VO surgery, and early intervention with physical exercise may represent a means of preventing the microvascular alterations induced by chronic cerebral hypoperfusion.

  13. Tissue-type plasminogen activator induces synaptic vesicle endocytosis in cerebral cortical neurons.

    PubMed

    Yepes, M; Wu, F; Torre, E; Cuellar-Giraldo, D; Jia, D; Cheng, L

    2016-04-05

    The release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons plays a central role in the development of synaptic plasticity, adaptation to metabolic stress and neuronal survival. Our earlier studies indicate that by inducing the recruitment of the cytoskeletal protein βII-spectrin and voltage-gated calcium channels to the active zone, tPA promotes Ca(2+)-dependent translocation of synaptic vesicles (SVs) to the synaptic release site where they release their load of neurotransmitters into the synaptic cleft. Here we used a combination of in vivo and in vitro experiments to investigate whether this effect leads to depletion of SVs in the presynaptic terminal. Our data indicate that tPA promotes SV endocytosis via a mechanism that does not require the conversion of plasminogen into plasmin. Instead, we show that tPA induces calcineurin-mediated dynamin I dephosphorylation, which is followed by dynamin I-induced recruitment of the actin-binding protein profilin II to the presynaptic membrane, and profilin II-induced F-actin formation. We report that this tPA-induced sequence of events leads to the association of newly formed SVs with F-actin clusters in the endocytic zone. In summary, the data presented here indicate that following the exocytotic release of neurotransmitters tPA activates the mechanism whereby SVs are retrieved from the presynaptic membrane and endocytosed to replenish the pool of vesicles available for a new cycle of exocytosis. Together, these results indicate that in murine cerebral cortical neurons tPA plays a central role coupling SVs exocytosis and endocytosis.

  14. Unilateral intracarotid injection of holmium microspheres to induce bilateral MRI-validated cerebral embolization in rats.

    PubMed

    de Lange, Fellery; Dieleman, Jan M; Blezer, Erwin L A; Houston, Ralph J F; Kalkman, Cor J; Nijsen, J Frank W

    2009-01-30

    Cerebral embolization models have been hindered by the fact that delivery is predominantly one-sided and cannot be quantified easily. We have developed a model for bilateral cerebral micro-embolization. By using holmium microspheres, it is possible to quantify intracerebral delivery using MRI. To validate the quantification of holmium microspheres a phantom study was performed in which concentration of microspheres in solution was compared with the number of holmium-induced artifacts on MRI. After that identical microspheres were administered by unilateral injection in the carotid artery, while the opposite carotid artery was clamped. On post-injection MRI scans, intracerebral delivery and right/left distribution of the microspheres was determined. In the phantom study it was shown that quantification by MRI is possible and that MRI artifacts represent single microspheres. In the rat brain, about one-third of the injected dose was consistently located on the contralateral side. The administration was reproducible regarding distribution and number of microspheres. The use of holmium microspheres enables quantification of delivered dose as single microspheres induce artifacts on MRI. By clamping the contralateral carotid artery, one-third of the dose is diverted to the contralateral hemisphere.

  15. Efficacy of Rho kinase inhibitor on cognitive impairment induced by chronic cerebral hypoperfusion in rats

    PubMed Central

    Zhang, Qiang; Zhang, Jun-Jian; Han, Zhong-Mou

    2015-01-01

    This work aims to explore the efficacy of Rho kinase inhibitor Fasudil on cognitive impairment induced by chronic cerebral hypoperfusion in rats. A total of 32 male adult Sprague Dawley (SD) rats were randomly divided into three groups: treatment group, control group and sham-operated group for severe carotid artery stenosis model. After two weeks, 8.35 mg/kg Fasudil and physiological saline were intraperitoneally applied twice per day in treatment group and control group, respectively. Morris water maze test was performed in each group to detect the changes of cognitive function and observe the hippocampal pathomorphology in rats after eight weeks. The average escape latency distinctly shortened (P < 0.01) and the percentage of swimming distance in the platform quadrant significantly increased (P < 0.01) in treatment group compared with those at corresponding time points in control group. The rate of carotid artery stenosis in rats had no statistical difference between treatment and control groups (P > 0.05). Fasudil effectively improved hippocampal pathomorphology. Rho kinase inhibitor obviously ameliorated cognitive impairment induced by chronic cerebral hypoperfusion in rats. PMID:25932185

  16. Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease

    PubMed Central

    French, Curtis R.; Seshadri, Sudha; Destefano, Anita L.; Fornage, Myriam; Arnold, Corey R.; Gage, Philip J.; Skarie, Jonathan M.; Dobyns, William B.; Millen, Kathleen J.; Liu, Ting; Dietz, William; Kume, Tsutomu; Hofker, Marten; Emery, Derek J.; Childs, Sarah J.; Waskiewicz, Andrew J.; Lehmann, Ordan J.

    2014-01-01

    Patients with cerebral small-vessel disease (CSVD) exhibit perturbed end-artery function and have an increased risk for stroke and age-related cognitive decline. Here, we used targeted genome-wide association (GWA) analysis and defined a CSVD locus adjacent to the forkhead transcription factor FOXC1. Moreover, we determined that the linked SNPs influence FOXC1 transcript levels and demonstrated that patients as young as 1 year of age with altered FOXC1 function exhibit CSVD. MRI analysis of patients with missense and nonsense mutations as well as FOXC1-encompassing segmental duplication and deletion revealed white matter hyperintensities, dilated perivascular spaces, and lacunar infarction. In a zebrafish model, overexpression or morpholino-induced suppression of foxc1 induced cerebral hemorrhage. Inhibition of foxc1 perturbed platelet-derived growth factor (Pdgf) signaling, impairing neural crest migration and the recruitment of mural cells, which are essential for vascular stability. GWA analysis also linked the FOXC1-interacting transcription factor PITX2 to CSVD, and both patients with PITX2 mutations and murine Pitx2–/– mutants displayed brain vascular phenotypes. Together, these results extend the genetic etiology of stroke and demonstrate an increasing developmental basis for human cerebrovascular disease. PMID:25250569

  17. CART attenuates endoplasmic reticulum stress response induced by cerebral ischemia and reperfusion through upregulating BDNF synthesis and secretion.

    PubMed

    Qiu, Bin; Hu, Shengdi; Liu, Libing; Chen, Man; Wang, Lai; Zeng, Xianwei; Zhu, Shigong

    2013-07-12

    Cocaine and amphetamine regulated transcript (CART), a neuropeptide, has shown strong neuroprotective effects against cerebral ischemia and reperfusion (I/R) injury in vivo and in vitro. Here, we report a new effect of CART on ER stress which is induced by cerebral I/R in a rat model of middle cerebral artery occlusion (MCAO) or by oxygen and glucose deprivation (OGD) in cultured cortical neurons, as well as a new functionality of BDNF in the neuroprotection by CART against the ER stress in cerebral I/R. The results showed that CART was effective in reducing the neuronal apoptosis and expression of ER stress markers (GRP78, CHOP and cleaved caspase12), and increasing the BDNF expression in I/R injury rat cortex both in vivo and in vitro. In addition, the effects of CART on ischemia-induced neuronal apoptosis and ER stress were suppressed by tyrosine receptor kinase B (TrkB) IgG, whereas the effects of CART on BDNF transcription, synthesis and secretion were abolished by CREB siRNA. This work suggests that CART is functional in inhibiting the cerebral I/R-induced ER stress and neuronal apoptosis by facilitating the transcription, synthesis and secretion of BDNF in a CREB-dependent way.

  18. Peroxynitrite-induced relaxation in isolated canine cerebral arteries and mechanisms of action.

    PubMed

    Li, Jianfeng; Li, Wenyan; Altura, Bella T; Altura, Burton M

    2004-04-01

    The present study was undertaken to determine the vascular actions of peroxynitrite (ONOO(-)), the product of superoxide and nitric oxide (NO), in isolated canine cerebral arteries and to gain insight into its potential mechanisms of action. In the absence of any vasoactive agent, ONOO(-) (from 10(-7) to 10(-6) M) was able to reduce the basal tension. In prostaglandin F2alpha-precontracted canine basilar arterial rings, ONOO(-) elicited concentration-dependent relaxation at concentrations from 10(-8) to 10(-5) M. The effective concentrations producing approximately 50% maximal relaxation (EC(50)) to ONOO(-) were 4.06 x 10(-6) and 4.12 x 10(-6) M in intact and denuded rings, respectively (P > 0.05). No significant differences in relaxation responses were found in ring preparations with or without endothelium (P > 0.05). The presence of either 5 microM methylene blue (MB) or 5 microM 1H-[1,2,4]oxadiazolo-[4,3-alpha]quinoxalin-1-one (ODQ) significantly inhibited the relaxations induced by ONOO(-). Tetraethylammonium chloride (T-2265) significantly decreased the ONOO(-)-induced relaxations in a concentration-dependent manner. However, ONOO(-) had no effect on rings precontracted by high KCL (P > 0.05). Addition of low concentrations of calyculin A (50 nM) was able to abolish the ONOO(-)-induced relaxation. Furthermore, ONOO(-) significantly inhibited calcium-induced contractions of K(+)-depolarized canine cerebral rings in a concentration-related manner. Lastly, a variety of pharmacological agents and antagonists including L-NMMA, l-arginine, indomethacin, atropine, naloxone, diphenhydramine, cimetine, glibenclamide, haloperidol, etc., did not influence the relaxant effects of ONOO(-) on the rings. Our new results suggest that ONOO(-)-triggered relaxation, on canine cerebral arteries, is mediated by elevation of cyclic guanosine monophosphate (cGMP) levels, membrane hyperpolarization via K+ channel activation, activation of myosin light chain phosphatase activity, and

  19. Inorganic Arsenic Induces NRF2-Regulated Antioxidant Defenses in Both Cerebral Cortex and Hippocampus in Vivo.

    PubMed

    Zhang, Yang; Duan, Xiaoxu; Li, Jinlong; Zhao, Shuo; Li, Wei; Zhao, Lu; Li, Wei; Nie, Huifang; Sun, Guifang; Li, Bing

    2016-08-01

    Inorganic arsenic is reported to induce the reactive oxygen species-mediated oxidative stress, which is supposed to be one of the main mechanisms of arsenic-related neurological diseases. Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of antioxidant defense systems, up-regulates the expression of target genes to fight against oxidative damages caused by harmful substances, including metals. In the present study, mice were used as a model to investigate the oxidative stress levels and the expressions of NRF2-regulated antioxidant substances in both cerebral cortex and hippocampus with 5, 10 and 20 mg/kg NaAsO2 exposure intra-gastrically. Our results showed that acute NaAsO2 treatment resulted in decreased total anti-oxidative capacity (T-AOC) and increased maleic dialdehyde production in the nervous system. We also detected rapidly elevation of NRF2 protein levels by enhancement of Nrf2 transcription, especially at 20 mg/kg NaAsO2 exposure group. In the meantime, mRNA and protein levels of Nrf2 encoding antioxidant enzymes heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1 (NQO1) and glutathione S-transferase (GST) were consistently elevated time- and dose-dependently both in the cerebral cortex and hippocampus. Taken together, the presence study demonstrated the activation of NRF2 pathway, an early antioxidant defensive response, in both cerebral cortex and hippocampus upon inorganic arsenic (iAs) exposure in vivo. A better knowledge on the roles of NRF2 pathway in maintaining cellular redox homeostasis would be helpful for the strategies on improvement of neurotoxicity related to this metalloid.

  20. Gene expression in the rat cerebral cortex: comparison of recovery sleep and hypnotic-induced sleep.

    PubMed

    Wisor, J P; Morairty, S R; Huynh, N T; Steininger, T L; Kilduff, T S

    2006-08-11

    Most hypnotic medications currently on the market target some aspect of GABAergic neurotransmission. Although all such compounds increase sleep, these drugs differentially affect the activity of the cerebral cortex as measured by the electroencephalogram. Whereas benzodiazepine medications such as triazolam tend to suppress slow wave activity in the cortex, the GABA(B) ligand gamma-hydroxybutyrate greatly enhances slow wave activity and the non-benzodiazepine, zolpidem, which binds to the omega1 site on the GABA(A) receptor/Cl(-) ionophore complex, is intermediate in this regard. Our previous studies have demonstrated that a small number of genes exhibit increased expression in the cerebral cortex of the mouse and rat during recovery sleep after sleep deprivation: egr-3, fra-2, grp78, grp94, ngfi-b, and nr4a3. Using these genes as a panel of biomarkers associated with sleep, we asked whether hypnotic medications induce similar molecular changes in the rat cerebral cortex to those observed when both sleep continuity and slow wave activity are enhanced during recovery sleep. We find that, although each drug increases the expression of a subset of genes in the panel of biomarkers, no drug fully replicates the molecular changes in the cortex associated with recovery sleep. Furthermore, high levels of slow wave activity in the cortex are correlated with increased expression of fra-2 whereas the expression of grp94 is correlated with body temperature. These results demonstrate that sleep-related changes in gene expression may be affected by physiological covariates of sleep and wakefulness rather than by vigilance state per se.

  1. Ozone autohemotherapy induces long-term cerebral metabolic changes in multiple sclerosis patients.

    PubMed

    Molinari, F; Simonetti, V; Franzini, M; Pandolfi, S; Vaiano, F; Valdenassi, L; Liboni, W

    2014-01-01

    Ozone autohemotherapy is an emerging therapeutic technique that is gaining increasing importance in treating neurological disorders. A validated and standard methodology to assess the effect of such therapy on brain metabolism and circulation is however still lacking. We used a near-infrared spectroscopy (NIRS) system to monitor the cerebral metabolism and a transcranial Doppler (TCD) to monitor the blood flow velocity in the middle cerebral arteries. Fifty-four subjects (32 neurological patients and 22 controls) were tested before, during, and after ozone autohemotherapy. We monitored the concentration changes in the level of oxygenated and deoxygenated haemoglobin, and in the level of the Cytochrome-c-oxidase (CYT-c). As a primary endpoint of the work, we showed the changes in the brain metabolism and circulation of the entire population. The concentration of oxygenated haemoglobin increased after the reinjection of the ozoned blood and remained higher than the beginning for another 1.5 hours. The concentration of the deoxygenated haemoglobin decreased during the therapy and the CYT-c concentration markedly increased about 1 hour after the reinjection. No significant changes were observed on the blood flow velocity. As secondary endpoint, we compared the NIRS metabolic pattern of 20 remitting-relapsing multiple sclerosis (MS) patients against 20 controls. We showed that by using only 7 NIRS variables it was possible to characterize the metabolic brain pattern of the two groups of subjects. The MS subjects showed a marked increase of the CYT-c activity and concentration about 40 minutes after the end of the autohemotherapy, possibly revealing a reduction of the chronic oxidative stress level typical of MS sufferers. From a technical point of view, this preliminary study showed that NIRS could be useful to show the effects of ozone autohemotherapy at cerebral level, in a long-term monitoring. The clinical result of this study is the quantitative measurement of the

  2. Diphenyl diselenide prevents cortico-cerebral mitochondrial dysfunction and oxidative stress induced by hypercholesterolemia in LDL receptor knockout mice.

    PubMed

    de Oliveira, Jade; Moreira, Eduardo Luiz Gasnhar; Mancini, Gianni; Hort, Mariana Appel; Latini, Alexandra; Ribeiro-do-Valle, Rosa Maria; Farina, Marcelo; da Rocha, João Batista Teixeira; de Bem, Andreza Fabro

    2013-10-01

    Recent studies have indicated a causal link between high dietary cholesterol intake and brain oxidative stress. In particular, we have previously shown a positive correlation between elevated plasma cholesterol levels, cortico-cerebral oxidative stress and mitochondrial dysfunction in low density lipoprotein receptor knockout (LDLr(-/-)) mice, a mouse model of familial hypercholesterolemia. Here we show that the organoselenium compound diphenyl diselenide (PhSe)2 (1 mg/kg; o.g., once a day for 30 days) significantly blunted the cortico-cerebral oxidative stress and mitochondrial dysfunction induced by a hypercholesterolemic diet in LDLr(-/-) mice. (PhSe)2 effectively prevented the inhibition of complex I and II activities, significantly increased the reduced glutathione (GSH) content and reduced lipoperoxidation in the cerebral cortex of hypercholesterolemic LDLr(-/-) mice. Overall, (PhSe)2 may be a promising molecule to protect against hypercholesterolemia-induced effects on the central nervous system, in addition to its already demonstrated antiatherogenic effects.

  3. ATP induces mild hypothermia in rats but has a strikingly detrimental impact on focal cerebral ischemia.

    PubMed

    Zhang, Meijuan; Li, Wenjin; Niu, Guangming; Leak, Rehana K; Chen, Jun; Zhang, Feng

    2013-01-01

    Ischemic stroke is a devastating condition lacking effective therapies. A promising approach to attenuate ischemic injury is mild hypothermia. Recent studies show that adenosine nucleotides can induce hypothermia in mice. The purpose of the present study was to test the hypothesis that adenosine 5'-triphosphate (ATP) induces mild hypothermia in rats and reduces ischemic brain injury. We found that intraperitoneal injections of ATP decreased core body temperature in a dose-dependent manner; the dose appropriate for mild hypothermia was 2 g/kg. When ATP-induced hypothermia was applied to stroke induced by middle cerebral artery occlusion, however, a neuroprotective effect was not observed. Instead, the infarct volume grew even larger in ATP-treated rats. This was accompanied by an increased rate of seizure events, hemorrhagic transformation, and higher mortality. Continuous monitoring of physiologic parameters revealed that ATP reduced heartbeat rate and blood pressure. ATP also increased blood glucose, accompanied by severe acidosis and hypocalcemia. Western blotting showed that ATP decreased levels of both phospho-Akt and total-Akt in the cortex. Our results reveal that, despite inducing hypothermia, ATP is not appropriate for protecting the brain against stroke. Instead, we show for the first time that ATP treatment is associated with exaggerated ischemic outcomes and dangerous systemic side effects.

  4. In Utero Bisphenol A Exposure Induces Abnormal Neuronal Migration in the Cerebral Cortex of Mice

    PubMed Central

    Ling, Wenting; Endo, Toshihiro; Kubo, Ken-ichiro; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

    2016-01-01

    Bisphenol A (BPA) has been known to have endocrine-disrupting activity to induce reproductive and behavioral abnormalities in offspring of laboratory animal species. However, morphological basis of this abnormality during brain development is largely unknown. Cerebral cortex plays a crucial role in higher brain function, and its precisely laminated structure is formed by neuronal migration. In the present study, transfecting a plasmid (pCAG-mCherry) by in utero electroporation (IUE), we visualized developing neurons and investigated the possible effects of in utero BPA exposure on neuronal migration. Pregnant mice were exposed to BPA by osmotic pump at estimated daily doses of 0, 40 (BPA-40), or 400 (BPA-400) μg/kg from embryonic day 14.5 (E14.5) to E18.5. IUE was performed at E14.5 and neuronal migration was analyzed at E18.5. Compared with the control group, neuronal migration in the cortical plate was significantly decreased in the BPA-40 group; however, there was no significant difference in the BPA-400 group. Among several neuronal migration-related genes and cortical layer-specific genes, TrkB in the BPA-400 group was found significantly upregulated. In conclusion, in utero exposure to low BPA dose was found to disrupt neuronal migration in the cerebral cortex in a dose-specific manner. PMID:26869994

  5. Krypton laser-induced photothrombotic distal middle cerebral artery occlusion without craniectomy in mice.

    PubMed

    Sugimori, Hiroshi; Yao, Hiroshi; Ooboshi, Hiroaki; Ibayashi, Setsuro; Iida, Mitsuo

    2004-08-01

    Recent advances in genetical engineering of the mouse have highlighted the importance of reproducible and less invasive models of cerebral ischemia in mice. In this paper, we developed minimally invasive and reproducible model of distal middle cerebral artery (MCA) occlusion in mice using krypton (Kr) laser-induced photothrombosis. C57BL/6 or BALB mice (n=8 each) were anesthetized with halothane. The skin was cut, the temporal muscle was retracted, and the right distal MCA was observed through the skull. A Kr laser beam of wavelength 568 nm was focused onto the MCA over the intact skull. Upon laser irradiation, intravenous administration of a rose bengal solution was begun. After 4 min of irradiation, the laser beam was refocused on the MCA just proximal to the first spot, and another 4-min irradiation was performed. Then, the right common carotid artery (CCA) was ligated. Three days later, the brain was removed, and infarct volume was determined. Infarction confined almost solely to the cortical area was produced in each mouse. Mean infarct volume in C57BL/6 mice was 25.2+/-13.7 mm3. The BALB mice group showed significantly larger and more reproducible infarction (44.1+/-5.2 mm3; the coefficient of variation was 12%) than did C57BL/6 mice (P<0.005). Our photothrombosis model of stroke in mice can be performed without craniectomy, and its reproducibility is satisfactory when using BALB mice.

  6. In Utero Bisphenol A Exposure Induces Abnormal Neuronal Migration in the Cerebral Cortex of Mice.

    PubMed

    Ling, Wenting; Endo, Toshihiro; Kubo, Ken-Ichiro; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

    2016-01-01

    Bisphenol A (BPA) has been known to have endocrine-disrupting activity to induce reproductive and behavioral abnormalities in offspring of laboratory animal species. However, morphological basis of this abnormality during brain development is largely unknown. Cerebral cortex plays a crucial role in higher brain function, and its precisely laminated structure is formed by neuronal migration. In the present study, transfecting a plasmid (pCAG-mCherry) by in utero electroporation (IUE), we visualized developing neurons and investigated the possible effects of in utero BPA exposure on neuronal migration. Pregnant mice were exposed to BPA by osmotic pump at estimated daily doses of 0, 40 (BPA-40), or 400 (BPA-400) μg/kg from embryonic day 14.5 (E14.5) to E18.5. IUE was performed at E14.5 and neuronal migration was analyzed at E18.5. Compared with the control group, neuronal migration in the cortical plate was significantly decreased in the BPA-40 group; however, there was no significant difference in the BPA-400 group. Among several neuronal migration-related genes and cortical layer-specific genes, TrkB in the BPA-400 group was found significantly upregulated. In conclusion, in utero exposure to low BPA dose was found to disrupt neuronal migration in the cerebral cortex in a dose-specific manner.

  7. Microglial reaction in focal cerebral ischaemia induced by intra-carotid homologous clot injection.

    PubMed

    Ng, Y K; Ling, E A

    2001-01-01

    This study examined the microglial reaction in a simulated thrombo-embolus ischaemia in rats given an intracarotid injection of a suspension of homologous blood clot. All rats including the controls receiving vehicle injection were perfused at 5 hours, and 1, 3 and 7 days post-operation. The brains were removed and processed for immunohistochemistry using a panel of monoclonal antibodies: OX-42, OX-18 and OX-6 for labeling of microglia. In rats given saline injection OX-42 immunoreactive microglial cells were observed to be distributed quite evenly throughout the whole brain. When injection of clot suspension was given, microglial cells responded vigorously, particularly in the ipsilateral hippocampus. Microglial reaction was also detected in the ipsilateral cerebral cortex, caudate as well as septal nuclei. The majority of the detected reactive microglial cells were hypertrophied showing thick or stout processes. Some rod-like and amoeboid microglia were also observed. Rarely did the reactive microglia express OX-6 immunoreactivity. All microglial cells were unreactive for OX-18. The actual mechanisms leading to the microglial activation as well as functions of reactive microglia in focal cerebral ischaemia remain speculative. In the absence of direct evidence, it could only be suggested that they may act as sensor cells for detection of subtle alterations in the microenvironment, probably in response to focal ischaemia and/or leakage of serum-derived factors induced by thrombo-embolus stroke.

  8. Transdifferentiation-Induced Neural Stem Cells Promote Recovery of Middle Cerebral Artery Stroke Rats

    PubMed Central

    Ma, Jianhua; Zhang, Maoying; Li, Shaowu; Wu, Bingshan; Nie, Xiaohu; Jiao, Jiao; Zhao, Hao; Wang, Shanshan; Yang, Yuanyuan; Zhang, Yesen; Sun, Yilin; Wicha, Max S.; Chang, Alfred E.; Gao, Shaorong; Li, Qiao; Xu, Ruxiang

    2015-01-01

    Induced neural stem cells (iNSCs) can be directly transdifferentiated from somatic cells. One potential clinical application of the iNSCs is for nerve regeneration. However, it is unknown whether iNSCs function in disease models. We produced transdifferentiated iNSCs by conditional overexpressing Oct4, Sox2, Klf4, c-Mycin mouse embryonic fibroblasts. They expanded readily in vitro and expressed NSC mRNA profile and protein markers. These iNSCs differentiated into mature astrocytes, neurons and oligodendrocytes in vitro. Importantly, they reduced lesion size, promoted the recovery of motor and sensory function as well as metabolism status in middle cerebral artery stroke rats. These iNSCs secreted nerve growth factors, which was associated with observed protection of neurons from apoptosis. Furthermore, iNSCs migrated to and passed through the lesion in the cerebral cortex, where Tuj1+ neurons were detected. These findings have revealed the function of transdifferentiated iNSCs in vivo, and thus provide experimental evidence to support the development of personalized regenerative therapy for CNS diseases by using genetically engineered autologous somatic cells. PMID:26352672

  9. Chrysin improves cognitive deficits and brain damage induced by chronic cerebral hypoperfusion in rats.

    PubMed

    He, Xiao-Li; Wang, Yue-Hua; Bi, Ming-Gang; Du, Guan-Hua

    2012-04-05

    Chronic cerebral hypoperfusion, induced by permanent occlusion of bilateral common carotid arteries (2VO), is related to neurological disorders and contributes to cognitive decline. Chrysin (5,7-dihydroxyflavone) is an important member of the flavonoid family. The aim of this study is to investigate the effects of chrysin on cognitive deficits and brain damage in this rat 2VO model. At 52days after ligation, the escape latency in Morris water maze was significantly increased in rats subjected to 2VO, the neuronal damage was also increased accompanied by a large proliferation in glial fibrillary acidic protein (GFAP) immunoreactivity with marked white matter lesions, and neuronal cell apoptosis, all of which were significantly alleviated by long treatment of chrysin (30mg/kg). Biochemical examinations revealed that chrysin decreased lipid peroxide, reduced the increased activities of superoxide dismutase, and attenuated the decreased activities of glutathione peroxidase in 2VO rats. The results suggest that chrysin may have therapeutic potential for the treatment of neurodegeneration and dementia caused by decreased cerebral blood flow, which is most likely related, at least in part, to its anti-inflammatory and antioxidant properties.

  10. Transdifferentiation-Induced Neural Stem Cells Promote Recovery of Middle Cerebral Artery Stroke Rats.

    PubMed

    Yao, Hui; Gao, Mou; Ma, Jianhua; Zhang, Maoying; Li, Shaowu; Wu, Bingshan; Nie, Xiaohu; Jiao, Jiao; Zhao, Hao; Wang, Shanshan; Yang, Yuanyuan; Zhang, Yesen; Sun, Yilin; Wicha, Max S; Chang, Alfred E; Gao, Shaorong; Li, Qiao; Xu, Ruxiang

    2015-01-01

    Induced neural stem cells (iNSCs) can be directly transdifferentiated from somatic cells. One potential clinical application of the iNSCs is for nerve regeneration. However, it is unknown whether iNSCs function in disease models. We produced transdifferentiated iNSCs by conditional overexpressing Oct4, Sox2, Klf4, c-Mycin mouse embryonic fibroblasts. They expanded readily in vitro and expressed NSC mRNA profile and protein markers. These iNSCs differentiated into mature astrocytes, neurons and oligodendrocytes in vitro. Importantly, they reduced lesion size, promoted the recovery of motor and sensory function as well as metabolism status in middle cerebral artery stroke rats. These iNSCs secreted nerve growth factors, which was associated with observed protection of neurons from apoptosis. Furthermore, iNSCs migrated to and passed through the lesion in the cerebral cortex, where Tuj1+ neurons were detected. These findings have revealed the function of transdifferentiated iNSCs in vivo, and thus provide experimental evidence to support the development of personalized regenerative therapy for CNS diseases by using genetically engineered autologous somatic cells.

  11. Thermoregulatory changes induced by cholinomimetic substances introduced into the cerebral ventricles of sheep.

    PubMed Central

    Johnson, K G

    1975-01-01

    1 Thermoregulatory responses have been recorded from Welsh Mountain sheep exposed to warm, neutral or cold environments while injections of cholinomimetic drugs and/or their antagonists have been given into a lateral cerebral ventricle. 2. Carbachol and physostigmine inhibited panting of animals at high ambient temperature (ta), caused vasoconstriction and initiated shivering at neutral ta, and accentuated shivering at low ta. Rectal temperature (tre) invariably increased. Oxotremorine had apparently identical effects. 3. Nicotine and another ganglionic stimulant, the quaternary methyl derivative of dopamine, had no effects on thermoregulation. 4.Atropine given 10 min before injections of carbachol, physostigmine or oxotremorine completely inhibited their hyperthermic effects, but pretreatment with the ganglion-blocking drug, pempidine, caused no inhibition. The cholinergic synapses that respond to cholinomimetic drugs injected into the lateral cerebral ventricles of sheep are therefore muscarinic and not nicotinic. 5. When atropine was given to sheep exposed to cold, no detectable reduction of shivering occurred and tre decreased only slightly, even with doses of atropine far greater than needed to inhibit shivering induced by physostigmine. This may be because shivering is controlled by neural pathways unaffected by drugs administered intracerebroventricularly or because the cholinergic synapses activated by physostigmine do not carry the input from cold sensors. PMID:1148492

  12. Functional response of cerebral blood flow induced by somatosensory stimulation in rats with subarachnoid hemorrhage

    NASA Astrophysics Data System (ADS)

    Li, Zhiguo; Huang, Qin; Liu, Peng; Li, Pengcheng; Ma, Lianting; Lu, Jinling

    2015-09-01

    Subarachnoid hemorrhage (SAH) is often accompanied by cerebral vasospasm (CVS), which is the phenomenon of narrowing of large cerebral arteries, and then can produce delayed ischemic neurological deficit (DIND) such as lateralized sensory dysfunction. CVS was regarded as a major contributor to DIND in patients with SAH. However, therapy for preventing vasospasm after SAH to improve the outcomes may not work all the time. It is important to find answers to the relationship between CVS and DIND after SAH. How local cerebral blood flow (CBF) is regulated during functional activation after SAH still remains poorly understood, whereas, the regulation of CBF may play an important role in weakening the impact of CVS on cortex function. Therefore, it is worthwhile to evaluate the functional response of CBF in the activated cortex in an SAH animal model. Most evaluation of the effect of SAH is presently carried out by neurological behavioral scales. The functional imaging of cortical activation during sensory stimulation may help to reflect the function of the somatosensory cortex more locally than the behavioral scales do. We investigated the functional response of CBF in the somatosensory cortex induced by an electrical stimulation to contralateral forepaw via laser speckle imaging in a rat SAH model. Nineteen Sprague-Dawley rats from two groups (control group, n=10 and SAH group, n=9) were studied. SAH was induced in rats by double injection of autologous blood into the cisterna magna after CSF aspiration. The same surgical procedure was applied in the control group without CSF aspiration or blood injection. Significant CVS was found in the SAH group. Meanwhile, we observed a delayed peak of CBF response in rats with SAH compared with those in the control group, whereas no significant difference was found in magnitude, duration, and areas under curve of relative CBF changes between the two groups. The results suggest that the regulation function of local CBF during

  13. Piperine suppresses cerebral ischemia-reperfusion-induced inflammation through the repression of COX-2, NOS-2, and NF-κB in middle cerebral artery occlusion rat model.

    PubMed

    Vaibhav, Kumar; Shrivastava, Pallavi; Javed, Hayate; Khan, Andleeb; Ahmed, Md Ejaz; Tabassum, Rizwana; Khan, Mohd Moshahid; Khuwaja, Gulrana; Islam, Farah; Siddiqui, M Saeed; Safhi, Mohammed M; Islam, Fakhrul

    2012-08-01

    The pathophysiological mechanisms leading to neuronal injury in middle cerebral artery occlusion (MCAO) model of cerebral stroke are complex and multifactorial that form the bases of behavioral deficits and inflammation mediated damage. The present study demonstrates the effect of piperine pretreatment (10 mg/kg b wt, once daily p.o. for 15 days) on cerebral ischemia-induced inflammation in male Wistar rats. The right middle cerebral artery was occluded for 2 h followed by reperfusion for 22 h. A maximum infarct volume (57.80 %) was observed in ischemic MCAO group. However, piperine administration prior to ischemia showed a significant reduction in infarct volume (28.29 %; p < 0.05) and neuronal loss (12.72 %; p < 0.01). As a result of piperine pretreatment, a significant improvement in behavioral outputs of MCAO rats (p < 0.05-0.01) was observed. Piperine successfully reduced the level of proinflammatory cytokines IL-1β, IL-6 and TNF-α, in ischemic group (p < 0.01). Ischemic group brain has shown edematous morphology with vacuolated architecture and pyknotic nuclei in H & E staining which was successfully ameliorated by piperine administration. Moreover, piperine also succeeded in lowering the expression of COX-2, NOS-2, and NF-κB (p < 0.01). Both cytosolic and nuclear NF-κB were down-regulated in ischemic group pre-administered with piperine (p < 0.01). The present study suggests that piperine is able to salvage the ischemic penumbral zone neurons by virtue of its anti-inflammatory property, thereby limiting ischemic cell death.

  14. Enhancement of Intratumoral Chemotherapy with Cisplatin with or without Microwave Ablation and Lipiodol. Future Concept for Local Treatment in Lung Cancer

    PubMed Central

    Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Stopek, Joshua; Kosmidis, Efstratios; Vogl, Thomas; Linsmeier, Bernd; Tsakiridis, Kosmas; Lampaki, Sofia; Lazaridis, George; Mpakas, Andreas; Browning, Robert; Papaiwannou, Antonis; Drevelegas, Antonis; Baka, Sofia; Karavasilis, Vasilis; Mpoukovinas, Ioannis; Turner, J Francis; Zarogoulidis, Konstantinos; Brachmann, Johannes

    2015-01-01

    Novel therapies for lung cancer are being explored nowadays with local therapies being the tip of the arrow. Intratumoral chemotherapy administration and local microwave ablation have been investigated in several studies. It has been previously proposed that lipiodol has the ability to modify the microenvironment matrix. In our current study we investigated this theory in BALBC mice. In total 160 BALBC mice were divided in eight groups: a) control, b) cisplatin, c) microwave, d) microwave and lipiodol, e) cisplatin and lipiodol, f) microwave and cisplatin, g) lipiodol and h) lipiodol, cisplatin and microwave. Lewis lung carcinoma cell lines (106) were injected into the right back leg of each mouse. After the 8th day, when the tumor volume was about 100mm3 the therapy application was initiated, once per week for four weeks. Magnetic resonance imaging was performed for each tumor when a mouse died or when sacrificed if they were still alive by the end of the experiment (8-Canal multifunctional spool; NORAS MRI products, Gmbh, Germany). Imaging and survival revealed efficient tumor apoptosis for the groups b,c,d,e and f. However; severe toxicity was observed in group h and no follow up was available for this group after the second week of therapy administration. Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect. Future modification of lipiodol might provide a more efficient method of therapy enhancement. Combination of drug and microwave ablation is possible and has an efficient apoptotic effect. PMID:25663938

  15. Enhancement of Intratumoral Chemotherapy with Cisplatin with or without Microwave Ablation and Lipiodol. Future Concept for Local Treatment in Lung Cancer.

    PubMed

    Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Stopek, Joshua; Kosmidis, Efstratios; Vogl, Thomas; Linsmeier, Bernd; Tsakiridis, Kosmas; Lampaki, Sofia; Lazaridis, George; Mpakas, Andreas; Browning, Robert; Papaiwannou, Antonis; Drevelegas, Antonis; Baka, Sofia; Karavasilis, Vasilis; Mpoukovinas, Ioannis; Turner, J Francis; Zarogoulidis, Konstantinos; Brachmann, Johannes

    2015-01-01

    Novel therapies for lung cancer are being explored nowadays with local therapies being the tip of the arrow. Intratumoral chemotherapy administration and local microwave ablation have been investigated in several studies. It has been previously proposed that lipiodol has the ability to modify the microenvironment matrix. In our current study we investigated this theory in BALBC mice. In total 160 BALBC mice were divided in eight groups: a) control, b) cisplatin, c) microwave, d) microwave and lipiodol, e) cisplatin and lipiodol, f) microwave and cisplatin, g) lipiodol and h) lipiodol, cisplatin and microwave. Lewis lung carcinoma cell lines (10(6)) were injected into the right back leg of each mouse. After the 8th day, when the tumor volume was about 100mm(3) the therapy application was initiated, once per week for four weeks. Magnetic resonance imaging was performed for each tumor when a mouse died or when sacrificed if they were still alive by the end of the experiment (8-Canal multifunctional spool; NORAS MRI products, Gmbh, Germany). Imaging and survival revealed efficient tumor apoptosis for the groups b,c,d,e and f. However; severe toxicity was observed in group h and no follow up was available for this group after the second week of therapy administration. Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect. Future modification of lipiodol might provide a more efficient method of therapy enhancement. Combination of drug and microwave ablation is possible and has an efficient apoptotic effect.

  16. Regional cerebral blood flow changes during visually induced subjective sadness in healthy elderly persons.

    PubMed

    Paradiso, Sergio; Robinson, Robert G; Boles Ponto, Laura L; Watkins, G Leonard; Hichwa, Richard D

    2003-01-01

    This study examined regional cerebral blood flow (rCBF) changes associated with visually induced sad affect in healthy elderly persons. Subjects viewed sadness-laden, happiness-laden, and emotionally neutral image sets while rCBF was recorded using [(15)O] water PET. The sad image set included human faces and scenery/objects ("scenes"). To control for secondary sensory processing, the neutral and happy comparison sets included exclusively either human faces or scenes. During the sad condition, the ventral prefrontal and temporal cortices were more active compared with happy and neutral scenes conditions and the thalamus was more active compared with happy and neutral faces conditions. Ventral prefrontal cortex and thalamus were associated with processing of sad visual stimuli, whether compared with neutral or happy stimuli. The specific findings associated with sad affect were contingent on the comparison stimuli content (scenes or human faces), not affect (i.e., comparison with neutral or happy conditions).

  17. Cerebral Networks Linked to Itch-related Sensations Induced by Histamine and Capsaicin.

    PubMed

    Vierow, Verena; Forster, Clemens; Vogelgsang, Rebekka; Dörfler, Arnd; Handwerker, Herman O

    2015-07-01

    This functional magnetic resonance imaging (fMRI) study explored the central nervous processing of itch induced by histamine and capsaicin, delivered via inactivated cowhage spicules, and the influence of low-dose naltrexone. Scratch bouts were delivered at regular intervals after spicule insertion in order temporarily to suppress the itch. At the end of each trial the subjects rated their itch and scratch-related sensations. Stepwise multiple regression analyses were employed for identifying cerebral networks contributing to the intensities of "itching", "burning", "stinging", "pricking" and "itch relief by scratching". In the capsaicin experiments a network for "burning" was identified, which included the posterior insula, caudate and putamen. In the histamine experiments networks for "itching" and "itch relief" were found, which included operculum, hippocampus and amygdala. Naltrexone generally reduced fMRI activation and the correlations between fMRI signal and ratings. Furthermore, scratching was significantly less pleasant under naltrexone.

  18. Neuroprotective effects of Tilia americana var. mexicana on damage induced by cerebral ischaemia in mice.

    PubMed

    Angeles-López, Guadalupe E; González-Trujano, Ma Eva; Gómez, Claudia; Chánez-Cárdenas, Ma Elena; Ventura-Martinez, Rosa

    2016-09-01

    Tilia americana var. mexicana (T. americana) is a plant widely used in Mexico for its medicinal properties on the central nervous system. In the present study, we designed a protocol to investigate the neuroprotective effects of non-polar and polar extracts of T. americana on damage induced by cerebral ischaemia in mice. Vehicle or extracts were administered immediately after ischaemia. Functional neurological deficit, survival percentage and infarct area were determined in each experimental group. Results showed that groups treated with non-polar or polar extracts of T. americana had increased survival rate, improved neurological deficits and diminished the infarct area in relation to the ischaemic group. In conclusion, this study confirms the neuroprotective activity of T. americana, suggests a possible synergism between non-polar and polar constituents and supports its potential as a useful aid in the clinical management of stroke.

  19. Antioxidants prevent depletion of [Mg2+]i induced by alcohol in cultured canine cerebral vascular smooth muscle cells: possible relationship to alcohol-induced stroke.

    PubMed

    Li, W; Zheng, T; Altura, B T; Altura, B M

    2001-07-01

    Low serum concentrations of Mg(2+) ions have been reported, recently, in patients with coronary disease, atherosclerosis, and stroke as well as in patients with cerebral hemorrhage. The aim of the present study was to determine whether potent antioxidants [alpha-tocopherol and pyrrolidine dithiocarbamate (PDTC)] can prevent or ameliorate intracellular Mg(2+) ([Mg(2+)](i)) depletion associated with cerebral vascular injury induced by alcohol. Exposure of cultured canine cerebral vascular smooth muscle cells to alcohol (10-100 mM) for 24 h induced marked depletion in [Mg(2+)](i) (i.e., approximately 30-65%, depending upon alcohol concentration). Treatment of the cultured cells with either PDTC (0.1 microM) or alpha-tocopherol (15 microM) for 24 h, alone, failed to interfere with basal [Mg(2+)](i) levels. However, preincubation of the cells with either alpha-tocopherol or PDTC for 24 h completely inhibited the depletion of [Mg(2+)](i) induced by exposure to 10-100 mM ethanol. These results indicate that alpha-tocopherol and PDTC prevent decreases in [Mg(2+)](i) produced by ethanol. Moreover, these new results suggest that such protective effects of alpha-tocopherol and PDTC on cerebral vascular cells might be useful therapeutic tools in prevention and amelioration of cerebral vascular injury and stroke in alcoholics.

  20. Neurophysiological changes induced by the botulinum toxin type A injection in children with cerebral palsy.

    PubMed

    Frascarelli, Flaminia; Di Rosa, Giuseppe; Bisozzi, Eleonora; Castelli, Enrico; Santilli, Valter

    2011-01-01

    In the last few years botulinum toxin type A (BTX-A) has been widely used in the management of spasticity in children with cerebral palsy in order to reduce hypertonicity and improve functional outcomes enhancing motor skill development. The botulinum toxin injection seems to interact with intrafusal and extrafusal fibers producing a reduction of hypertone both through synaptic blockade and inhibition of stretch reflex loop and these changes may influence not only the spinal cord but also the central nervous system (CNS). The purpose of our study was to determine the neurophysiological changes induced by the BTX-A through an evaluation of cortical somatosensory Evoked Potential (SEP) and Soleus H wave, that is the index of excitability of stretch reflex loop. Eighteen children with Cerebral Palsy (CP), aged between 5 and 12, were recruited at Children's Hospital "Bambino Gesù" of Rome. All children were evaluated with appropriate clinical scales before and 1 month after the BTX-A injection. Neurophysiological measurements were performed before, and 1 month after botulinum toxin injection through lower limb SEPs, M-wave and Soleus H wave recording. After the injection the results showed a statistically significant improvement both of clinical scales and the neurophysiological variables. These findings suggest that spasticity itself can be considered as a factor affecting the cortical SEPs. And even though it seems that BTX-A does not have any direct central effect on sensory pathways we suppose an indirect mechanism on modulation of afferent fibers Ia due to the modification induced by BTX-A to central loop reflex. © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  1. Citrulline uptake in rat cerebral cortex slices: modulation by Thioacetamide -Induced hepatic failure.

    PubMed

    Zielińska, Magdalena; Obara-Michlewska, Marta; Hilgier, Wojciech; Albrecht, Jan

    2014-12-01

    L-citrulline (Cit) is a co-product of NO synthesis and a direct L-arginine (Arg) precursor for de novo NO synthesis. Acute liver failure (ALF) is associated with increased nitric oxide (NO) and cyclic GMP (cGMP) synthesis in the brain, indirectly implicating a role for active transport of Cit. In the present study we characterized [(3)H]Cit uptake to the cortical brain slices obtained from control rats and rats with thioacetamide (TAA)-induced ALF ("TAA slices"). In both control and TAA slices the uptake was partially Na(+)-dependent and markedly inhibited by substrates of systems L and N, including L-glutamine (Gln), which accumulates in excess in brain during ALF. Cit uptake was not affected by Arg, the y(+)/y(+)L transport system substrate, nor by amino acids taken up by systems A, xc (-)or XAG. The Vmax of the uptake in TAA slices was ~60 % higher than in control slices. Chromatographic (HPLC) analysis revealed a ~30 % increase of Cit concentration in the cerebral cortical homogenates of TAA rats. The activity of argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL), the two enzymes of Cit-NO cycle catalyzing synthesis of Arg, showed an increase in TAA rats, consistent with increased ASS and ASL protein expression, by ~30 and ~20 %, respectively. The increased Cit-NO cycle activity was paralleled by increased expression of mRNA coding for inducible nitric oxide synthase (iNOS). Taken together, the results suggest a role for Cit in the activation of cerebral NO synthesis during ALF.

  2. Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion.

    PubMed

    Yang, Ying; Ju, Jieyang; Deng, Min; Wang, Jing; Liu, Hui; Xiong, Li; Zhang, Junjian

    2017-01-17

    Hypoxia inducible factor 1α (HIF-1α), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH) triggered long-lasting accumulation of HIF-1α protein in the hippocampus of rats. However, the role of the stabilized HIF-1α in CCH is obscure. Here, we knock down endogenous HIF-1α to determine whether and how HIF-1α affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1α small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock down HIF-1α gene expression in the hippocampus and other brain areas. Permanent bilateral common carotid artery occlusions, known as 2-vessel occlusions (2VOs), were used to induce CCH in rats. Angiogenesis, oxidative stress, histopathological changes of the brain, and cognitive function were tested. Knockdown of HIF-1α prior to 2VO significantly exacerbates the impairment of learning and memory after four weeks of CCH. Mechanically, reduced cerebral angiogenesis, increased oxidative damage, and increased density of astrocytes and microglia in the cortex and some subregions of hippocampus are also shown after four weeks of CCH. Furthermore, HIF-1α knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-1α-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1α during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit.

  3. Cerebral oxidative stress induces spatial working memory dysfunction in uremic mice: neuroprotective effect of tempol.

    PubMed

    Fujisaki, Kiichiro; Tsuruya, Kazuhiko; Yamato, Mayumi; Toyonaga, Jiro; Noguchi, Hideko; Nakano, Toshiaki; Taniguchi, Masatomo; Tokumoto, Masanori; Hirakata, Hideki; Kitazono, Takanari

    2014-03-01

    Chronic kidney disease (CKD) is frequently associated with uremic encephalopathy and cognitive impairment. Recent studies have demonstrated that cerebral oxidative stress contributes to cognitive dysfunction. Although oxidative stress has been reported to increase in the uremic rat brain, the relationship between increased oxidative stress and cognitive impairment in uremia is unclear. In the present study, the effects of tempol (TMP), an antioxidant drug, were investigated in uremic mice. CKD was induced in male C57BL/6 mice (n = 8) by left nephrectomy and 2/3 electrocoagulation of the right renal cortex. Working memory performance was tested by the radial arm water maze test. We have prepared two protocols ('time course study' and 'treatment study'). First, we examined the working memory test and histological examination of mouse brains after 4 and 8 weeks. Next, we investigated the effect of TMP (3 mM) against uremia-induced neurodegeneration and oxidative stress in the mouse brain. Eight weeks after CKD induction, vehicle-treated mice made significantly more errors than sham-operated control mice, while TMP improved working memory performance in CKD mice. CKD was associated with accumulation of 8-hydroxy-2'-deoxyguanosine in the hippocampal neuronal cells, but not in TMP-treated CKD mice. Increased numbers of pyknotic neuronal cells were observed in the hippocampus of CKD mice at 8 weeks, but pyknotic neuronal cell numbers were decreased under the influence of TMP in uremic mice. The present study provided evidence that uremia is associated with spatial working memory dysfunction in mice and that treatment with TMP protects against cerebral oxidative stress and improves cognitive dysfunction in uremic mice, suggesting their potential usefulness for the treatment of cognitive dysfunction in uremia.

  4. Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion

    PubMed Central

    Yang, Ying; Ju, Jieyang; Deng, Min; Wang, Jing; Liu, Hui; Xiong, Li; Zhang, Junjian

    2017-01-01

    Hypoxia inducible factor 1α (HIF-1α), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH) triggered long-lasting accumulation of HIF-1α protein in the hippocampus of rats. However, the role of the stabilized HIF-1α in CCH is obscure. Here, we knock down endogenous HIF-1α to determine whether and how HIF-1α affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1α small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock down HIF-1α gene expression in the hippocampus and other brain areas. Permanent bilateral common carotid artery occlusions, known as 2-vessel occlusions (2VOs), were used to induce CCH in rats. Angiogenesis, oxidative stress, histopathological changes of the brain, and cognitive function were tested. Knockdown of HIF-1α prior to 2VO significantly exacerbates the impairment of learning and memory after four weeks of CCH. Mechanically, reduced cerebral angiogenesis, increased oxidative damage, and increased density of astrocytes and microglia in the cortex and some subregions of hippocampus are also shown after four weeks of CCH. Furthermore, HIF-1α knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-1α-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1α during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit. PMID:28106731

  5. Cerebral venous thrombosis due to cryptogenic organising pneumopathy with antiphospholipid syndrome worsened by heparin-induced thrombocytopenia.

    PubMed

    Hsieh, J; Kuzmanovic, I; Vargas, M I; Momjian-Mayor, I

    2013-07-09

    Cerebral venous thrombosis (CVT) has usually been ascribed to prothrombotic conditions, oral contraceptives, pregnancy, malignancy, infection, head injury or mechanical precipitants. The case reported here illustrates two rare causes of CVT observed in the same patient: the presence of antiphospholipid antibodies associated with an asymptomatic cryptogenic organising pneumopathy (COP) which were considered the origin of the venous cerebral thrombosis and heparin-induced thrombocytopenia (HIT) which was responsible for the worsening of the thrombosis observed a few days after the introduction of treatment. Moreover, we provide here additional positive experience in the treatment of both, CVT and HIT, by fondaparinux with bridging to warfarin given their successful evolution under this anticoagulant option.

  6. Long-Term Outcome of Transcatheter Subsegmental and Segmental Arterial Chemoemobolization Using Lipiodol for Hepatocellular Carcinoma

    SciTech Connect

    Takaki, Satoshi; Sakaguchi, Hiroshi; Anai, Hiroshi Tanaka, Toshihiro; Yamamoto, Kiyosei; Morimoto, Kengo; Nishiofuku, Hideyuki; Inoue, Masayoshi; Sueyoshi, Satoru; Nagata, Takeshi; Hidaka, Teruyuki; Uchida, Hideo; Kichikawa, Kimihiko

    2012-06-15

    Purpose: To clarify the efficacy of transcatheter hepatic sub-subsegmental, subsegmental, and segmental arterial chemoembolization using lipiodol (subseg/seg lip-TACE) for hepatocellular carcinoma (HCC), long-term outcomes of patients who had been treated using subseg/seg lip-TACE alone were retrospectively examined. Materials and Methods: Subjects comprised 199 patients with HCC (T1/2/{>=}3 = 30/108/61; Child-Pugh A/B/C = 115/52/32; Japan Integrated Staging [JIS] score {<=}1/2/{>=}3 = 88/64/47) who underwent subseg/seg lip-TACE using lipiodol mixed with an anticancer drug followed by injection of gelatin sponge particles. Each patient was followed-up every 3 months, and repeat subseg/seg lip-TACE and/or conventional lip-TACE was performed in cases showing recurrence. One-, 3-, 5-, 7-, and 10-year cumulative survival rates were calculated. Subgroup analyses were performed by stratifying the population according to T-factor, Child-Pugh classification, and JIS score. Results: Median duration of follow-up was 3.8 years (range 0.2 to 16.4). Median overall survival was 3.8 years. One-, 3-, 5-, 7- and 10-year survival rates were 91.5, 66.1, 38.8, 20.3, and 9.4% for all patients, and 95.5, 76.9, 51.9, 27.9 and 20.4% for patients with JIS {<=}1, respectively. Significant survival differences were found across two subgroups of staging systems (T2 vs. T3{<=} [P = 0.0012] and JIS score {<=}1 vs. 2 [P = 0.0036]). Conclusion: This study demonstrated that subseg/seg lip-TACE is a feasible treatment for obtaining prolonged survival in patients with localized HCC showing rich vasculature. Outcomes are influenced by both tumor stage and liver function, as seen in the best prolonged survival in patients with JIS score {<=}1.

  7. Alcohol-induced apoptosis of canine cerebral vascular smooth muscle cells: role of extracellular and intracellular calcium ions.

    PubMed

    Li, Wenyan; Li, Jianfeng; Liu, Weiming; Altura, Bella T; Altura, Burton M

    2004-01-16

    Exposure of canine cerebral vascular smooth muscle cells (VSMCs) to ethanol (10, 25 and 100 mM) for 1, 3 and 5 days induced apoptosis with its typical characteristics of nuclear shrinkage, condensation, and DNA breakage as well as formation of apoptotic bodies observed by fluorescence staining, terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling and comet assays. Such effects of alcohol on cerebral VSMCs were time- and concentration-dependent. The threshold ethanol concentration for induction of the apoptotic process was found to be 10 mM. Extracellular and intracellular Ca2+ chelators, i.e. ethylglycol-bisbeta-aminoethylether-N,N,N'N'-tetraacetic acid (EGTA, 5 mM) and 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetra-acetic acid AM (BAPTA, 10(-6) M), respectively, ameliorated greatly the number of cerebral VSMCs which underwent apoptosis. Verapamil, however, failed to inhibit apoptosis of cerebral VSMCs. From these new findings, we suggest that alcohol-induced apoptosis may contribute to alcohol-induced brain-vascular damage and stroke. In addition, our findings point to potential caution for humans who imbibe two or more standard drinks per day or who undergo 'binge drinking'.

  8. Overexpression of Nrf2 Protects Cerebral Cortical Neurons from Ethanol-Induced Apoptotic DeathS⃞

    PubMed Central

    Narasimhan, Madhusudhanan; Mahimainathan, Lenin; Rathinam, Mary Latha; Riar, Amanjot Kaur

    2011-01-01

    Ethanol (ETOH) can cause apoptotic death of neurons by depleting GSH with an associated increase in oxidative stress. The current study illustrates a means to overcome this ETOH-induced neurotoxicity by enhancing GSH through boosting Nrf2, a transcription factor that controls GSH homeostasis. ETOH treatment caused a significant increase in Nrf2 protein, transcript expression, Nrf2-DNA binding activity, and expression of its transcriptional target, NQO1, in primary cortical neuron (PCNs). However, this increase in Nrf2 did not maintain GSH levels in response to ETOH, and apoptotic death still occurred. To elucidate this phenomenon, we silenced Nrf2 in neurons and found that ETOH-induced GSH depletion and the increase in superoxide levels were exacerbated. Furthermore, Nrf2 knockdown resulted in significantly increased (P < 0.05) caspase 3 activity and apoptosis. Adenovirus-mediated overexpression of Nrf2 prevented ETOH-induced depletion of GSH from the medium and high GSH subpopulations and prevented ETOH-related apoptotic death. These studies illustrate the importance of Nrf2-dependent maintenance of GSH homeostasis in cerebral cortical neurons in the defense against oxidative stress and apoptotic death elicited by ETOH exposure. PMID:21873460

  9. Toxoplasma gondii Upregulates Interleukin-12 To Prevent Plasmodium berghei-Induced Experimental Cerebral Malaria

    PubMed Central

    Settles, Erik W.; Moser, Lindsey A.; Harris, Tajie H.

    2014-01-01

    A chronic infection with the parasite Toxoplasma gondii has previously been shown to protect mice against subsequent viral, bacterial, or protozoal infections. Here we have shown that a chronic T. gondii infection can prevent Plasmodium berghei ANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. Treatment with soluble T. gondii antigens (STAg) reduced parasite sequestration and T cell infiltration in the brains of P. berghei-infected mice. Administration of STAg also preserved blood-brain barrier function, reduced ECM symptoms, and significantly decreased mortality. STAg treatment 24 h post-P. berghei infection led to a rapid increase in serum levels of interleukin 12 (IL-12) and gamma interferon (IFN-γ). By 5 days after P. berghei infection, STAg-treated mice had reduced IFN-γ levels compared to those of mock-treated mice, suggesting that reductions in IFN-γ at the time of ECM onset protected against lethality. Using IL-10- and IL-12βR-deficient mice, we found that STAg-induced protection from ECM is IL-10 independent but IL-12 dependent. Treatment of P. berghei-infected mice with recombinant IL-12 significantly decreased parasitemia and mortality. These data suggest that IL-12, either induced by STAg or injected as a recombinant protein, mediates protection from ECM-associated pathology potentially through early induction of IFN-γ and reduction in parasitemia. These results highlight the importance of early IL-12 induction in protection against ECM. PMID:24396042

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

    PubMed

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

    2011-06-17

    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. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Quantitative analysis of iron concentration and expression of ferroportin 1 in the cortex and hippocampus of rats induced by cerebral ischemia.

    PubMed

    Li, Lin; Li, Yan-wei; Zhao, Jin-ying; Liu, Yue-Ze; Holscher, Christian

    2009-11-01

    Iron overload induced by brain ischemia has been shown to be involved in neurodegenerative disease. Little is known about the relationship between brain ischemia and ferroportin 1 (FP1). The aims of this study are: (i) to determine whether iron accumulation in the brain is induced by cerebral hypoperfusion; and (ii) to test whether expression of FP1 is influenced by cerebral ischemia. The common carotid arteries (CCA) of rats were ligated bilaterally to induce cerebral ischemia, and the iron concentration of the cortex and hippocampus was measured by graphite furnace atomic absorption spectrometry. Iron was stained by Perl's method. The expression of FP1 mRNA and protein was shown by the reverse transcriptase polymerase chain reaction and immunohistochemical methods. The iron concentration in the cortex and hippocampus of ischemic rats had increased on day 7 (CCA7) and significantly on day 28 (CCA28) compared to control rats. More iron granules had been deposited in the cerebral cortex and hippocampus in rats with bilaterally ligated CCA on CCA7 and CCA28. In ischemic rats, FP1 expression in the cerebral cortex and hippocampus was decreased by CCA7 and this was more marked by CCA28 compared to control rats. We therefore concluded that iron deposition in the cerebral cortex and hippocampus of rats is induced by cerebral ischemia. Iron deposition may be attributed to the decrease in FP1 expression, and this inhibition of FP1 expression could be a major contributor to the formation of iron deposits in cerebral ischemia.

  12. Hydrogen peroxide induces apoptosis in cerebral vascular smooth muscle cells: possible relation to neurodegenerative diseases and strokes.

    PubMed

    Li, Jianfeng; Li, Wenyan; Su, Jialin; Liu, Weimin; Altura, Bella T; Altura, Burton M

    2003-12-15

    Recently, reactive oxygen species (ROS) have been suggested as important mediators of brain damage in a number of disease states, including traumatic brain injury, neurodegenerative diseases and strokes. Apoptosis has been suggested to play an important role in neurodegenerative diseases, traumatic brain injury and strokes. The aim of this study was to determine whether or not cerebral vascular smooth muscle cells (CVSMCs) undergo apoptosis following treatment with hydrogen peroxide (H2O2). Herein, we demonstrate, for the first time, that H2O2 can induce apoptosis in a concentration-dependent manner in primary cultured CVSMCs, as measured by several morphological and biochemical criteria. H2O2-induced apoptosis may be initiated by stimulating Ca2+-dependent endonuclease activity. The present new data suggest that apoptosis in cerebral VSMCs, induced by ROS, such as H2O2, could play important roles in neruodegenerative processes, traumatic brain injury and strokes.

  13. Cerebral Perfusion and Gray Matter Changes Associated With Chemotherapy-Induced Peripheral Neuropathy.

    PubMed

    Nudelman, Kelly N H; McDonald, Brenna C; Wang, Yang; Smith, Dori J; West, John D; O'Neill, Darren P; Zanville, Noah R; Champion, Victoria L; Schneider, Bryan P; Saykin, Andrew J

    2016-03-01

    To investigate the longitudinal relationship between chemotherapy-induced peripheral neuropathy (CIPN) symptoms (sx) and brain perfusion changes in patients with breast cancer. Interaction of CIPN-sx perfusion effects with known chemotherapy-associated gray matter density decrease was also assessed to elucidate the relationship between CIPN and previously reported cancer treatment-related brain structural changes. Patients with breast cancer treated with (n = 24) or without (n = 23) chemotherapy underwent clinical examination and brain magnetic resonance imaging at the following three time points: before treatment (baseline), 1 month after treatment completion, and 1 year after the 1-month assessment. CIPN-sx were evaluated with the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity four-item sensory-specific scale. Perfusion and gray matter density were assessed using voxel-based pulsed arterial spin labeling and morphometric analyses and tested for association with CIPN-sx in the patients who received chemotherapy. Patients who received chemotherapy reported significantly increased CIPN-sx from baseline to 1 month, with partial recovery by 1 year (P < .001). CIPN-sx increase from baseline to 1 month was significantly greater for patients who received chemotherapy compared with those who did not (P = .001). At 1 month, neuroimaging showed that for the group that received chemotherapy, CIPN-sx were positively associated with cerebral perfusion in the right superior frontal gyrus and cingulate gyrus, regions associated with pain processing (P < .001). Longitudinal magnetic resonance imaging analysis in the group receiving chemotherapy indicated that CIPN-sx and associated perfusion changes from baseline to 1 month were also positively correlated with gray matter density change (P < .005). Peripheral neuropathy symptoms after systemic chemotherapy for breast cancer are associated with changes in cerebral perfusion and gray

  14. Cerebral blood flow velocity response to induced and spontaneous sudden changes in arterial blood pressure.

    PubMed

    Panerai, R B; Dawson, S L; Eames, P J; Potter, J F

    2001-05-01

    The influence of different types of maneuvers that can induce sudden changes of arterial blood pressure (ABP) on the cerebral blood flow velocity (CBFV) response was studied in 56 normal subjects (mean age 62 yr, range 23-80). ABP was recorded in the finger with a Finapres device, and bilateral recordings of CBFV were performed with Doppler ultrasound of the middle cerebral arteries. Recordings were performed at rest (baseline) and during the thigh cuff test, lower body negative pressure, cold pressor test, hand grip, and Valsalva maneuver. From baseline recordings, positive and negative spontaneous transients were also selected. Stability of PCO2 was monitored with transcutaneous measurements. Dynamic autoregulatory index (ARI), impulse, and step responses were obtained for 1-min segments of data for the eight conditions by fitting a mathematical model to the ABP-CBFV baseline and transient data (Aaslid's model) and by the Wiener-Laguerre moving-average method. Impulse responses were similar for the right- and left-side recordings, and their temporal pattern was not influenced by type of maneuver. Step responses showed a sudden rise at time 0 and then started to fall back to their original level, indicating an active autoregulation. ARI was also independent of the type of maneuver, giving an overall mean of 4.7 +/- 2.9 (n = 602 recordings). Amplitudes of the impulse and step responses, however, were significantly influenced by type of maneuver and were highly correlated with the resistance-area product before the sudden change in ABP (r = -0.93, P < 0.0004). These results suggest that amplitude of the CBFV step response is sensitive to the point of operation of the instantaneous ABP-CBFV relationship, which can be shifted by different maneuvers. Various degrees of sympathetic nervous system activation resulting from different ABP-stimulating maneuvers were not reflected by CBFV dynamic autoregulatory responses within the physiological range of ABP.

  15. Cerebral Perfusion and Gray Matter Changes Associated With Chemotherapy-Induced Peripheral Neuropathy

    PubMed Central

    Nudelman, Kelly N.H.; McDonald, Brenna C.; Wang, Yang; Smith, Dori J.; West, John D.; O'Neill, Darren P.; Zanville, Noah R.; Champion, Victoria L.; Schneider, Bryan P.

    2016-01-01

    Purpose To investigate the longitudinal relationship between chemotherapy-induced peripheral neuropathy (CIPN) symptoms (sx) and brain perfusion changes in patients with breast cancer. Interaction of CIPN-sx perfusion effects with known chemotherapy-associated gray matter density decrease was also assessed to elucidate the relationship between CIPN and previously reported cancer treatment–related brain structural changes. Methods Patients with breast cancer treated with (n = 24) or without (n = 23) chemotherapy underwent clinical examination and brain magnetic resonance imaging at the following three time points: before treatment (baseline), 1 month after treatment completion, and 1 year after the 1-month assessment. CIPN-sx were evaluated with the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity four-item sensory-specific scale. Perfusion and gray matter density were assessed using voxel-based pulsed arterial spin labeling and morphometric analyses and tested for association with CIPN-sx in the patients who received chemotherapy. Results Patients who received chemotherapy reported significantly increased CIPN-sx from baseline to 1 month, with partial recovery by 1 year (P < .001). CIPN-sx increase from baseline to 1 month was significantly greater for patients who received chemotherapy compared with those who did not (P = .001). At 1 month, neuroimaging showed that for the group that received chemotherapy, CIPN-sx were positively associated with cerebral perfusion in the right superior frontal gyrus and cingulate gyrus, regions associated with pain processing (P < .001). Longitudinal magnetic resonance imaging analysis in the group receiving chemotherapy indicated that CIPN-sx and associated perfusion changes from baseline to 1 month were also positively correlated with gray matter density change (P < .005). Conclusion Peripheral neuropathy symptoms after systemic chemotherapy for breast cancer are associated with

  16. [Improvement of the viscosity and the intrahepatic distribution of miriplatin-lipiodol suspension].

    PubMed

    Kishimoto, Shuichi; Adachi, Shingo; Masui, Aya; Suzuki, Ryosuke; Fukushima, Shoji

    2014-11-01

    The effects of warming or emulsification with the water-soluble contrast medium, Iomeron (IOM), on reducing the viscosity of miriplatin-lipiodol (MPT-LPD) suspension were studied. Reduction in the viscosity of MPT-LPD suspension was ob- served upon increasing the temperature. Although the O/W MPT-LPD emulsion with a low ratio of MPT-LPD to IOM reduced the viscosity, the effect was lesser than that achieved with the warming treatment. Radiographic images of the liver obtained after administration of the emulsion into the rat portal vein showed that warming resulted in improved intrahepatic distribution of the formulation, which was dependent on the reduction of viscosity. Emulsification also led to better intrahepatic distribution, but this distribution did not depend on the viscosity of the formulation. The MPT-LPD emulsion showed different distribution properties from the MPT-LPD suspension, and it was difficult to estimate the intrahepatic distribution property from the viscosity of the emulsion. Thus, we suggest that emulsification and warming of MPT-LPD are effective methods for improving the intrahepatic distribution of the MPT formulation.

  17. 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.

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

    PubMed

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

    2016-09-01

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

  19. Paradoxical Air Microembolism Induces Cerebral Bioelectrical Abnormalities and Occasionally Headache in Patent Foramen Ovale Patients With Migraine

    PubMed Central

    Sevgi, Eser Başak; Erdener, Sefik Evren; Demirci, Mehmet; Topcuoglu, Mehmet Akif; Dalkara, Turgay

    2012-01-01

    Background Although controversial, paradoxical embolism via patent foramen ovale (PFO) may account for some of the migraine attacks in a subset of migraine with aura (MA) patients. Induction of MA attacks with air bubble injection during transcranial Doppler ultrasound in MA patients with PFO supports this view. It is likely that cerebral embolism in patients with right-to-left shunt induces bioelectrical abnormalities to initiate MA under some conditions. Methods and Results We investigated changes in cerebral bioelectrical activity after intravenous microbubble injection in 10 MA patients with large PFO and right-to-left cardiac shunt. Eight PFO patients without migraine but with large right-to-left shunt and 12 MA patients without PFO served as controls. Four MA patients with PFO were reexamined with sham injections of saline without microbubbles. Bioelectrical activity was evaluated using spectral electroencephalography and, passage of microbubbles through cerebral arteries was monitored with transcranial Doppler ultrasound. Microbubble embolism caused significant electroencephalographic power increase in MA+PFO patients but not in control groups including the sham-injected MA+PFO patients. Headache developed in 2 MA with PFO patients after microbubble injection. Conclusions These findings demonstrate that air microembolism through large PFOs may cause cerebral bioelectrical disturbances and, occasionally, headache in MA patients, which may reflect an increased reactivity of their brain to transient subclinical hypoxia–ischemia, and suggest that paradoxical embolism is not a common cause of migraine but may induce headache in the presence of a large PFO and facilitating conditions. PMID:23316313

  20. 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

  1. A Salt-Induced Reno-Cerebral Reflex Activates Renin-Angiotensin Systems and Promotes CKD Progression

    PubMed Central

    Cao, Wei; Li, Aiqing; Wang, Liangliang; Zhou, Zhanmei; Su, Zhengxiu; Bin, Wei; Wilcox, Christopher S.

    2015-01-01

    Salt intake promotes progression of CKD by uncertain mechanisms. We hypothesized that a salt-induced reno-cerebral reflex activates a renin-angiotensin axis to promote CKD. Sham-operated and 5/6-nephrectomized rats received a normal-salt (0.4%), low-salt (0.02%), or high-salt (4%) diet for 2 weeks. High salt in 5/6-nephrectomized rats increased renal NADPH oxidase, inflammation, BP, and albuminuria. Furthermore, high salt activated the intrarenal and cerebral, but not the systemic, renin-angiotensin axes and increased the activity of renal sympathetic nerves and neurons in the forebrain of these rats. Renal fibrosis was increased 2.2-fold by high versus low salt, but intracerebroventricular tempol, losartan, or clonidine reduced this fibrosis by 65%, 69%, or 59%, respectively, and renal denervation or deafferentation reduced this fibrosis by 43% or 38%, respectively (all P<0.05). Salt-induced fibrosis persisted after normalization of BP with hydralazine. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral reflex that is activated by salt and promotes oxidative stress, fibrosis, and progression of CKD independent of BP. PMID:25635129

  2. Protective Effects of Ferulic Acid against Chronic Cerebral Hypoperfusion-Induced Swallowing Dysfunction in Rats

    PubMed Central

    Asano, Takashi; Matsuzaki, Hirokazu; Iwata, Naohiro; Xuan, Meiyan; Kamiuchi, Shinya; Hibino, Yasuhide; Sakamoto, Takeshi; Okazaki, Mari

    2017-01-01

    Ferulic acid (FA), a phenolic phytochemical, has been reported to exert antioxidative and neuroprotective effects. In this study, we investigated the protective effects of FA against the dysfunction of the swallowing reflex induced by ligation of bilateral common carotid arteries (2VO) in rats. In 2VO rats, topical administration of water or citric acid to the pharyngolaryngeal region evoked a diminished number of swallowing events with prolonged latency compared to sham-operated control rats. 2VO rats had an increased level of superoxide anion radical, and decreased dopamine and tyrosine hydroxylase enzyme levels in the striatum, suggesting that 2VO augmented cerebral oxidative stress and impaired the striatal dopaminergic system. Furthermore, substance P (SP) expression in the laryngopharyngeal mucosa, which is believed to be positively regulated by dopaminergic signaling in the basal ganglia, was decreased in 2VO rats. Oral treatment with FA (30 mg/kg) for 3 weeks (from one week before 2VO to two weeks after) improved the swallowing reflex and maintained levels of striatal dopamine and laryngopharyngeal SP expression in 2VO rats. These results suggest that FA maintains the swallowing reflex by protecting the dopamine-SP system against ischemia-induced oxidative damage in 2VO rats. PMID:28273833

  3. Cinnamaldehyde reduces IL-1beta-induced cyclooxygenase-2 activity in rat cerebral microvascular endothelial cells.

    PubMed

    Guo, Jian-You; Huo, Hai-Ru; Zhao, Bao-Sheng; Liu, Hong-Bin; Li, Lan-Fang; Ma, Yue-Ying; Guo, Shu-Ying; Jiang, Ting-Liang

    2006-05-10

    Cinnamaldehyde is a principle compound isolated from Guizhi-Tang, which is a famous traditional Chinese medical formula used to treat influenza, common cold and other pyretic conditions. The aim of the present study was to investigate the effects of cinnamaldehyde on expression and activity of cyclooxygenase (COX) and prostaglandin E(2) (PGE(2)) in rat cerebral microvascular endothelial cells (RCMEC). RCMEC were cultured, and identified by immunohistochemistry for von Willebrand factor in cytoplasm of the cells. Then cells were incubated in M199 medium containing interleukin (IL)-1beta in the presence or absence of cinnamaldehyde. After incubation, the medium was collected and the amount of PGE(2) was measured by enzyme-linked immunosorbent assay (ELISA). The cells were harvested, mRNA expression and activity of COX were analyzed by real-time reverse transcription-polymerase chain reaction (RT-PCR) with SYBR Green dye and ELISA respectively. Positive immunostaining for von Willebrand factor was present diffusely in the cytoplasm of >95% RCMEC. IL-1beta increased the mRNA expression and activity of COX-2, and production of PGE(2) in a dose- and time-dependent manner in RCMEC, while mRNA and activity of COX-1 were not significantly altered. Cinnamaldehyde significantly decreased IL-1beta-induced COX-2 activity and PGE(2) production in a dose-dependent manner, while it showed no inhibitory effect on IL-1beta-induced COX-2 mRNA expression in cultured RCMEC. In conclusion, cinnamaldehyde reduces IL-1beta-induced COX-2 activity, but not IL-1beta-induced COX-2 mRNA expression, and consequently inhibits production of PGE(2) in cultured RCMEC.

  4. Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents.

    PubMed

    Bhattacharya, Pallab; Pandey, Anand Kumar; Paul, Sudip; Patnaik, Ranjana; Yavagal, Dileep R

    2013-01-01

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

  5. Procaspase-9 induces its cleavage by transnitrosylating XIAP via the Thioredoxin system during cerebral ischemia-reperfusion in rats

    PubMed Central

    Zhang, Dengyue; Zhao, Ningjun; Ma, Bin; Wang, Yan; Zhang, Gongliang; Yan, Xianliang; Hu, Shuqun; Xu, Tie

    2016-01-01

    Transnitrosylation is an important mechanism by which nitric oxide (NO) modulates cell signaling pathways. For instance, SNO-caspase-3 can transnitrosylate the X-linked inhibitor of apoptosis (XIAP) to enhance apoptosis. XIAP is a potent antagonist of caspase apoptotic activity. Decrease in XIAP activity via nitrosylation results in SNO-XIAP-mediated caspase activation. Considering the functional liaison of procaspase-9 and XIAP, we hypothesized that procaspase-9 nitrosylates XIAP directly. Our data confirmed that cerebral ischemia-reperfusion induced XIAP nitrosylation, procaspase-9 denitrosylation and cleavage. Interestingly, the time courses of the nitrosylation of procaspase-9 and XIAP were negatively correlated, which was more prominent after cerebral ischemia-reperfusion, suggesting a direct interaction. The nitrosylation of XIAP, as well as the denitrosylation and cleavage of procaspase-9, were inhibited by DNCB, TrxR1 AS-ODNs, or TAT-AVPY treatment. Meanwhile, DNCB, TrxR1 AS-ODNs, or TAT-AVPY also inhibited the decrease in hippocampal CA1 neurons induced by ischemia-reperfusion in rats. The denitrosylation and cleavage of procaspase-9 induced by OGD/reoxygenation in SH-SY5Y cells were inhibited when cells were co-transfected with wild-type procaspase-9 and XIAP mutant (C449G). These data suggest that cerebral ischemia-reperfusion induces a transnitrosylation from procaspase-9 to XIAP via the Trx system to consequently cause apoptosis. Additionally, Cys325 is a critical S-nitrosylation site of procaspase-9. PMID:27052476

  6. Ginsenoside Rg1 prevents cerebral and cerebellar injury induced by obstructive jaundice in rats via inducing expression of TIPE-2.

    PubMed

    Zhou, Tingting; Zu, Guo; Zhou, Lu; Che, Ningwei; Guo, Jing; Liang, Zhanhua

    2016-01-01

    The aim of the study was to analyze the effect of Ginsenoside Rg1 (Rg1) on cerebral and cerebellar injury in experimental obstructive jaundice (OJ). OJ was done by ligature and section of extrahepatic biliary duct. Rg1 was injected intraperitoneally (10 mg kg(-1)d(-1) or 20 mg kg(-1) d(-1)). Comparison of serum total bile salts (TBA), total bilirubin (TBil), direct bilirubin (DBil), TNF-α, IL-6 and IL-1β among groups. Malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were determined, also apoptosis and mRNA and protein levels of TIPE2 (TNF-α-inducible protein 8-like 2) were tested in cerebrum and cerebellum. Our results showed that Rg1 reduced MDA and apoptosis in cerebrum and cerebellum induced by OJ, also GSH and antioxidant enzyme activity were raised obviously in rats treated with Rg1. Moreover, decreased mRNA and protein levels of TIPE2 in OJ rats and Rg1 could improve the decreased mRNA and protein levels of TIPE2 in OJ rats. In conclusion, Rg1 decreased oxidative stress and apoptosis, also recovered the antioxidant status and mRNA and protein levels of TIPE2 in the cerebrum and cerebellum of OJ rats. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Effect of age on exercise-induced alterations in cognitive executive function: relationship to cerebral perfusion.

    PubMed

    Lucas, Samuel J E; Ainslie, Philip N; Murrell, Carissa J; Thomas, Kate N; Franz, Elizabeth A; Cotter, James D

    2012-08-01

    Regular exercise improves the age-related decline in cerebral blood flow (CBF) and is associated with improved cognitive function; however, less is known about the direct relationship between CBF and cognitive function. We examined the influence of healthy aging on the capability of acute exercise to improve cognition, and whether exercise-induced improvements in cognition are related to CBF and cortical hemodynamics. Middle cerebral artery blood flow velocity (MCAv; Doppler) and cortical hemodynamics (NIRS) were measured in 13 young (24±5 y) and 9 older (62±3 y) participants at rest and during cycling at 30% and 70% of heart rate range (HRR). Cognitive performance was assessed using a computer-adapted Stroop task (i.e., test of executive function cognition) at rest and during exercise. Average response times on the Stroop task were slower for the older compared to younger group for both simple and difficult tasks (P<0.01). Independent of age, difficult-task response times improved during exercise (P<0.01), with the improvement greater at 70% HRR exercise (P=0.04 vs. 30% HRR). Higher MCAv was correlated with faster response times for simple and difficult tasks at rest (R(2)=0.47 and R(2)=0.47, respectively), but this relation uncoupled progressively during exercise. Exercise-induced increases in MCAv were similar and unaltered during cognitive tasks for both age groups. In contrast, prefrontal cortical hemodynamic NIRS measures [oxyhemoglobin (O(2)Hb) and total hemoglobin (tHb)] were differentially affected by exercise intensity, age and cognitive task; e.g., there were smaller increases in [O(2)Hb] and [tHb] in the older group between exercise intensities (P<0.05). These data indicate that: 1) Regardless of age, cognitive (executive) function is improved while exercising; 2) while MCAv is strongly related to cognition at rest, this relation becomes uncoupled during exercise, and 3) there is dissociation between global CBF and regional cortical oxygenation and

  8. Cerebral watershed infarcts may be induced by hemodynamic changes in blood flow.

    PubMed

    Shi, Jingfei; Meng, Ran; Konakondla, Sanjay; Ding, Yuchuan; Duan, Yunxia; Wu, Di; Wang, Bincheng; Luo, Yinghao; Ji, Xunming

    2017-06-01

    A watershed infarct is defined as an ischemic lesion at the border zones between territories of two major arteries. The pathogenesis of watershed infarcts, specifically whether they are caused by hemodynamic or embolic mechanisms, has long been debated. In this study, we aimed to examine whether watershed infarcts can be induced by altering the hemodynamic conditions in rats. In phase one, to determine the proper clamping duration for a reproducible infarct, 30 rats were equally divided into 5 subgroups and underwent bilateral common carotid artery (CCA) clamping for different durations (0.5, 1.0, 1.5, 2.0, and 3.0 hours). In phase two, to analyze the types of infarcts induced by bilateral CCA clamping, 40 rats were subjected to bilateral CCA clamping for 2 hours. As a control, 8 rats underwent all the operation procedures except bilateral CCA clamping. We performed 7.0T magnetic resonance imaging on the surviving rats on the second day to evaluate the extent of the infarcts. We further identified and examined the infarcts with brain slices stained using 2, 3, 5-triphenyltetrazolium chloride (TTC) on the third day. After 2 hours of bilateral CCA clamping, cerebral infarction occurred in 42% of surviving rats (13/31). The majority of the ischemic lesions were located in watershed regions of the brain, demonstrated by both MRI and TTC staining. Watershed infarcts were induced through changing hemodynamic conditions by bilateral CCA clamping in rats. This method may lead to the development of a reliable rodent model for watershed infarcts.

  9. A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice

    PubMed Central

    Choi, Ko-Eun; Hall, Casey L.; Sun, Jin-Mei; Wei, Ling; Mohamad, Osama; Dix, Thomas A.; Yu, Shan P.

    2012-01-01

    Compelling evidence from preclinical and clinical studies has shown that mild to moderate hypothermia is neuroprotective against ischemic stroke. Clinical applications of hypothermia therapy, however, have been hindered by current methods of physical cooling, which is generally inefficient and impractical in clinical situations. In this report, we demonstrate the potential of pharmacologically induced hypothermia (PIH) by the novel neurotensin receptor 1 (NTR1) agonist ABS-201 in a focal ischemic model of adult mice. ABS-201 (1.5–2.5 mg/kg, i.p.) reduces body and brain temperature by 2–5°C in 15–30 min in a dose-dependent manner without causing shivering or altering physiological parameters. Infarct volumes at 24 h after stroke are reduced by ∼30–40% when PIH therapy is initiated either immediately after stroke induction or after 30–60 min delay. ABS-201 treatment increases bcl-2 expression, decreases caspase-3 activation, and TUNEL-positive cells in the peri-infarct region, and suppresses autophagic cell death compared to stroke controls. The PIH therapy using ABS-201 improves recovery of sensorimotor function as tested 21 d after stroke. These results suggest that PIH induced by neurotensin analogs represented by ABS-201 are promising candidates for treatment of ischemic stroke and possibly for other ischemic or traumatic injuries. Choi, K.-E., Hall, C. L., Sun, J.-M., Wei, L., Mohamad, O., Dix, T. A., Yu, S. P. A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice. PMID:22459147

  10. Ketogenic diet prevents seizure and reduces myoclonic jerks in rats with cardiac arrest-induced cerebral hypoxia.

    PubMed

    Tai, Kwok-Keung; Truong, Daniel D

    2007-09-20

    Although the mechanism underlying the anti-epileptic effects of a ketogenic diet (KD) is not known, KD is reported to be an effective treatment for intractable epilepsy, in particular among children. Here, we evaluated whether a KD can reduce posthypoxic seizure and myoclonic jerks in a rat model of cardiac arrest-induced cerebral hypoxia. In this study, rats were divided into two groups: one group received a normal diet while the other group was fed a KD for 25 days before being subjected to cardiac arrest-induced cerebral hypoxia. We found that rats fed a normal diet developed seizures and severe myoclonic jerks in response to auditory stimuli after the hypoxic insults, whereas the rats on the KD did not develop seizure and showed much less severe myoclonic jerks in response to auditory stimuli. The results suggested that the KD has beneficial effects against posthypoxic seizure and myoclonus.

  11. [Changes in the activity of the ciliary apparatus of the cerebral aqueduct ependymal cells induced by some cerebrospinal fluid neurotransmitters].

    PubMed

    2010-01-01

    In vitro investigation of the effect of the neurotransmitter amino acids on motile activity of the ciliary apparatus of cerebral (Sylvian) aqueduct ependymal cells in the newborn rats has shown that the addition of glutamate, GABA, glycine, and taurine to the nutrient medium induced deceleration and, finally, complete disappearance of motile activity of the ciliary apparatus. Inhibition and blocking of the ciliary activity induced by the neurotransmitters, especially by high concentrations of glutamate, indicate the existence of respective receptors on the membrane of the cerebral aqueduct ependymal cells. This involvement of the receptors was confirmed in the experiments with the preliminary introduction of ion channel blockers (ketamine, strychnine, and bicuculine) into the culture medium that resulted in the attenuation of neurotransmitter destructive effect and the prolongation of motile activity of the ciliary apparatus.

  12. CD8+ T Cells Induce Fatal Brainstem Pathology during Cerebral Malaria via Luminal Antigen-Specific Engagement of Brain Vasculature.

    PubMed

    Swanson, Phillip A; Hart, Geoffrey T; Russo, Matthew V; Nayak, Debasis; Yazew, Takele; Peña, Mirna; Khan, Shahid M; Janse, Chris J; Pierce, Susan K; McGavern, Dorian B

    2016-12-01

    Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8+ T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs) from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8+ T cells interacted with the lumen of brain vascular endothelial cells (ECs), where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-γ, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8+ T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4) therapy prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8+ T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen

  13. CD8+ T Cells Induce Fatal Brainstem Pathology during Cerebral Malaria via Luminal Antigen-Specific Engagement of Brain Vasculature

    PubMed Central

    Swanson, Phillip A.; Hart, Geoffrey T.; Russo, Matthew V.; Nayak, Debasis; Yazew, Takele; Peña, Mirna; Khan, Shahid M.; Pierce, Susan K.; McGavern, Dorian B.

    2016-01-01

    Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8+ T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs) from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8+ T cells interacted with the lumen of brain vascular endothelial cells (ECs), where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-γ, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8+ T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4) therapy prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8+ T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen

  14. Ischemic postconditioning may not influence early brain injury induced by focal cerebral ischemia/reperfusion in rats

    PubMed Central

    Kim, Yoo Kyung; Shin, Jin Woo; Joung, Kyoung Woon

    2010-01-01

    Background Experimental studies have shown that ischemic postconditioning can reduce neuronal injury in the setting of cerebral ischemia, but the mechanisms are not yet clearly elucidated. This study was conducted to determine whether ischemic postconditioning can alter expression of heat shock protein 70 and reduce acute phase neuronal injury in rats subjected to transient focal cerebral ischemia/reperfusion. Methods Focal cerebral ischemia was induced by intraluminal middle cerebral artery occlusion for 60 min in twenty male Sprague-Dawley rats (250-300 g). Rats were randomized into control group and an ischemic postconditioning group (10 rats per group). The animals of control group had no intervention either before or after MCA occlusion. Ischemic postconditioning was elicited by 3 cycles of 30 s reperfusion interspersed by 10 s ischemia immediately after onset of reperfusion. The infarct ratios, brain edema ratios and motor behavior deficits were analyzed 24 hrs after ischemic insult. Caspase-3 reactive cells and cells showing heat shock protein 70 activity were counted in the caudoputamen and frontoparietal cortex. Results Ischemic postconditiong did not reduce infarct size and brain edema ratios compared to control group. Neurologic scores were not significantly different between groups. The number of caspase-3 reactive cells in the ischemic postconditioning group was not significantly different than the value of the control group in the caudoputamen and frontoparietal cortex. The number of cells showing heat shock protein 70 activity was not significantly different than the control group, as well. Conclusions These results suggest that ischemic postconditioning may not influence the early brain damage induced by focal cerebral ischemia in rats. PMID:20498797

  15. Vasodilation induced by oxygen/glucose deprivation is attenuated in cerebral arteries of SUR2 null mice

    PubMed Central

    Adebiyi, Adebowale; McNally, Elizabeth M.

    2011-01-01

    Physiological functions of arterial smooth muscle cell ATP-sensitive K+ (KATP) channels, which are composed of inwardly rectifying K+ channel 6.1 and sulfonylurea receptor (SUR)-2 subunits, during metabolic inhibition are unresolved. In the present study, we used a genetic model to investigate the physiological functions of SUR2-containing KATP channels in mediating vasodilation to hypoxia, oxygen and glucose deprivation (OGD) or metabolic inhibition, and functional recovery following these insults. Data indicate that SUR2B is the only SUR isoform expressed in murine cerebral artery smooth muscle cells. Pressurized SUR2 wild-type (SUR2wt) and SUR2 null (SUR2nl) mouse cerebral arteries developed similar levels of myogenic tone and dilated similarly to hypoxia (<10 mmHg Po2). In contrast, vasodilation induced by pinacidil, a KATP channel opener, was ∼71% smaller in SUR2nl arteries. Human cerebral arteries also expressed SUR2B, developed myogenic tone, and dilated in response to hypoxia and pinacidil. OGD, oligomycin B (a mitochondrial ATP synthase blocker), and CCCP (a mitochondrial uncoupler) all induced vasodilations that were ∼39–61% smaller in SUR2nl than in SUR2wt arteries. The restoration of oxygen and glucose following OGD or removal of oligomycin B and CCCP resulted in partial recovery of tone in both SUR2wt and SUR2nl cerebral arteries. However, SURnl arteries regained ∼60–82% more tone than did SUR2wt arteries. These data indicate that SUR2-containing KATP channels are functional molecular targets for OGD, but not hypoxic, vasodilation in cerebral arteries. In addition, OGD activation of SUR2-containing KATP channels may contribute to postischemic loss of myogenic tone. PMID:21784985

  16. Ischemia-Reperfusion Induced Neovascularization in the Cerebral Cortex of the Ovine Fetus

    PubMed Central

    Virgintino, Daniela; Girolamo, Francesco; Rizzi, Marco; Ahmedli, Nigar; Sadowska, Grazyna B.; Stopa, Edward G.; Zhang, Jiyong; Stonestreet, Barbara S.

    2014-01-01

    Information is limited regarding the effects of injury on neovascularization in the immature brain. We investigated effects of ischemia on cerebral cortical neovascularization after exposure of fetuses to 30 minutes of cerebral ischemia and 48- (I/R-48) or 72- (I/R-72) hours of reperfusion or sham-control treatment (Non-I/R). Immunohistochemical and morphometric analyses of cerebral cortical sections included immunostaining for glial fibrillary acidic protein and collagen type IV (Coll IV), a molecular component of the vascular basal lamina, to determine the glial-vascular network in fetal brains, and Ki67 as a proliferation marker. Cerebral cortices from I/R-48 and I/R-72 fetuses exhibited general responses to ischemia, including reactive astrocyte morphology, which was not observed in Non-I/R fetuses. Cell bodies of reactive, proliferating astrocytes along with large end-feet surrounded walls of cerebral cortical microvessels in addition to the thick Coll IV-enriched basal lamina. Morphometric analysis of Non-I/R with I/R-48 and I/R-72 groups revealed increased Coll IV density in I/R-72 cerebral cortical microvessels (p < 0.01), which also frequently displayed a sprouting appearance, characterized by growing tip cells and activated pericytes. Increases in cerebral cortical basic fibroblast growth factor were associated with neovascularization. We conclude that increased neovascularization occurs within 72 hours after ischemia in fetal cerebral cortices. PMID:24806298

  17. Transarterial Chemoembolization With Cisplatin as Second-Line Treatment for Hepatocellular Carcinoma Unresponsive to Chemoembolization With Epirubicin-Lipiodol Emulsion

    SciTech Connect

    Maeda, Noboru Osuga, Keigo; Higashihara, Hiroki; Tomoda, Kaname; Mikami, Koji; Nakazawa, Tetsuro; Nakamura, Hironobu; Tomiyama, Noriyuki

    2012-02-15

    Purpose: The purpose of this retrospective study was to investigate the efficacy of transarterial chemoembolization (TACE) using cisplatin as a second-line treatment for advanced hepatocellular carcinoma (HCC) unresponsive to TACE using epirubicin-Lipiodol emulsion at our institution. Materials and Methods: Between January 2006 and March 2009, 51 patients with unresectable HCC underwent TACE using cisplatin. All patients had shown persistent viable tumor or tumor progression after at least 2 sessions of TACE using epirubicin-Lipiodol emulsion. TACE procedures consisted of arterial injection of a mixture of Lipiodol and cisplatin (30-100 mg [mean 57 {+-} 21]) (n = 29) or arterial infusion of cisplatin (30-100 mg [mean 87 {+-} 19]) solution (n = 22) followed by injection of 1-mm porous gelatin particles. Early tumor response was assessed by contrast-enhanced computed tomography (CT) according to Response Evaluation Criteria in Solid Tumors (RECIST) and European Association for the Study of the Liver (EASL) criteria. Overall survival and progression-free survival was calculated using the Kaplan-Meier method. Toxicity was assessed according to NCI-CTCAE version 3 criteria. Results: Response rates were 11.8 and 27.5% by RECIST and EASL criteria, respectively. Overall survival rates were 61.9, 48.2, and 28.9% at 1, 2, and 3 years, respectively, and the median survival time was 15.4 months. Progression-free survival rate was 35.2% at 1 year, and median progression-free survival time was 3.1 months. No major complications were observed, and the occurrence of postembolization syndrome was minimal. Grade 3 to 4 toxicities included thrombocytopenia (5.8%), increased aspartate aminotransferase (AST) level (35.3%), and increased alanine aminotransferase (ALT) level (23.5%). Conclusions: witching the TACE anticancer drug from epirubicin to cisplatin might be the feasible option for advanced HCC, even when considered resistant to the initial form of TACE.

  18. Local cerebral hypothermia induced by selective infusion of cold lactated ringer's: a feasibility study in rhesus monkeys.

    PubMed

    Wang, Bincheng; Wu, Di; Dornbos Iii, David; Shi, Jingfei; Ma, Yanhui; Zhang, Mo; Liu, Yumei; Chen, Jian; Ding, Yuchuan; Luo, Yinghao; Ji, Xunming

    2016-06-01

    Hypothermia has shown promise as a neuroprotective strategy for stroke. The use of whole body hypothermia has limited clinical utility due to many severe side effects. Selective brain cooling, or local brain hypothermia, has been previously proposed as an alternative treatment strategy. This study investigated the safety, feasibility, and efficacy of selective brain hypothermia induced by local infusion of ice-cold lactated Ringer's solution in rhesus monkeys. Eight male rhesus monkeys were used in this study. Brain temperature in the territory supplied by middle cerebral artery (MCA) was reduced by infusing 100 mL of ice-cold (0 °C) lactated Ringer's solution over 20 min via a micro-catheter placed in the proximal MCA (n = 4). Vital signs and the temperature of the brain and rectum were monitored before and after infusion. Transcranial Doppler, Magnetic resonance imaging (MRI), and digital subtraction angiography (DSA) were used to evaluate cerebral blood flow, cerebrovascular reactivity (CVR), cerebral edema, and vasospasm. Another cohort of rhesus monkeys (n = 4) were used as systemic cooling controls. Oxygen saturation, blood pressure, heart rate, and hematologic analysis of the two groups remained within the normal range after infusion. Mild cerebral hypothermia (<35 °C) was achieved in 10 min (0.3 °C/min) and was maintained for 20 min in local cortex and striatum following local infusion. The average lowest cerebral temperature in the locally cooled animals was 33.9 ± 0.3 °C in the striatum following 20-min infusion. This was not observed in animals cooled by systemic infusion. The decreases in the rectal temperature for local and systemic infusion were 0.5 ± 0.2 °C and 0.5 ± 0.3 °C, respectively. Selective brain cooling did not cause any cerebral edema as determined by MRI or vasospasm in the perfused vessel based on DSA. Selective cerebral hypothermia did not significantly alter CVR. Local infusion of ice-cold lactated Ringer

  19. A rare case of chemotherapy induced reversible cerebral vasoconstriction syndrome in a patient of acute lymphocytic leukemia.

    PubMed

    Sankhe, Shilpa; Kamath, Namita; Sahu, Arpita

    2015-01-01

    Neurotoxic reactions of chemotherapy occur frequently and are often dose limiting side effects of chemotherapy. It is important to differentiate these various nonneoplastic effects from metastases, or sometimes even from each other, since the therapeutic approach differs accordingly. To arrive at a definitive and comprehensive diagnosis, the radiologist should integrate imaging findings, clinical signs, and laboratory results together. Here we present a unique case of chemotherapy induced reversible cerebral vasoconstriction syndrome in a 13-year-old patient of acute lymphoblastic leukemia.

  20. Detection of time window of cerebral blood flow response induced by sciatic nerve stimulation using temporal clustering analysis

    NASA Astrophysics Data System (ADS)

    Wang, Zheng; Luo, Qingming; Cheng, Haiying; Zeng, Shaoqun

    2003-07-01

    In many studies on functional neuroimaging, change in local cerebral blood flow (CBF) induced by sensory stimulation is used as a substitutive marker for change in cortical neuronal activity by Roy and Sherrington"s postulation. The purpose of this study is to evaluate the close temporal relationship between evoked local CBF and neuronal activity through utilizing temporal clustering analysis (TCA) method to analyze the dataset obtained by high-resolution laser speckle imaging (LSI). We mapped a relatively large somatosensory area of cerebral cortex in successively and followed variations of cerebral blood flow under sciatic nerve stimulation in anesthetized rats using LSI technique. Then we illustrated TCA method on the optical imaging signals and investigated the temporal characteristics of CBF activation. Contralateral somatosensory cortical microflow was activated to increase promptly in less than 1 second after the onset of 2 seconds electrical stimulation (pulse parameters: 0.5ms, 5Hz, 350mV). The data of the present study may possibly shed light on the development question of functional magnetic resonance imaging (fMRI) whether the ultimate spatial resolution attainable by fMRI is limited by the physiology of the cerebral blood flow response to activation or by the hardware and signal-to-noise ratio.

  1. Chronic ethanol exposure during adolescence in rats induces motor impairments and cerebral cortex damage associated with oxidative stress.

    PubMed

    Teixeira, Francisco Bruno; Santana, Luana Nazaré da Silva; Bezerra, Fernando Romualdo; De Carvalho, Sabrina; Fontes-Júnior, Enéas Andrade; Prediger, Rui Daniel; Crespo-López, Maria Elena; Maia, Cristiane Socorro Ferraz; Lima, Rafael Rodrigues

    2014-01-01

    Binge drinking is common among adolescents, and this type of ethanol exposure may lead to long-term nervous system damage. In the current study, we evaluated motor performance and tissue alterations in the cerebral cortex of rats subjected to intermittent intoxication with ethanol from adolescence to adulthood. Adolescent male Wistar rats (35 days old) were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v) during 55 days by gavage to complete 90 days of age. The open field, inclined plane and the rotarod tests were used to assess the spontaneous locomotor activity and motor coordination performance in adult animals. Following completion of behavioral tests, half of animals were submitted to immunohistochemical evaluation of NeuN (marker of neuronal bodies), GFAP (a marker of astrocytes) and Iba1 (microglia marker) in the cerebral cortex while the other half of the animals were subjected to analysis of oxidative stress markers by biochemical assays. Chronic ethanol intoxication in rats from adolescence to adulthood induced significant motor deficits including impaired spontaneous locomotion, coordination and muscle strength. These behavioral impairments were accompanied by marked changes in all cellular populations evaluated as well as increased levels of nitrite and lipid peroxidation in the cerebral cortex. These findings indicate that continuous ethanol intoxication from adolescence to adulthood is able to provide neurobehavioral and neurodegenerative damage to cerebral cortex.

  2. Extremely low frequency magnetic field induced changes in motor behaviour of gerbils submitted to global cerebral ischemia.

    PubMed

    Rauš, Snežana; Selaković, Vesna; Radenović, Lidija; Prolić, Zlatko; Janać, Branka

    2012-03-17

    The purpose of this study was to evaluate behavioural effects of an extremely low frequency magnetic field (ELF-MF) in 3-month-old Mongolian gerbils submitted to global cerebral ischemia. After 10-min occlusion of both common carotid arteries, the gerbils were placed in the vicinity of an electromagnet and continuously exposed to ELF-MF (50Hz, 0.5mT) for 7 days. Their behaviour (locomotion, stereotypy, rotations, and immobility) was monitored on days 1, 2, 4, 7, and 14 after reperfusion for 60min in the open field. It was shown that the 10-min global cerebral ischemia per se induced a significant motor activity increase (locomotion, stereotypy and rotations), and consequently immobility decrease until day 4 after reperfusion, compared to control gerbils. Exposure to ELF-MF inhibited development of ischemia-induced motor hyperactivity during the whole period of registration, but significantly in the first 2 days after reperfusion, when the postischemic hyperactivity was most evident. Motor activity of these gerbils was still significantly increased compared to control ones, but only on day 1 after reperfusion. Our results revealed that the applied ELF-MF (50Hz, 0.5mT) decreased motor hyperactivity induced by the 10-min global cerebral ischemia, via modulation of the processes that underlie this behavioural response.

  3. Current evidence for AMPK activation involvement on resveratrol-induced neuroprotection in cerebral ischemia.

    PubMed

    Pineda-Ramírez, Narayana; Gutiérrez Aguilar, Germán Fernando; Espinoza-Rojo, Mónica; Aguilera, Penélope

    2017-02-14

    Cerebral ischemia is a neurological condition in which energetics and oxidative stress are dysregulated. Resveratrol is a stilbene with potent pharmacological effects associated with its antioxidant properties. In the brain, resveratrol produces protective responses against ischemia, decreases infarct volume and improves neurological function. Adenosine monophosphate-activated protein kinase (AMPK) is a cellular sensor that acts as a switch to initiate adaptive changes in response to fluctuations in energy metabolism. In ischemia, AMPK is activated, nevertheless conflicting results about its contribution to protection have become apparent, and this matter continues without resolution. Interestingly, AMPK activation by resveratrol has been implicated in regulating cell survival in different experimental models. Although resveratrol's ability to regulate AMPK directly or after signaling is only beginning to be understood, targeting this enzyme by resveratrol in brain suggest that it could contribute to the amelioration of some pathologic features induced after an energetic deficit. The present review discusses the potential role of resveratrol in regulating AMPK activity on brain before, during, or after ischemia and offer suggestions for feasible future studies.

  4. Mirror visual feedback induces lower neuromuscular activity in children with spastic hemiparetic cerebral palsy.

    PubMed

    Feltham, Max G; Ledebt, Annick; Deconinck, Frederik J A; Savelsbergh, Geert J P

    2010-01-01

    The study examined the effects of mirror feedback information on neuromuscular activation during bimanual coordination in eight children with spastic hemiparetic cerebral palsy (SHCP) and a matched control group. The 'mirror box' creates a visual illusion, which gives rise to a visual perception of a zero lag, symmetric movement between the two arms. The study incorporated two additional visual feedback conditions by placing a glass or opaque screen between the arms. During bilateral symmetric circular arm movements mirror visual feedback induced lower neuromuscular intensities in the shoulder muscles of the less impaired arm of children with SHCP compared to the other visual conditions. In addition, the mirror lead to shorter relative durations of eccentric and concentric activity in the elbow muscles of the more impaired arm, whereas no effects of visual feedback were found in a matched control group. These results suggest that replacing veridical visual information of the more impaired arm with a mirror reflection of the less impaired arm improves the motor control of children with SHCP during interlimb coupling. The effects of the availability of visual feedback in individuals with hemiparesis are discussed with reference to: (1) increase ipsilateral motor cortex excitability and (2) congruence between afferent (visual) feedback and the internal copy of the motor commands.

  5. Tetracycline inhibits local inflammation induced by cerebral ischemia via modulating autophagy.

    PubMed

    Jiang, Yongjun; Zhu, Juehua; Wu, Li; Xu, Gelin; Dai, Jianwu; Liu, Xinfeng

    2012-01-01

    Tetracycline exerts neuroprotection via suppressing the local inflammation induced by cerebral ischemia. However, the underlying mechanism is not completely clear. The mRNA and protein expressions of tumor necrosis factor α and interleukin 6 and the number of activated microglia were measured to detect the inflammatory process in the ischemic hemisphere. The key proteins of nuclear factor kappa B pathway and the binding activity of nuclear factor kappa B were also measured. Two key components of autophagy, Beclin 1 and LC3, were detected by western blotting. Pretreatment with tetracycline inhibited the mRNA and protein expressions of tumor necrosis factor α and interleukin 6 and decreased the numbers of activated and phagocytotic microglia. Tetracycline down regulated the total and phosphorylated expressions of IKK, IκB and p65 (P<0.05). The autophagy inhibitor, 3-methyladenine, inhibited inflammation and activation of nuclear factor kappa B pathway. The levels of Beclin 1 and LC3 were decreased by 3-methyladenine and tetracycline. Our data suggested that pretreatment of tetracycline may inhibit autophagy in the ischemic stroke brain and then suppress the inflammatory process via inhibiting the activation of nuclear factor kappa B pathway.

  6. Tetracycline Inhibits Local Inflammation Induced by Cerebral Ischemia via Modulating Autophagy

    PubMed Central

    Jiang, Yongjun; Zhu, Juehua; Wu, Li; Xu, Gelin; Dai, Jianwu; Liu, Xinfeng

    2012-01-01

    Background Tetracycline exerts neuroprotection via suppressing the local inflammation induced by cerebral ischemia. However, the underlying mechanism is not completely clear. Methodology/Principal Findings The mRNA and protein expressions of tumor necrosis factor α and interleukin 6 and the number of activated microglia were measured to detect the inflammatory process in the ischemic hemisphere. The key proteins of nuclear factor kappa B pathway and the binding activity of nuclear factor kappa B were also measured. Two key components of autophagy, Beclin 1 and LC3, were detected by western blotting. Pretreatment with tetracycline inhibited the mRNA and protein expressions of tumor necrosis factor α and interleukin 6 and decreased the numbers of activated and phagocytotic microglia. Tetracycline down regulated the total and phosphorylated expressions of IKK, IκB and p65 (P<0.05). The autophagy inhibitor, 3-methyladenine, inhibited inflammation and activation of nuclear factor kappa B pathway. The levels of Beclin 1 and LC3 were decreased by 3-methyladenine and tetracycline. Conclusions/Significance Our data suggested that pretreatment of tetracycline may inhibit autophagy in the ischemic stroke brain and then suppress the inflammatory process via inhibiting the activation of nuclear factor kappa B pathway. PMID:23144925

  7. Walking-induced muscle fatigue impairs postural control in adolescents with unilateral spastic cerebral palsy.

    PubMed

    Vitiello, Damien; Pochon, Ludmilla; Malatesta, Davide; Girard, Olivier; Newman, Christopher J; Degache, Francis

    2016-01-01

    Fatigue is likely to be an important limiting factor in adolescents with spastic cerebral palsy (CP). To determine the effects of walking-induced fatigue on postural control adjustments in adolescents with unilateral CP and their typically developing (TD) peers. Ten adolescents with CP (14.2 ± 1.7 yr) and 10 age-, weight- and height-matched TD adolescents (14.1 ± 1.9 yr) walked for 15 min on a treadmill at their preferred walking speed. Before and after this task, voluntary strength capacity of knee extensors (MVC) and postural control were evaluated in 3 conditions: eyes open (EO), eyes closed (EC) and with dual cognitive task (EODT). After walking, MVC decreased significantly in CP (-11%, P<0.05) but not in TD. The CoP area was only significantly increased in CP (90%, 34% and 60% for EO, EC and EODT conditions, respectively). The CoP length was significantly increased in the EO condition in CP and TD (20% and 21%) and was significantly increased in the EODT condition by 18% in CP only. Unlike TD adolescents, treadmill walking for 15 min at their preferred speed lead to significant knee extensor strength losses and impairments in postural control in adolescents with unilateral spastic CP. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion.

    PubMed

    Ma, Jing; Bo, Shu-Hong; Lu, Xiao-Tong; Xu, A-Jing; Zhang, Jian

    2016-09-01

    Carnosine is a dipeptide that scavenges free radicals, inhibits inflammation in the central nervous system, and protects against ischemic and hypoxic brain damage through its anti-oxidative and anti-apoptotic actions. Therefore, we hypothesized that carnosine would also protect against white matter damage caused by subcortical ischemic injury. White matter damage was induced by right unilateral common carotid artery occlusion in mice. The animals were treated with 200, 500 or 750 mg/kg carnosine by intraperitoneal injection 30 minutes before injury and every other day after injury. Then, 37 days later, Klüver-Barrera staining, toluidine blue staining and immunofluorescence staining were performed. Carnosine (200, 500 mg/kg) substantially reduced damage to the white matter in the corpus callosum, internal capsule and optic tract, and it rescued expression of myelin basic protein, and alleviated the loss of oligodendrocytes. However, carnosine at the higher dose of 750 mg/kg did not have the same effects as the 200 and 500 mg/kg doses. These findings show that carnosine, at a particular dose range, protects against white matter damage caused by chronic cerebral ischemia in mice, likely by reducing oligodendroglial cell loss.

  9. Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion

    PubMed Central

    Ma, Jing; Bo, Shu-hong; Lu, Xiao-tong; Xu, A-jing; Zhang, Jian

    2016-01-01

    Carnosine is a dipeptide that scavenges free radicals, inhibits inflammation in the central nervous system, and protects against ischemic and hypoxic brain damage through its anti-oxidative and anti-apoptotic actions. Therefore, we hypothesized that carnosine would also protect against white matter damage caused by subcortical ischemic injury. White matter damage was induced by right unilateral common carotid artery occlusion in mice. The animals were treated with 200, 500 or 750 mg/kg carnosine by intraperitoneal injection 30 minutes before injury and every other day after injury. Then, 37 days later, Klüver-Barrera staining, toluidine blue staining and immunofluorescence staining were performed. Carnosine (200, 500 mg/kg) substantially reduced damage to the white matter in the corpus callosum, internal capsule and optic tract, and it rescued expression of myelin basic protein, and alleviated the loss of oligodendrocytes. However, carnosine at the higher dose of 750 mg/kg did not have the same effects as the 200 and 500 mg/kg doses. These findings show that carnosine, at a particular dose range, protects against white matter damage caused by chronic cerebral ischemia in mice, likely by reducing oligodendroglial cell loss. PMID:27857746

  10. Catalase prevents elevation of [Ca(2+)](i) induced by alcohol in cultured canine cerebral vascular smooth muscle cells: Possible relationship to alcohol-induced stroke and brain pathology.

    PubMed

    Li, Wenyan; Liu, Weimin; Altura, Bella T; Altura, Burton M

    2003-01-15

    Several studies have suggested that alcohol-induced brain injury is associated with generation of reactive oxygen species (ROS). The recent findings, that antioxidants (Vitamin E and pyrrolidine dithiocarbamate (PDTC)) prevent intracellular Ca(2+) ([Ca(2+)](i)) overload in cerebral vascular smooth muscle cells, induced by alcohol, demonstrate indirectly that ROS formation is related to cerebral vascular injury. The present experiments were designed to test the hypothesis that catalase, an hydrogen peroxide (H(2)O(2)) scavenging enzyme, can prevent or ameliorate alcohol-induced elevation of [Ca(2+)](i). Preincubation of cultured canine cerebral vascular smooth muscle cells with catalase (20-1000 units/ml) didn't produce any apparent changes from controls in resting levels of [Ca(2+)](i) after 1-3 days. Exposure of the cerebral vascular cells to culture media containing 10-100mM ethanol resulted in significant rises in [Ca(2+)](i) (p<0.01). Although exposure of these cells to a low concentration of catalase (20 units/ml) failed to prevent the increased level of [Ca(2+)](i) induced by ethanol, concomitant addition of higher concentrations of catalase (100-1000 units/ml) and ethanol (10-100mM) inhibited or ameliorated the rises of [Ca(2+)](i) induced by ethanol either at 24h or at 3 days, in a concentration-dependent manner. Catalase, in the range of 100-200 units/ml, inhibited approximately 50% of the [Ca(2+)](i) increases caused by ethanol in the first 24h. Catalase at a concentration of 1000 units/ml inhibited completely excessive [Ca(2+)](i) accumulation. The present results when viewed in light of other recently published data suggest that H(2)O(2) generation may be one of the earliest events triggered by alcohol in alcohol-induced brain-vascular damage, neurobehavioral actions and stroke.

  11. [Digital angiography and lipiodol computerized tomography in the anatomopathological framework of hepatocarcinoma].

    PubMed

    Pozzi-Mucelli, R; Pozzi-Mucelli, R; Pagnan, L; Dalla Palma, L

    1994-12-01

    The introduction of therapies other than conventional surgery of hepatocellular carcinoma (HCC) requires an accurate pathologic classification, which is important because it is well known that HCC may have multicentric growth. The Liver Cancer Study Group of Japan has proposed a classification dividing HCCs into three macroscopic forms from the pathologic point of view: nodular, massive and infiltrating HCCs. The nodular type is subdivided into four types: single nodular type, single nodular type with surrounding proliferation, multinodular fused type and multinodular type. Forty-six HCC patients were examined with Lipiodol Computed Tomography (LCT) to investigate the agreement between pathologic and imaging findings. LCT proved to be in close agreement with pathologic findings. Sixteen cases were classified as type I (single nodular type), 8 as type II (single nodular type with limited foci), 1 as type III (multinodular fused type), 18 as type IV (multiple nodular type with diffuse foci) and 3 cases as type V (massive form). No cases of infiltrative forms were observed in our series. Based on LCT findings, the capabilities of digital subtraction angiography (DSA) were studied in the pathologic classification of HCCs. DSA exhibited some limitations in the pathologic classification of HCCs in 5 of 16 patients with type I lesions. In these cases DSA suggested false-positive diagnoses because of regenerative nodules in cirrhotic liver in 3 cases and of daughter nodules (not confirmed at LCT) in 2 cases. In 7 of 8 patients with type II HCCs, DSA failed to show the daughter nodules surrounding the main nodule. In the 18 patients with multiple distant nodules (type IV), DSA was less sensitive in defining nodule number and site. In the massive form, the information obtained with LCT and DSA was comparable. In conclusion, LCT should be considered a basic examination in the study of HCC extent. Based on LCT findings, the most appropriate treatment can be selected, be it

  12. Transarterial Infusion Chemotherapy Using Cisplatin-Lipiodol Suspension With or Without Embolization for Unresectable Hepatocellular Carcinoma

    SciTech Connect

    Kawaoka, Tomokazu; Aikata, Hiroshi Takaki, Shintaro; Katamura, Yoshio; Hiramatsu, Akira; Waki, Koji; Takahashi, Shoichi; Hieda, Masashi; Toyota, Naoyuki; Ito, Katsuhide; Chayama, Kazuaki

    2009-07-15

    We evaluate the long-term prognosis and prognostic factors in patients treated with transarterial infusion chemotherapy using cisplatin-lipiodol (CDDP/LPD) suspension with or without embolization for unresectable hepatocellular carcinoma (HCC). Study subjects were 107 patients with HCC treated with repeated transarterial infusion chemotherapy alone using CDDP/LPD (adjusted as CDDP 10mg/LPD 1ml). The median number of transarterial infusion procedures was two (range, one to nine), the mean dose of CDDP per transarterial infusion chemotherapy session was 30 mg (range, 5.0-67.5 mg), and the median total dose of transarterial infusion chemotherapy per patient was 60 mg (range, 10-390 mg). Survival rates were 86% at 1 year, 40% at 3 years, 20% at 5 years, and 16% at 7 years. For patients with >90% LPD accumulation after the first transarterial infusion chemotherapy, rates were 98% at 1 year, 60% at 3 years, and 22% at 5 years. Multivariate analysis identified >90% LPD accumulation after the first transarterial infusion chemotherapy (p = 0.001), absence of portal vein tumor thrombosis (PVTT; p < 0.001), and Child-Pugh class A (p = 0.012) as independent determinants of survival. Anaphylactic shock was observed in two patients, at the fifth transarterial infusion chemotherapy session in one and the ninth in the other. In conclusion, transarterial infusion chemotherapy with CDDP/LPD appears to be a useful treatment option for patients with unresectable HCC without PVTT and in Child-Pugh class A. LPD accumulation after the first transarterial infusion chemotherapy is an important prognostic factor. Careful consideration should be given to the possibility of anaphylactic shock upon repeat infusion with CDDP/LPD.

  13. Effect of lipiodol and methylene blue on the thoracoscopic preoperative positioning.

    PubMed

    Zhang, Chuan-Yu; Yu, Hua-Long; Liu, Shi-He; Jiang, Gang; Wang, Yong-Jie

    2015-01-01

    The aim of this study was to compare and analyze the site-specific accuracy of mixture of lipiodol and methylene blue (MLM) (0.6 ml, 1:5) and pure methylene blue (0.5 ml) on the rabbit lungs. In this study, CT-guided percutaneous injection of MLM and methylene blue. Compare the staining degree by biopsy of lung tissue. Use 4 points system to evaluate the site-specific accuracy at 6h and 24 h after injection. For MLM, evaluate its radiopacity by radiation. When evaluate the positioning, 2 points mean acceptable, 3 points mean excellent. The results indicated that the staining range of MLM is obvious less than that of methylene blue (0.6 vs. 1.0 cm, P<0.01), but the staining capacity of MLM is higher than that of methylene blue (2.8 vs. 2.2, P = 0.01). About the staining abilities which are evaluated as excellent, MLM group accounts for 81%, methylene blue group accounts for 38% (P = 0.011). About the radiopacity which are evaluated as acceptable or excellent, MLM group accounts for 62%. With good direct vision, the suitable positioning rate of MLM can be 100%, which is better than that of methylene blue. In conclusion, percutaneous injection of MLM can be used to lung positioning. The result shows that use MLM is better than only using methylene blue. But it is necessary to do the investigation in human beings in order to confirm the feasibility of its clinical application.

  14. Effect of lipiodol and methylene blue on the thoracoscopic preoperative positioning

    PubMed Central

    Zhang, Chuan-Yu; Yu, Hua-Long; Liu, Shi-He; Jiang, Gang; Wang, Yong-Jie

    2015-01-01

    The aim of this study was to compare and analyze the site-specific accuracy of mixture of lipiodol and methylene blue (MLM) (0.6 ml, 1:5) and pure methylene blue (0.5 ml) on the rabbit lungs. In this study, CT-guided percutaneous injection of MLM and methylene blue. Compare the staining degree by biopsy of lung tissue. Use 4 points system to evaluate the site-specific accuracy at 6h and 24 h after injection. For MLM, evaluate its radiopacity by radiation. When evaluate the positioning, 2 points mean acceptable, 3 points mean excellent. The results indicated that the staining range of MLM is obvious less than that of methylene blue (0.6 vs. 1.0 cm, P<0.01), but the staining capacity of MLM is higher than that of methylene blue (2.8 vs. 2.2, P = 0.01). About the staining abilities which are evaluated as excellent, MLM group accounts for 81%, methylene blue group accounts for 38% (P = 0.011). About the radiopacity which are evaluated as acceptable or excellent, MLM group accounts for 62%. With good direct vision, the suitable positioning rate of MLM can be 100%, which is better than that of methylene blue. In conclusion, percutaneous injection of MLM can be used to lung positioning. The result shows that use MLM is better than only using methylene blue. But it is necessary to do the investigation in human beings in order to confirm the feasibility of its clinical application. PMID:26221301

  15. Sources of activator calcium for potassium- and serotonin-induced constriction of isolated bovine cerebral arteries

    SciTech Connect

    Not Available

    1986-03-01

    Previous in vitro studies with the calcium channel blockers (CCB) indirectly suggest that K/sup +/ and serotonin (5HT) constrict bovine middle cerebral arteries (BMCA) by promoting the influx of extracellular calcium (Ca) through CCB-sensitive channels. In this study, the authors directly determined the sources of activator Ca for K/sup +/- and 5HT-induced constriction of BMCA, using radiolabelled /sup 4/)2%Ca and /sup 3/H-sorbitol. EGTA-resistant Ca uptake, an estimate of Ca influx into vascular smooth muscle, was determined by exposure to Ca-deficient 2 mM EGTA solutions at 1/sup 0/C. The total Ca content of BMCA was 4.4 nmole/mg (wet wt.) after equilibration at 37/sup 0/C. The total exchangeable Ca content was 1.64 nmole/mg after 1 hr of /sup 45/Ca loading; the Ca content of the extracellular water was 0.30 nmole/mg, as estimated from the /sup 3/H-sorbitol space (0.25 ul/mg). The EGTA-resistant Ca uptake at 1 hr was 134 pmole/mg. K/sup +/ and 5HT significantly increased EGTA-resistant Ca uptake during 5 min of /sup 45/Ca loading; for K/sup +/, Ca uptake increased from 71 to 202 pmole/mg, and for 5HT, from 65 to 102 pmole/mg. Verapamil (10/sup -5/ M) or nifedipine (3.3 x 10/sup -7/ M) significantly blocked the increase in EGTA-resistant Ca uptake induced by K/sup +/ or 5HT. These results provide direct evidence that K/sup +/ or 5HT may constrict BMCA by promoting the influx of extracellular Ca through CCB-sensitive channels.

  16. Cerebral white matter oxidation and nitrosylation in young rodents with kaolin-induced hydrocephalus.

    PubMed

    Del Bigio, Marc R; Khan, Osaama H; da Silva Lopes, Luiza; Juliet, Packiasamy A R

    2012-04-01

    Hydrocephalus is associated with reduced blood flow in periventricular white matter. To investigate hypoxic and oxidative damage in the brains of rats with hydrocephalus, kaolin was injected into the cisterna magna of newborn 7- and 21-day-old Sprague-Dawley rats, and ventricle size was assessed by magnetic resonance imaging at 7, 21, and 42 days of age. In-situ evidence of hypoxia in periventricular capillaries and glial cells was shown by pimonidazole hydrochloride binding. Biochemical assay of thiobarbituric acid reaction and immunohistochemical detection of malondialdehyde and 4-hydroxy-2-nonenal indicated the presence of lipid peroxidation in white matter. Biochemical assay of nitrite indicated increased nitric oxide production. Nitrotyrosine immunohistochemistry showed nitrosylated proteins in white matter reactive microglia and astrocytes. Activities of the antioxidant enzymes catalase and glutathione peroxidase were not increased, and altered hypoxia-inducible factor 1α was not detected by quantitative reverse transcription-polymerase chain reaction. Cerebral vascular endothelial growth factor expression determined by quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay was not changed, but vascular endothelial growth factor immunoreactivity was increased in reactive astrocytes of hydrocephalic white matter. To determine if nitric oxide synthase is involved in the pathogenesis, we induced hydrocephalus in 7-day-old wild-type and neuronal nitric oxide synthase-deficient mice. At 7 days, the wild-type and mutant mice exhibited equally severe ventriculomegaly and no behavioral differences, although increased glial fibrillary acidic protein was less in the mutant mice. We conclude that hypoxia, via peroxidation and nitrosylation, contributes to brain changes in young rodents with hydrocephalus and that compensatory mechanisms are negligible.

  17. Brown propolis attenuates cerebral ischemia-induced oxidative damage via affecting antioxidant enzyme system in mice.

    PubMed

    Bazmandegan, Gholamreza; Boroushaki, Mohammad Taher; Shamsizadeh, Ali; Ayoobi, Fatemeh; Hakimizadeh, Elham; Allahtavakoli, Mohammad

    2017-01-01

    Oxidative stress plays a critical role in ischemic brain injury. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) are the enzymes underlying the endogenous antioxidant mechanisms affected by stroke and are considered as oxidative stress biomarkers. Brown propolis (BP) is a bioactive natural product with a set of biological activities that in turn may differ depending on the area from which the substance is originated. The aim of this study was to investigate the effect of water-extracted brown propolis (WEBPs), from two regions of Iran, against cerebral ischemia-induced oxidative injury in a mouse model of stroke. Experimentally, the chemical characterization and total polyphenol content were determined using GC/MS and Folin-Ciocalteu assay respectively. Seventy-two adult male mice were randomly divided into the surgical sham group, control group (treated with vehicle), and four groups of WEBPs-treated animals. The WEBPs were administered at the doses of 100 and 200mg/kg IP, during four different time points. Oxidative stress biomarkers (SOD and GPx activity, SOD/GPx ratio), lipid peroxidation (LPO) index (malondialdehyde content) and infarct volume were measured 48h post stroke. Behavioral tests were evaluated 24 and 48h after stroke. WEBPs treatment resulted in significant restoration of antioxidant enzymes activity and a subsequent decrease in LPO as well as the infarct volume compared to the control group. Sensory-motor impairment and neurological deficits were improved significantly as well. These results indicate that Iranian BP confers neuroprotection on the stroke-induced neuronal damage via an antioxidant mechanism which seems to be mediated by the endogenous antioxidant system. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. Mas receptor deficiency exacerbates lipopolysaccharide-induced cerebral and systemic inflammation in mice.

    PubMed

    Oliveira-Lima, Onésia C; Pinto, Mauro C X; Duchene, Johan; Qadri, Fatimunnisa; Souza, Laura L; Alenina, Natalia; Bader, Michael; Santos, Robson A S; Carvalho-Tavares, Juliana

    2015-12-01

    Beyond the classical actions of the renin-angiotensin system on the regulation of cardiovascular homeostasis, several studies have shown its involvement in acute and chronic inflammation. The G protein-coupled receptor Mas is a functional binding site for the angiotensin-(1-7); however, its role in the immune system has not been fully elucidated. In this study, we evaluated the effect of genetic deletion of Mas receptor in lipopolysaccharide (LPS)-induced systemic and cerebral inflammation in mice. Inflammatory response was triggered in Mas deficient (Mas(-/-)) and C57BL/6 wild-type (WT) mice (8-12 weeks-old) by intraperitoneal injection of LPS (5 mg/kg). Mas(-/-) mice presented more intense hypothermia compared to WT mice 24 h after LPS injection. Systemically, the bone marrow of Mas(-/-) mice contained a lower number of neutrophils and monocytes 3 h and 24 h after LPS injection, respectively. The plasma levels of inflammatory mediators KC, MCP-1 and IL-10 were higher in Mas(-/-) mice 24 h after LPS injection in comparison to WT. In the brain, Mas(-/-) animals had a significant increase in the number of adherent leukocytes to the brain microvasculature compared to WT mice, as well as, increased number of monocytes and neutrophils recruited to the pia-mater. The elevated number of adherent leukocytes on brain microvasculature in Mas(-/-) mice was associated with increased expression of CD11b - the alpha-subunit of the Mac-1 integrin - in bone marrow neutrophils 3h after LPS injection, and with increased brain levels of chemoattractants KC, MIP-2 and MCP-1, 24 h later. In conclusion, we demonstrated that Mas receptor deficiency results in exacerbated inflammation in LPS-challenged mice, which suggest a potential role for the Mas receptor as a regulator of systemic and brain inflammatory response induced by LPS. Copyright © 2015 Elsevier GmbH. All rights reserved.

  19. Protocatechualdehyde Protects Against Cerebral Ischemia-Reperfusion-Induced Oxidative Injury Via Protein Kinase Cε/Nrf2/HO-1 Pathway.

    PubMed

    Guo, Chao; Wang, Shiquan; Duan, Jialin; Jia, Na; Zhu, Yanrong; Ding, Yi; Guan, Yue; Wei, Guo; Yin, Ying; Xi, Miaomaio; Wen, Aidong

    2017-03-01

    Oxidative stress is closely related to the pathogenesis of ischemic stroke. Protocatechualdehyde (PCA) is a phenolic acid compound that has the putative antioxidant activities. The present study was aimed to investigate the molecular mechanisms involved in the antioxidative effect of PCA against cerebral ischemia/reperfusion (I/R) injury. The experiment stroke model was produced in Sprague-Dawley rats via middle cerebral artery occlusion (MCAO). To model ischemia-like conditions in vitro, differentiated SH-SY5Y cells were exposed to transient oxygen and glucose deprivation (OGD). Treatment with PCA significantly improved neurologic score, reduced infarct volume and necrotic neurons, and also decreased reactive oxygen species (ROS) production, 4-hydroxynonenal (4-HNE), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) contents at 24 h after reperfusion. Meanwhile, PCA significantly increased the transcription nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expressions in the ischemic cerebral cortex as shown by immunofluorescence staining and Western blot analysis. In vitro experiment showed that PCA protected differentiated SH-SY5Y cells against OGD-induced injury. Likewise, PCA also increased markedly the Nrf2 and HO-1 expressions in a dose-dependent manner. The neuroprotection effect of PCA was abolished by knockdown of Nrf2 and HO-1. Moreover, knockdown of protein kinase Cε (PKCε) also blocked PCA-induced Nfr2 nuclear translocation, HO-1 expression, and neuroprotection. Taken together, these results provide evidences that PCA can protect against cerebral ischemia-reperfusion-induced oxidative injury, and the neuroprotective effect involves the PKCε/Nrf2/HO-1 pathway.

  20. 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.

  1. The phosphatidylinositol-3 kinase/Akt pathway mediates geranylgeranylacetone-induced neuroprotection against cerebral infarction in rats.

    PubMed

    Abe, Eiji; Fujiki, Minoru; Nagai, Yasuyuki; Shiqi, Kong; Kubo, Takeshi; Ishii, Keisuke; Abe, Tatsuya; Kobayashi, Hidenori

    2010-05-12

    Previous studies demonstrated the cytoprotective effect of geranylgeranylacetone (GGA), a heat shock protein inducer, against ischemic insult. Phosphatidylinositol-3 kinase/Akt (PI3K/Akt) is thought to be an important factor that mediates neuroprotection. However, the signaling pathways in the brain in vivo after oral GGA administration remain unclear. We measured and compared infarction volumes to investigate the effect of GGA on cerebral infarction induced by permanent middle cerebral artery occlusion in rats. We evaluated the effects of pretreatment with 5-hydroxydecanoate (5HD), a specific mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel inhibitor; diazoxide (DZX), a selective mitoK(ATP) channel opener and wortmannin (Wort), a specific PI3K inhibitor of GGA-induced neuroprotection against infarction volumes. To clarify the relationship between PI3K/Akt activation and neuroprotection, we used immunoblot analysis to determine the amount of p-Akt proteins present after GGA administration with or without Wort treatment. Neuroprotective effects of GGA (pretreatment with a single oral GGA dose (800 mg/kg) 48 h before ischemia) were prevented by 5HD, DZX and Wort pretreatment, which indicates that the selective mitoK(ATP) channel and the PI3K/Akt pathway may mediate GGA-dependent protection. Oral GGA-induced p-Akt and GGA pretreatment enhanced ischemia-induced p-Akt, both of which were prevented by Wort pretreatment. These results suggest that a single oral dose of GGA induces p-Akt and that GGA plays an important role in neuroprotection against cerebral ischemia through the mitoK(ATP) channel opening. (c) 2010 Elsevier B.V. All rights reserved.

  2. Relative cerebral blood volume is a potential biomarker in late delayed radiation-induced brain injury.

    PubMed

    Xie, Ying; Huang, Haiwei; Guo, Junjie; Zhou, Dongxiao

    2017-08-10

    To assess whether relative cerebral blood volume (rCBV) can provide information to reliably evaluate the stages of late delayed radiation-induced brain injury. Forty patients diagnosed with late delayed radiation-induced brain injury were enrolled. The patients were examined using a 1.5T magnetic resonance imaging (MRI) system equipped with an 8-channel head coil. An echo planar imaging (EPI) sequence was used in perfusion-weighted imaging (PWI). The location of 1H-MR spectroscopy scanning was acquired by a point-resolved spectroscopy sequence. Lesions of the temporal lobe were divided into one of two groups according to rCBV value: rCBV<1 (low rCBV [group 1; n = 45]); and rCBV>1 (elevated rCBV [group 2; n = 14]). PWI and MRS parameters, as well as morphological lesion types, in these two groups were compared. Morphological severity was assessed independently and agreed on by two imaging specialists (J.L. and H.X.S., with 16 and 24 years' experience, respectively). If necessary, a third imaging professor (Z.M.H.) with 30 years' experience resolved disagreement(s). Standards for evaluating morphological lesion types were based on previously published criteria. After testing the skewness of data, the Mann-Whitney U-test or Student's t-test was used, as appropriate. rCBV, relative cerebral blood flow (rCBF), and relative mean transit time (rMTT) in group 2 (n = 14) were significantly higher than in group 1 (n = 45) (rCBV: 1.21 ± 0.38 vs. 0.72 ± 0.32, respectively; P < 0.001; rCBF: 1.13 ± 0.02 vs. 0.74 ± 0.04, respectively; P < 0.001; rMTT: 1.10 ± 0.26 vs. 0.96 ± 0.20, P < 0.001). The levels of choline-containing compounds (CHO) / creatine (Cr) and CHO/N-acetylaspartate (NAA) in group 1 were significantly greater than in group 2 (CHO/Cr: 1.89 ± 1.83 vs. 1.22 ± 1.31, respectively; P = 0.016; CHO/NAA: 1.85 ± 3.50 vs. 1.17 ± 0.75, respectively; P = 0.022). More severe morphological lesions were

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-07-12

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

  5. Control of Cerebral Blood Velocity with Furosemide-Induced Hypovolemia and Upright Tilt

    DTIC Science & Technology

    2010-11-25

    cardiovascular and cerebrovascular control mechanisms, subjects abstained from caffeine , exercise, and alcohol for 24 h before the experiment. Additionally...does not necessarily imply unchanging flow. For exam - ple, Heistad and Kontos (17) suggested implicitly that cerebral autoregulation reflects the

  6. HO-1 Signaling Activation by Pterostilbene Treatment Attenuates Mitochondrial Oxidative Damage Induced by Cerebral Ischemia Reperfusion Injury.

    PubMed

    Yang, Yang; Wang, Jiayi; Li, Yue; Fan, Chongxi; Jiang, Shuai; Zhao, Lei; Di, Shouyin; Xin, Zhenlong; Wang, Bodong; Wu, Guiling; Li, Xia; Li, Zhiqing; Gao, Xu; Dong, Yushu; Qu, Yan

    2016-05-01

    Ischemia reperfusion (IR) injury (IRI) is harmful to the cerebral system and causes mitochondrial oxidative stress. The antioxidant response element (ARE)-mediated antioxidant pathway plays an important role in maintaining the redox status of the brain. Heme oxygenase-1 (HO-1), combined with potent AREs in the promoter of HO-1, is a highly effective therapeutic target for protection against cerebral IRI. Pterostilbene (PTE), a natural dimethylated analog of resveratrol from blueberries, is a strong natural antioxidant. PTE has been shown to be beneficial for some nervous system diseases and may regulate HO-1 signaling. This study was designed to investigate the protective effects of PTE on cerebral IRI and to elucidate potential mechanisms underlying those effects. Mouse brains and cultured HT22 neuron cells were subjected to IRI. Prior to this procedure, the brains or cells were exposed to PTE in the absence or presence of the HO-1 inhibitor ZnPP or HO-1 small interfering RNA (siRNA). PTE conferred a cerebral protective effect, as shown by increased neurological scores, viable neurons and decreased brain edema as well as a decreased ion content and apoptotic ratio in vivo. PTE also increased the cell viability and decreased the lactate dehydrogenase (LDH) leakage and apoptotic ratio in vitro. ZnPP and HO-1 siRNA both blocked PTE-mediated cerebral protection by inhibiting HO-1 signaling and further inhibited two HO-1 signaling-related antioxidant molecules: quinone oxidoreductase 1 (NQO1) and glutathione S-transferases (GSTs), which are induced by PTE. PTE also promoted a well-preserved mitochondrial membrane potential (MMP), mitochondria complex I activity, and mitochondria complex IV activity, increased the mitochondrial cytochrome c level, and decreased the cytosolic cytochrome c level. However, this PTE-elevated mitochondrial function was reversed by ZnPP or HO-1 siRNA treatment. In summary, our results demonstrate that PTE treatment attenuates cerebral IRI by

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

    PubMed Central

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

    2014-01-01

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

  8. Multimodal neuroprotection induced by PACAP38 in oxygen-glucose deprivation and middle cerebral artery occlusion stroke models.

    PubMed

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

    2012-11-01

    Pituitary adenylate cyclase activating peptide (PACAP), a potent neuropeptide which crosses the blood-brain barrier, is known to provide neuroprotection in rat stroke models of middle cerebral artery occlusion (MCAO) by mechanism(s) which deserve clarification. We confirmed that following i.v. injection of 30 ng/kg of PACAP38 in rats exposed to 2 h of MCAO focal cerebral ischemia and 48 h reoxygenation, 50 % neuroprotection was measured by reduced caspase-3 activity and volume of cerebral infarction. Similar neuroprotective effects were measured upon PACAP38 treatment of oxygen-glucose deprivation and reoxygenation of brain cortical neurons. The neuroprotection was temporally associated with increased expression of brain-derived neurotrophic factor, phosphorylation of its receptor-tropomyosin-related kinase receptor type B (trkB), activation of phosphoinositide 3-kinase and Akt, and reduction of extracellular signal-regulated kinases 1/2 phosphorylation. PACAP38 increased expression of neuronal markers beta-tubulin III, microtubule-associated protein-2, and growth-associated protein-43. PACAP38 induced stimulation of Rac and suppression of Rho GTPase activities. PACAP38 downregulated the nerve growth factor receptor (p75(NTR)) and associated Nogo-(Neurite outgrowth-A) receptor. Collectively, these in vitro and in vivo results propose that PACAP exhibits neuroprotective effects in cerebral ischemia by three mechanisms: a direct one, mediated by PACAP receptors, and two indirect, induced by neurotrophin release, activation of the trkB receptors and attenuation of neuronal growth inhibitory signaling molecules p75(NTR) and Nogo receptor.

  9. Neuroprotective effects of gallic acid against hypoxia/reoxygenation-induced mitochondrial dysfunctions in vitro and cerebral ischemia/reperfusion injury in vivo.

    PubMed

    Sun, Jing; Li, Yun-Zi; Ding, Yin-Hui; Wang, Jin; Geng, Ji; Yang, Huan; Ren, Jie; Tang, Jin-Yan; Gao, Jing

    2014-11-17

    Oxidative stress and mitochondrial dysfunction are frequently implicated in the pathology of secondary neuronal damage following cerebral ischemia/reperfusion. Recent evidence suggests that gallic acid (GA) reverses oxidative stress in rat model of streptozotocin-induced dementia, but the roles and mechanisms of GA on cerebral ischemia/reperfusion injury remain unknown. Here we investigated the potential roles and mechanisms of GA in hypoxia/reoxygenation induced by sodium hydrosulfite (Na2S2O4) in vitro and cerebral ischemia/reperfusion induced by middle cerebral artery occlusion (MCAO) in vivo. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, 5, 5', 6, 6'-tetrachloro-1, 1', 3, 3'-tetraethylbenzimidazol carbocyanine iodide (JC-1), Dichlorofluorescin diacetate (DCF-DA) and MitoSOX fluorescent assay, Clark-type oxygen electrode, firefly luciferase assay, and calcium-induced mitochondrial swelling were conducted to detect cell death, mitochondrial membrane potential (MMP), intracellular and mitochondrial reactive oxygen species (ROS), oxygen consumption, ATP level, and mitochondrial permeability transition pore (MPTP) viability. We firstly find that modulation of the mitochondrial dysfunction is an important mechanism by GA attenuating hypoxia/reoxygenation insult. To further assess the effects of GA on cerebral ischemia/reperfusion injury, 2, 3, 5-triphenyl-tetrazolium chloride (TTC) staining, dUTP nick-end labeling (TUNEL) assay, and Cytochrome C (Cyt C) release were performed in MCAO rats. The results support that GA is useful against cerebral ischemia/reperfusion injury as a potential protective agent.

  10. PGE(2) -EP(2) signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-κB.

    PubMed

    Aoki, T; Nishimura, M; Matsuoka, T; Yamamoto, K; Furuyashiki, T; Kataoka, H; Kitaoka, S; Ishibashi, R; Ishibazawa, A; Miyamoto, S; Morishita, R; Ando, J; Hashimoto, N; Nozaki, K; Narumiya, S

    2011-07-01

    Cerebral aneurysm is a frequent cerebrovascular event and a major cause of fatal subarachnoid haemorrhage, but there is no medical treatment for this condition. Haemodynamic stress and, recently, chronic inflammation have been proposed as major causes of cerebral aneurysm. Nevertheless, links between haemodynamic stress and chronic inflammation remain ill-defined, and to clarify such links, we evaluated the effects of prostaglandin E(2) (PGE(2) ), a mediator of inflammation, on the formation of cerebral aneurysms. Expression of COX and prostaglandin E synthase (PGES) and PGE receptors were examined in human and rodent cerebral aneurysm. The incidence, size and inflammation of cerebral aneurysms were evaluated in rats treated with COX-2 inhibitors and mice lacking each prostaglandin receptor. Effects of shear stress and PGE receptor signalling on expression of pro-inflammatory molecules were studied in primary cultures of human endothelial cells (ECs). COX-2, microsomal PGES-1 and prostaglandin E receptor 2 (EP(2) ) were induced in ECs in the walls of cerebral aneurysms. Shear stress applied to primary ECs induced COX-2 and EP(2) . Inhibition or loss of COX-2 or EP(2) in vivo attenuated each other's expression, suppressed nuclear factor κB (NF-κB)-mediated chronic inflammation and reduced incidence of cerebral aneurysm. EP(2) stimulation in primary ECs induced NF-κB activation and expression of the chemokine (C-C motif) ligand 2, essential for cerebral aneurysm. These results suggest that shear stress activated PGE(2) -EP(2) pathway in ECs and amplified chronic inflammation via NF-κB. We propose EP(2) as a therapeutic target in cerebral aneurysm. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  11. Toll Like Receptor 4 Affects the Cerebral Biochemical Changes Induced by MPTP Treatment.

    PubMed

    Conte, Carmela; Roscini, Luca; Sardella, Roccaldo; Mariucci, Giuseppina; Scorzoni, Stefania; Beccari, Tommaso; Corte, Laura

    2017-02-01

    The etiology and pathogenesis of Parkinson's disease (PD) are still unclear. However, multiple lines of evidence suggest a critical role of the toll like receptor 4 (TLR4) in inflammatory response and neuronal death. Neuroinflammation may be associated with the misfolding and aggregation of proteins accompanied by a change in their secondary structure. Recent findings also suggest that biochemical perturbations in cerebral lipid content could contribute to the pathogenesis of central nervous system (CNS) disorders, including PD. Thus, it is of great importance to determine the biochemical changes that occur in PD. In this respect, Fourier Transform Infrared (FTIR) spectroscopy represents a useful tool to detect molecular alterations in biological systems in response to stress stimuli. By relying upon FTIR approach, this study was designed to elucidate the potential role of TLR4 in biochemical changes induced by methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin in a mouse model of PD. The analysis of the FTIR spectra was performed in different brain regions of both wild type (WT) and toll like receptor 4-deficient (TLR4(-/-)) mice. It revealed that each brain region exhibited a characteristic molecular fingerprint at baseline, with no significant differences between genotypes. Conversely, WT and TLR4(-/-) mice showed differential biochemical response to MPTP toxicity, principally related to lipid and protein composition. These differences appeared to be characteristic for each brain area. Furthermore, the present study showed that WT mice resulted more vulnerable than TLR4(-/-) animals to striatal dopamine (DA) depletion following MPTP treatment. These results support the hypothesis of a possible involvement of TLR4 in biochemical changes occurring in neurodegeneration.

  12. Aspergillus flavus induces granulomatous cerebral aspergillosis in mice with display of distinct cytokine profile.

    PubMed

    Anand, R; Shankar, J; Tiwary, B N; Singh, A P

    2015-04-01

    Aspergillus flavus is one of the leading Aspergillus spp. resulting in invasive aspergillosis of central nervous system (CNS) in human beings. Immunological status in aspergillosis of central nervous system remains elusive in case of both immunocompetent and immunocompromised patients. Since cytokines are the major mediators of host response, evaluation of disease pathology along with cytokine profile in brain may provide snapshots of neuro-immunological response. An intravenous model of A. flavus infection was utilized to determine the pathogenicity of infection and cytokine profile in the brain of male BALB/c mice. Enumeration of colony forming units and histopathological analyses were performed on the brain tissue at distinct time periods. The kinetics of cytokines (TNF-α, IFN-γ, IL-12/IL-23p40, IL-6, IL-23, IL-17A and IL-4) was evaluated at 6, 12, 24, 48, 72 and 96h post infection (hPI) in brain homogenates using murine cytokine specific enzyme linked immunosorbent assay. Histological analysis exhibited the hyphae with leukocyte infiltrations leading to formation of granulomata along with ischemia and pyknosis of neurons in the brain of infected mice. Diseased mice displayed increased secretion of IFN-γ, IL-12p40 and IL-6 with a concomitant reduction in the secretion of Th2 cytokine IL-4, and Th17 promoting cytokine, IL-23 during the late phase of infection. A.flavus induced inflammatory granulomatous cerebral aspergillosis in mice, characterized by a marked increase in the Th1 cytokines and neurons undergoing necrosis. A marked increase in necrosis of neurons with concurrent inflammatory responses might have led to the host mortality during late phase of infection.

  13. Chronic lead treatment accelerates photochemically induced platelet aggregation in cerebral microvessels of mice, in vivo

    SciTech Connect

    Al Dhaheri, A.H.; El-Sabban, F.; Fahim, M.A.

    1995-04-01

    Effects of two chronic treatment levels with lead on platelet aggregation in cerebral (pial) microcirculation of the mouse were investigated. Exposure to lead was made by subcutaneous injections for 7 days of lead acetate dissolved in 5% glucose solution, vehicle. Two doses of lead were used, a low dose of 0.1 mg/kg and a high dose of 1.0 mg/kg. Adult male mice were divided into three groups, 10 each; one group was injected with vehicle (control), another was injected with the low dose, and the third was injected with the high dose. Additional mice were used for the determination of hematological parameters and for the lead level in serum of the three groups. On the eighth day, platelet aggregation in pial microvessels of these groups of mice was carried out in vivo. Animals were anesthetized (urethane, 1-2 mg/g, ip), the trachea was intubated, and a craniotomy was performed. Platelet aggregation in pial microvessels was induced photochemically, by activation of circulating sodium fluorescein (0.1 mg/25 g, iv) with an intense mercury light. The time required for the first platelet aggregate to appear in pial arterioles was significantly shorter in the lead-treated mice than in control. This effect was in a dose-dependent manner; 113 {+-} 44 sec for low dose and 71 {+-} 18 sec for high dose vs 155 {+-} 25 sec for control, P < 0.02 and P < 0.001, respectively. Between the two lead-treated groups, the high dose significantly (P < 0.05) shortened the time to first aggregate. These data evidenced an increased susceptibility to cerebrovascular thrombosis as a result of exposure to lead. 26 refs., 4 figs., 2 tabs.

  14. Hypothermia-induced ischemic tolerance is associated with Drp1 inhibition in cerebral ischemia-reperfusion injury of mice.

    PubMed

    Tang, Yingying; Liu, Xiaojie; Zhao, Jie; Tan, Xueying; Liu, Bing; Zhang, Gaofeng; Sun, Lixin; Han, Dengyang; Chen, Huailong; Wang, Mingshan

    2016-09-01

    Excessive mitochondrial fission activation has been implicated in cerebral ischemia-reperfusion (IR) injury. Hypothermia is effective in preventing cerebral ischemic damage. However, effects of hypothermia on ischemia-induced mitochondrial fission activation is not well known. Therefore, the aim of this study was to investigate whether hypothermia protect the brain by inhibiting mitochondrial fission-related proteins activation following cerebral IR injury. Adult male C57BL/6 mice were subjected to transient forebrain ischemia induced by 15min of bilateral common carotid artery occlusion (BCCAO). Mice were divided into three groups (n=48 each): Hypothermia (HT) group, with mild hypothermia (32-34°C) for 4h; Normothermia (NT) group, similarly as HT group except for cooling; Sham group, with vessels exposed but without occlusion or cooling. Hematoxylin and eosin (HE), Nissl staining, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and behavioral testing (n=6 each) demonstrated that hypothermia significantly decreased ischemia-induced neuronal injury. The expressions of Dynamin related protein 1 (Drp1) and Cytochrome C (Cyto C) (n=6 each) in mice hippocampus were measured at 3, 6, 24, and 72h of reperfusion. IR injury significantly increased expressions of total Drp1, phosphorylated Drp1 (P-Drp1 S616) and Cyto C under normothermia. However, mild hypothermia inhibited Drp1 activation and Cyto C cytosolic release, preserved neural cells integrity and reduced neuronal necrosis and apoptosis. These findings indicated that mild hypothermia-induced neuroprotective effects against ischemia-reperfusion injury is associated with suppressing mitochondrial fission-related proteins activation and apoptosis execution.

  15. Importance of extracellular Ca2+ and intracellular Ca2+ release in ethanol-induced contraction of cerebral arterial smooth muscle.

    PubMed

    Yang, Z; Wang, J; Zheng, T; Altura, B T; Altura, B M

    2001-07-01

    The present study was designed to investigate the roles of extracellular Ca2+ ([Ca2+]0) influx and intracellular free Ca2+ ([Ca2+]i) release in ethanol-induced contractions of isolated canine cerebral arteries and primary cultured, cerebral vascular smooth muscle cells. Ethanol (20-200 mM) produced significant contractions in isolated canine basilar arterial rings in a concentration-dependent manner. Removal of [Ca2+]0 and pretreatment of canine basilar arterial rings with verapamil (an antagonist of voltage-gated Ca2+ channels), thapsigargin (a selective antagonist of the sarcoplasmic reticulum Ca2+ pump), caffeine plus ryanodine (a specific antagonist of ryanodine-sensitive Ca2+ release), or heparin (an inositol 1,4,5,-trisphosphate [InsP3]-mediated Ca2+ release antagonist) markedly attenuated (approximately 50%-80%) ethanol-induced contractions. The absence of [Ca2+]0 and preincubation of primary single smooth muscle cells obtained from canine basilar arteries with verapamil, thapsigargin, heparin, or caffeine plus ryanodine markedly attenuated (approximately 50%-80%) the transient and sustained elevations in [Ca2+]i induced by ethanol. Results of the present study suggest to us that both Ca2+ influx through voltage-gated Ca2+ channels and Ca2+ release from intracellular stores (both InsP3 sensitive and ryanodine sensitive) are required for ethanol-induced contractions of isolated canine basilar arteries.

  16. Importance of PKC and PI3Ks in ethanol-induced contraction of cerebral arterial smooth muscle.

    PubMed

    Yang, Z W; Wang, J; Zheng, T; Altura, B T; Altura, B M

    2001-05-01

    We investigated the relationships of two potential intracellular signaling pathways, protein kinase C (PKC) and phosphatidylinositol 3-kinases (PI3Ks), to ethanol-induced contractions in cerebral arteries. Ethanol (20-200 mM) induces concentration-dependent constriction in isolated canine basilar arteries that is inhibited in a concentration-dependent manner by pretreatment of these vessels with 10(-9)-10(-3) M Gö-6976 (an antagonist selective for PKC-alpha and PKC-betaI), 10(-10)-10(-4) M bisindolylmaleimide I (a specific antagonist of PKC), and 10(-10)-10(-4) M wortmannin or 10(-8)-10(-2) M LY-294002 (selective antagonists of PI3Ks). Ethanol-induced increases in intracellular Ca(2+) concentration (from approximately 100 to approximately 500 nM) in canine basilar smooth muscle cells are also suppressed markedly (approximately 20-70%) in the presence of a similar concentration range of Gö-6976, bisindolymaleimide I, wortmannin, or LY-294002. This study suggests that activation of PKC isoforms and PI3Ks appears to be an important signaling pathway in ethanol-induced vasoconstriction of cerebral blood vessels.

  17. Apocynin protects against global cerebral ischemia-reperfusion-induced oxidative stress and injury in the gerbil hippocampus.

    PubMed

    Wang, Qun; Tompkins, Kenneth D; Simonyi, Agnes; Korthuis, Ronald J; Sun, Albert Y; Sun, Grace Y

    2006-05-23

    Increased production of reactive oxygen species (ROS) following cerebral ischemia-reperfusion (I/R) is an important underlying cause for neuronal injury leading to delayed neuronal death (DND). In this study, apocynin, a specific inhibitor for NADPH oxidase, was used to test whether suppression of ROS by the NADPH oxidase inhibitor can protect against ischemia-induced ROS generation and decrease DND. Global cerebral ischemia was induced in gerbils by a 5-min occlusion of bilateral common carotid arteries (CCA). Using measurement of 4-hydroxy-2-nonenal (HNE) as a marker for lipid peroxidation, apocynin (5 mg/kg body weight) injected i.p. 30 min prior to ischemia significantly attenuated the early increase in HNE in hippocampus measured at 3 h after I/R. Apocynin also protected against I/R-induced neuronal degeneration and DND, oxidative DNA damage, and glial cell activation. Taken together, the neuroprotective effects of apocynin against ROS production during early phase of I/R and subsequent I/R-induced neuronal damage provide strong evidence that inhibition of NADPH oxidase could be a promising therapeutic mechanism to protect against stroke damage in the brain.

  18. Functional magnetic resonance imaging evaluation of brain function reorganization in cerebral stroke patients after constraint-induced movement therapy.

    PubMed

    Zhao, Jun; Zhang, Tong; Xu, Jianmin; Wang, Mingli; Zhao, Shengjie

    2012-05-25

    In this study, stroke patients received constraint-induced movement therapy for 3 weeks. Before and after constraint-induced movement therapy, the flexibility of their upper limbs on the affected side was assessed using the Wolf motor function test, and daily use of their affected limbs was assessed using the movement activities log, and cerebral functional reorganization was assessed by functional magnetic resonance imaging. The Wolf motor function test score and the movement activities log quantity and quality scores were significantly increased, while action performance time in the Wolf motor function test was significantly decreased after constraint-induced movement therapy. By functional magnetic resonance imaging examination, only scattered activation points were visible on the affected side before therapy. In contrast, the volume of the activated area was increased after therapy. The activation volume in the sensorimotor area was significantly different before and after therapy, and the activation area increased and appeared adjusted. In addition to the activated area around the lesions being decreased, there were also some new activated areas, including the supplementary movement area, premotor area and the ipsilateral sensorimotor area. Our findings indicate that constraint-induced movement therapy significantly improves the movement ability and daily use of the affected upper limbs in stroke patients and promotes cerebral functional reorganization.

  19. Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

    PubMed Central

    Chen, Shao-Jun; Yang, Jia-Fang; Kong, Fan-Ping; Ren, Ji-Long; Hao, Ke; Li, Min; Yuan, Yuan; Chen, Xin-Can; Yu, Ri-Sheng; Li, Jun-Fa; Leng, Gareth; Chen, Xue-Qun; Du, Ji-Zeng

    2014-01-01

    Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: (i) both CRFR1 and AQP4 are expressed; (ii) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca2+, and PKCε; and (iii) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1+ and AQP4+, we show that transfected CRFR1+ contributes to edema via transfected AQP4+. In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema. PMID:25146699

  20. Electroacupuncture-induced neuroprotection against focal cerebral ischemia in the rat is mediated by adenosine A1 receptors

    PubMed Central

    Dai, Qin-xue; Geng, Wu-jun; Zhuang, Xiu-xiu; Wang, Hong-fa; Mo, Yun-chang; Xin, He; Chen, Jiang-fan; Wang, Jun-lu

    2017-01-01

    The activation of adenosine A1 receptors is important for protecting against ischemic brain injury and pretreatment with electroacupuncture has been shown to mitigate ischemic brain insult. The aim of this study was to test whether the adenosine A1 receptor mediates electroacupuncture pretreatment-induced neuroprotection against ischemic brain injury. We first performed 30 minutes of electroacupuncture pretreatment at the Baihui acupoint (GV20), delivered with a current of 1 mA, a frequency of 2/15 Hz, and a depth of 1 mm. High-performance liquid chromatography found that adenosine triphosphate and adenosine levels peaked in the cerebral cortex at 15 minutes and 120 minutes after electroacupuncture pretreatment, respectively. We further examined the effect of 15 or 120 minutes electroacupuncture treatment on ischemic brain injury in a rat middle cerebral artery-occlusion model. We found that at 24 hours reperfusion,120 minutes after electroacupuncture pretreatment, but not for 15 minutes, significantly reduced behavioral deficits and infarct volumes. Last, we demonstrated that the protective effect gained by 120 minutes after electroacupuncture treatment before ischemic injury was abolished by pretreatment with the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (1 mg/kg, intraperitoneally). Our results suggest that pretreatment with electroacupuncture at the Baihui acupoint elicits protection against transient cerebral ischemia via action at adenosine A1 receptors. PMID:28400804

  1. Treatment with dehydroepiandrosterone increases peripheral benzodiazepine receptors of mitochondria from cerebral cortex in D-galactose-induced aged rats.

    PubMed

    Chen, Chunfu; Lang, Senyang; Zuo, Pingping; Yang, Nan; Wang, Xiangqing

    2008-12-01

    The aim of this study was to determine whether dehydroepiandrosterone (DHEA) could regulate the expression of peripheral benzodiazepine receptors of mitochondria in cerebral cortex. The rats were divided into five groups. Those, in the vehicle-physiological or senescent group, received physiological or d-galactose (subcutaneously) once a day. Rats, in the vehicle-dimethyl sulfoxide- or DHEA-treated senescent group, received 2% of dimethyl sulfoxide or DHEA (intraperitoneally) every other day besides D-galactose (subcutaneously) once a day. Rats in the DHEA-treated normal group received physiological once a day and DHEA every other day. After 8-week, spatial learning was assessed for 5 days by water maze methods. Following behavioural testing, the cerebral cortex mitochondria were purified for PK11195 binding analysis. When compared to the respective vehicle, D-galactose alone induced a significant impairment in water maze performance accompanied by a reduction (30.7%) in peripheral benzodiazepine receptor density of mitochondria, and DHEA displayed a significant enhancement in learning memory accompanied by the elevation (18.3%) of peripheral benzodiazepine receptor density but not affinity in senescent rats. DHEA showed insignificant effects on both learning/memory ability and peripheral benzodiazepine receptors in normal rats when compared to physiological saline. These results suggest that chronic treatment with DHEA enhance cognitive function and increase peripheral benzodiazepine receptor density in cerebral cortex mitochondria in middle-aged senescent rats.

  2. Intra-carotid cold magnesium sulfate infusion induces selective cerebral hypothermia and neuroprotection in rats with transient middle cerebral artery occlusion.

    PubMed

    Song, Wei; Wu, Yong-Ming; Ji, Zhong; Ji, Ya-Bin; Wang, Sheng-Nan; Pan, Su-Yue

    2013-04-01

    Local hypothermia induced by intra-arterial infusion of cold saline reduces brain injury in ischemic stroke. Administration of magnesium sulfate through the internal carotid artery is also known to reduce ischemic brain damage. The neuroprotective effects of combination therapy with local endovascular hypothermia and intra-carotid magnesium sulfate infusion has not been evaluated. The aim of the study was to determine whether infusion of intra-carotid cold magnesium offers neuroprotective efficacy superior to cold saline infusion alone. Sixty-eight Sprague-Dawley rats were subjected to 3 h of middle cerebral artery occlusion and were randomly divided into six groups: sham-operated group; stroke control group; local cold magnesium infusion group; local cold saline infusion group; local normothermic magnesium infusion group; and local normothermic saline infusion group. Before reperfusion, ischemic rats received local infusion or no treatment. Infarct volume, neurological deficit, and brain water content were evaluated at 48 h after reperfusion. Selective brain hypothermia (33-34 °C) was successfully induced by intra-carotid cold infusion. Local cold saline infusion and local cold magnesium infusion reduced the infarct volumes by 48 % (p < 0.001) and 65 % (p < 0.001), respectively, compared with stroke controls. Brain water content was decreased significantly in animals treated with local cold magnesium infusion. Furthermore, the rats given a local cold magnesium infusion had the best neurological outcome. Local normothermic infusion failed to improve ischemic brain damage. These data suggest that local hypothermia induced by intra-carotid administration of cold magnesium is more effective in reducing acute ischemic damage than infusion of cold saline alone.

  3. Neuroprotective effects of the P2 receptor antagonist PPADS on focal cerebral ischaemia-induced injury in rats.

    PubMed

    Lämmer, A; Günther, A; Beck, A; Krügel, U; Kittner, H; Schneider, D; Illes, P; Franke, H

    2006-05-01

    After acute injury of the central nervous system extracellular adenosine 5'-triphosphate (ATP) can reach high concentrations as a result of cell damage and subsequent increase in membrane permeability. Released ATP may act as a toxic agent, which causes cellular degeneration and death, mediated through P2X and P2Y receptors. Mechanisms underlying the various effects of purinoceptor modulators in models of cerebral damage are still uncertain. In the present study the effect of P2 receptor inhibition after permanent middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats was investigated. Rats received either the non-selective P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) or artificial cerebrospinal fluid (ACSF) as control by the intracerebroventricular route. First, these treatments were administered 10 min before MCAO and subsequently twice daily for 1 or 7 days after MCAO. The functional recovery of motor and cognitive deficits was tested at an elevated T-labyrinth. The PPADS-treated group showed a significant reduction of paresis-induced sideslips compared with ACSF-treated animals. Infarct volume was reduced in the PPADS group in comparison with the ACSF group. A significant decrease in intermediately and profoundly injured cells in favour of intact cells in the PPADS group was revealed by quantification of celestine blue/acid fuchsin-stained cells in the peri-infarct area. The data provide further evidence for the involvement of P2 receptors in the pathophysiology of cerebral ischaemia in vivo. The inhibition of P2 receptors at least partially reduces functional and morphological deficits after an acute cerebral ischaemic event.

  4. Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model.

    PubMed

    Rao, Geeta; Xie, Jun; Hedrick, Andria; Awasthi, Vibhudutta

    2015-12-01

    Maintenance of cerebral viability and function is an important goal of critical care in victims of injury due to ischemia and hypovolemia. As part of the multiple organ dysfunction syndrome, the brain function after trauma is influenced by the systemic inflammatory response. We investigated the effect of EF24, an anti-inflammatory bis-chalcone, on cerebral bioenergetics in a rat model of 45% hemorrhagic shock. The rats were treated with EF24 (0.4 mg/kg) or EF24 with an artificial oxygen carrier liposome-encapsulated hemoglobin (LEH). The volume of LEH administered was equal to the shed blood. The brain was collected after 6 h of shock for biochemical assays. EF24 treatment showed significant recovery of ATP, phosphocreatine, and NAD/NADH ratio. It also increased citrate synthase activity and cytochrome c oxidase subunit IV expression which were reduced in shock brain. Furthermore, it reduced the shock-induced accumulation of pyruvate and pyruvate dehydrogenase kinase-1 expression, suggesting that EF24 treatment improves cerebral energetics by restoring perturbed pyruvate metabolism in the mitochondria. These effects of EF24 were associated with reduced poly(ADP-ribose) polymerase cleavage and a significant improvement in the levels of nerve growth factor and brain-derived neurotrophic factor in shock brain. Co-administration of LEH with EF24 was only marginally more effective as compared to the treatment with EF24 alone. These results show that EF24 treatment sets up a pro-survival phenotype in shock by resurrecting cerebral bioenergetics. Since EF24 was effective in the absence of accompanying fluid resuscitation, it has potential utility as a pre-hospital pharmacotherapy in shock due to accidental blood loss.

  5. Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer's disease rat model

    NASA Astrophysics Data System (ADS)

    Lin, Wei-Ting; Chen, Ran-Chou; Lu, Wen-Wei; Liu, Shing-Hwa; Yang, Feng-Yi

    2015-04-01

    The protein expressions of neurotrophic factors can be enhanced by low-intensity pulsed ultrasound (LIPUS) stimulation in the brain. The purpose of this study was to demonstrate the protective effect of LIPUS stimulation against aluminum-induced cerebral damage in Alzheimer's disease rat model. LIPUS was administered 7 days before each aluminum chloride (AlCl3) administration, and concomitantly given with AlCl3 daily for a period of 6 weeks. Neurotrophic factors in hippocampus were measured by western blot analysis. Behavioral changes in the Morris water maze and elevated plus maze were examined in rats after administration of AlCl3. Various biochemical analyses were performed to evaluate the extent of brain damages. LIPUS is capable of prompting levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in rat brain. AlCl3 administration resulted in a significant increase in the aluminum concentration, acetylcholinesterase activity and beta-amyloid (Aβ) deposition in AlCl3 treated rats. LIPUS stimulation significantly attenuated aluminum concentration, acetylcholinesterase activity, Aβ deposition and karyopyknosis in AlCl3 treated rats. Furthermore, LIPUS significantly improved memory retention in AlCl3-induced memory impairment. These experimental results indicate that LIPUS has neuroprotective effects against AlCl3-induced cerebral damages and cognitive dysfunction.

  6. Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer's disease rat model

    PubMed Central

    Lin, Wei-Ting; Chen, Ran-Chou; Lu, Wen-Wei; Liu, Shing-Hwa; Yang, Feng-Yi

    2015-01-01

    The protein expressions of neurotrophic factors can be enhanced by low-intensity pulsed ultrasound (LIPUS) stimulation in the brain. The purpose of this study was to demonstrate the protective effect of LIPUS stimulation against aluminum-induced cerebral damage in Alzheimer's disease rat model. LIPUS was administered 7 days before each aluminum chloride (AlCl3) administration, and concomitantly given with AlCl3 daily for a period of 6 weeks. Neurotrophic factors in hippocampus were measured by western blot analysis. Behavioral changes in the Morris water maze and elevated plus maze were examined in rats after administration of AlCl3. Various biochemical analyses were performed to evaluate the extent of brain damages. LIPUS is capable of prompting levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in rat brain. AlCl3 administration resulted in a significant increase in the aluminum concentration, acetylcholinesterase activity and beta-amyloid (Aβ) deposition in AlCl3 treated rats. LIPUS stimulation significantly attenuated aluminum concentration, acetylcholinesterase activity, Aβ deposition and karyopyknosis in AlCl3 treated rats. Furthermore, LIPUS significantly improved memory retention in AlCl3-induced memory impairment. These experimental results indicate that LIPUS has neuroprotective effects against AlCl3-induced cerebral damages and cognitive dysfunction. PMID:25873429

  7. Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer's disease rat model.

    PubMed

    Lin, Wei-Ting; Chen, Ran-Chou; Lu, Wen-Wei; Liu, Shing-Hwa; Yang, Feng-Yi

    2015-04-15

    The protein expressions of neurotrophic factors can be enhanced by low-intensity pulsed ultrasound (LIPUS) stimulation in the brain. The purpose of this study was to demonstrate the protective effect of LIPUS stimulation against aluminum-induced cerebral damage in Alzheimer's disease rat model. LIPUS was administered 7 days before each aluminum chloride (AlCl3) administration, and concomitantly given with AlCl3 daily for a period of 6 weeks. Neurotrophic factors in hippocampus were measured by western blot analysis. Behavioral changes in the Morris water maze and elevated plus maze were examined in rats after administration of AlCl3. Various biochemical analyses were performed to evaluate the extent of brain damages. LIPUS is capable of prompting levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in rat brain. AlCl3 administration resulted in a significant increase in the aluminum concentration, acetylcholinesterase activity and beta-amyloid (Aβ) deposition in AlCl3 treated rats. LIPUS stimulation significantly attenuated aluminum concentration, acetylcholinesterase activity, Aβ deposition and karyopyknosis in AlCl3 treated rats. Furthermore, LIPUS significantly improved memory retention in AlCl3-induced memory impairment. These experimental results indicate that LIPUS has neuroprotective effects against AlCl3-induced cerebral damages and cognitive dysfunction.

  8. Anti-inflammation and antioxidant effect of Cordymin, a peptide purified from the medicinal mushroom Cordyceps sinensis, in middle cerebral artery occlusion-induced focal cerebral ischemia in rats.

    PubMed

    Wang, Jie; Liu, Yong-Mei; Cao, Wei; Yao, Kui-Wu; Liu, Zhen-Quan; Guo, Jian-You

    2012-06-01

    Cordymin is a peptide purified from the medicinal mushroom Cordyceps sinensis. The present study investigated the effects of Cordymin in prevention of focal cerebral ischemic/reperfusion (IR) injury. The right middle cerebral artery occlusion model was used in the study. The effects of Cordymin on mortality rate, neurobehavior, grip strength, glutathione content, lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na(+)K(+)ATPase activity glutathione S transferase activity and on the regulation of C3 and C4 protein level, polymorphonuclear cells, interleukin-1β and tumor necrosis factor-α in a rat model were studied respectively. Treatment (orally) of Cordymin significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. Moreover, Cordymin significantly inhibited infiltration of polymorphonuclear cells and IR-induced up-regulation of the brain production of C3 protein level, interleukin-1β and tumor necrosis factor-α. Cordymin significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. Our findings suggest that cordymin have a neuroprotective effect in the ischemic brain, which is due to the inhibition of inflammation and increase of antioxidants activity related to lesion pathogenesis. Cordymin can be used as potential preventive agent against cerebral ischemia-reperfusion injury.

  9. Modified Constraint-Induced Therapy for Children with Hemiplegic Cerebral Palsy: A Randomized Trial

    ERIC Educational Resources Information Center

    Wallen, Margaret; Ziviani, Jenny; Naylor, Olivia; Evans, Ruth; Novak, Iona; Herbert, Robert D.

    2011-01-01

    Aim: Conventional constraint-based therapies are intensive and demanding to implement, particularly for children. Modified forms of constraint-based therapies that are family-centred may be more acceptable and feasible for families of children with cerebral palsy (CP)-but require rigorous evaluation using randomized trials. The aim of this study…

  10. Modified Constraint-Induced Therapy for Children with Hemiplegic Cerebral Palsy: A Randomized Trial

    ERIC Educational Resources Information Center

    Wallen, Margaret; Ziviani, Jenny; Naylor, Olivia; Evans, Ruth; Novak, Iona; Herbert, Robert D.

    2011-01-01

    Aim: Conventional constraint-based therapies are intensive and demanding to implement, particularly for children. Modified forms of constraint-based therapies that are family-centred may be more acceptable and feasible for families of children with cerebral palsy (CP)-but require rigorous evaluation using randomized trials. The aim of this study…

  11. Mirror Visual Feedback Induces Lower Neuromuscular Activity in Children with Spastic Hemiparetic Cerebral Palsy

    ERIC Educational Resources Information Center

    Feltham, Max G.; Ledebt, Annick; Deconinck, Frederik J. A.; Savelsbergh, Geert J. P.

    2010-01-01

    The study examined the effects of mirror feedback information on neuromuscular activation during bimanual coordination in eight children with spastic hemiparetic cerebral palsy (SHCP) and a matched control group. The "mirror box" creates a visual illusion, which gives rise to a visual perception of a zero lag, symmetric movement between the two…

  12. Mirror Visual Feedback Induces Lower Neuromuscular Activity in Children with Spastic Hemiparetic Cerebral Palsy

    ERIC Educational Resources Information Center

    Feltham, Max G.; Ledebt, Annick; Deconinck, Frederik J. A.; Savelsbergh, Geert J. P.

    2010-01-01

    The study examined the effects of mirror feedback information on neuromuscular activation during bimanual coordination in eight children with spastic hemiparetic cerebral palsy (SHCP) and a matched control group. The "mirror box" creates a visual illusion, which gives rise to a visual perception of a zero lag, symmetric movement between the two…

  13. Neprilysin protects against cerebral amyloid angiopathy and Aβ-induced degeneration of cerebrovascular smooth muscle cells.

    PubMed

    Miners, James Scott; Kehoe, Patrick; Love, Seth

    2011-09-01

    Neprilysin (NEP), which degrades amyloid-β (Aβ), is expressed by neurons and cerebrovascular smooth muscle cells (CVSMCs). NEP immunolabeling is reduced within cerebral blood vessels of Alzheimer's disease (AD) patients with cerebral amyloid angiopathy (CAA). We have now measured NEP enzyme activity in leptomeningeal and purified cerebral cortical blood vessel preparations from control and AD patients with and without CAA. Measurements were adjusted for smooth muscle actin (SMA) to control for variations in CVSMC content. NEP activity was reduced in CAA, in both controls and AD. In leptomeningeal vessels, NEP activity was related to APOE genotype, being highest in ε2-positive and lowest in ε4-positive brains. To assess the role of NEP in protecting CVSMCs from Aβ toxicity, we measured cell death in primary human adult CVSMCs exposed to Aβ(1-40) , Aβ(1-42) or Aβ(1-40(Dutch variant)) . Aβ(1-42) was most cytotoxic to CVSMCs. Aβ(1-42) -mediated cell death was increased following siRNA-mediated knockdown or thiorphan-mediated inhibition of NEP activity; conversely Aβ(1-42) -mediated cytotoxicity was reduced by the addition of somatostatin and NEP over-expression following transfection with NEP cDNA. Our findings suggest that NEP protects CVSMCs from Aβ toxicity and protects cerebral blood vessels from the development and complications of CAA.

  14. Preparation and Characterization of Hyaluronic Acid-Polycaprolactone Copolymer Micelles for the Drug Delivery of Radioactive Iodine-131 Labeled Lipiodol

    PubMed Central

    Chen, Shih-Cheng; Yang, Ming-Hui; Chung, Tze-Wen; Jhuang, Ting-Syuan; Yang, Jean-Dean; Chen, Ko-Chin; Chen, Wan-Jou; Huang, Ying-Fong; Jong, Shiang-Bin; Tsai, Wan-Chi; Lin, Po-Chiao

    2017-01-01

    Micelles, with the structure of amphiphilic molecules including a hydrophilic head and a hydrophobic tail, are recently developed as nanocarriers for the delivery of drugs with poor solubility. In addition, micelles have shown many advantages, such as enhanced permeation and retention (EPR) effects, prolonged circulation times, and increased endocytosis through surface modification. In this study, we measured the critical micelle concentrations, diameters, stability, and cytotoxicity and the cell uptake of micelles against hepatic cells with two kinds of hydrophilic materials: PEG-PCL and HA-g-PCL. We used 131I as a radioactive tracer to evaluate the stability, drug delivery, and cell uptake activity of the micelles. The results showed that HA-g-PCL micelles exhibited higher drug encapsulation efficiency and stability in aqueous solutions. In addition, the 131I-lipiodol loaded HA-g-PCL micelles had better affinity and higher cytotoxicity compared to HepG2 cells. PMID:28127555

  15. Cholinergic receptor blockade by scopolamine and mecamylamine exacerbates global cerebral ischemia induced memory dysfunction in C57BL/6J mice.

    PubMed

    Ray, R S; Rai, S; Katyal, A

    2014-12-01

    Global cerebral ischemia/reperfusion (GCI/R) injury encompasses complex pathophysiological sequalae, inducing loss of hippocampal neurons and behavioural deficits. Progressive neuronal death and memory dysfunctions culminate from several different mechanisms like oxidative stress, excitotoxicity, neuroinflammation and cholinergic hypofunction. Experimental evidences point to the beneficial effects of cholinomimetic agents such as rivastigmine and galantamine in improving memory outcomes following GCI/R injury. However, the direct implications of muscarinic and nicotinic receptor blockade during global cerebral ischemia/reperfusion injury have not been investigated. Therefore, we evaluated the relative involvement of muscarinic and nicotinic receptors in spatial/associative memory functions and neuronal damage during global cerebral ischemia reperfusion injury. The outcomes of present study support the idea that preservation of both muscarinic and nicotinic receptor functions is essential to alleviate hippocampal neuronal death in CA1 region following global cerebral ischemia/reperfusion injury.

  16. Successful treatment of refractory cerebral oedema in ecstasy/cocaine-induced fulminant hepatic failure using a new high-efficacy liver detoxification device (FPSA-Prometheus).

    PubMed

    Kramer, Ludwig; Bauer, Edith; Schenk, Peter; Steininger, Rudolf; Vigl, Marion; Mallek, Reinhold

    2003-09-15

    Ecstasy-induced fulminant hepatic failure is associated with high mortality. If complicated by cerebral oedema, orthotopic liver transplantation is the only established treatment. We report a case of combined ecstasy/cocaine-induced fulminant hepatic failure presenting with severe rhabdomyolysis, myocardial infarction and multiorgan failure. Transplantation was declined by the transplant surgeons because of a history of intravenous drug abuse. As excessive hyperammonaemia (318 mumol/l) and refractory transtentorial herniation developed, treatment with a new liver detoxification device combining high-flux haemodialysis and adsorption (FPSA-Prometheus) was initiated. Within a few hours of treatment, ammonia levels normalised. Cerebral oedema was greatly reduced by day 4 and hepatic function gradually recovered. Following neurologic rehabilitation for ischaemic sequelae of herniation, the patient was discharged from hospital with only minimal deficits. In conclusion, efficient extracorporeal detoxification may be an option for reversal of hyperammonaemia and refractory cerebral oedema in ecstasy/cocaine-induced acute liver failure.

  17. Intra-arterial iodine 131-labeled lipiodol as adjuvant therapy after curative liver resection for hepatocellular carcinoma: a phase 2 clinical study.

    PubMed

    Partensky, C; Sassolas, G; Henry, L; Paliard, P; Maddern, G J

    2000-11-01

    Intra-arterial lipiodol labeled with iodine 131 ((131)I-lipiodol) can be safely used as adjuvant therapy following curative liver resection for hepatocellular carcinoma (HCC). Phase 2 pilot study. Large teaching hospital. Twenty-eight patients (24 men and 4 women; median age, 61.5 years; range, 33-75 years) were treated from January 1991 to June 1997. The liver was cirrhotic in 7 cases and noncirrhotic in 21 cases. An equal number of 14 patients underwent a major and a minor resection, all with clear margins. Median diameter of solitary tumors or the larger tumor when multiple tumors occurred was 5.5 cm (range, 2.5-29 cm). Tumor encapsulation was present in 12 cases and absent in 16 cases. After informed consent, patients who had no evidence of residual or recurrent tumor on computed tomographic (CT) scan and no sign of liver failure 2 to 3 months after curative resection for HCC were included in the trial. Complete follow-up was obtained (median, 51 months; range, 5-93 months). A 1110-MBq dose of (131)I-lipiodol was administered into the hepatic artery using the Seldinger technique. Patients were kept in a radio-protected room for 5 days. Postinjection radioactive whole scintiscan was performed at 5 days and an abdominal CT scan at 1 month after the injection. A second injection was performed in 16 patients 2 years later using the same protocol. Procedure safety. All patients experienced transient fever during the first 12 hours following injection. There were no noted adverse clinical effects or significant alteration in hepatic function due to the procedure or at immediate and late follow-up. The radioactive scan demonstrated an intense liver uptake, which was homogeneous in 19 cases and heterogeneous in 9. Mild detectable thyroid and lung uptake occurred in 50% of cases. No lipiodol liver fixation was observed on the 1-month CT scan. At the time of follow-up, 6 patients had died and 12 had developed recurrences, with 5 of the 6 deaths belonging to the recurrent

  18. Target localization of 3D versus 4D cone beam computed tomography in lipiodol-guided stereotactic radiotherapy of hepatocellular carcinomas.

    PubMed

    Chan, Mark; Chiang, Chi Leung; Lee, Venus; Cheung, Steven; Leung, Ronnie; Wong, Matthew; Lee, Frankle; Blanck, Oliver

    2017-01-01

    Aim of this study was to comparatively evaluate the accuracy of respiration-correlated (4D) and uncorrelated (3D) cone beam computed tomography (CBCT) in localizing lipiodolized hepatocellular carcinomas during stereotactic body radiotherapy (SBRT). 4D-CBCT scans of eighteen HCCs were acquired during free-breathing SBRT following trans-arterial chemo-embolization (TACE) with lipiodol. Approximately 1320 x-ray projections per 4D-CBCT were collected and phase-sorted into ten bins. A 4D registration workflow was followed to register the reconstructed time-weighted average CBCT with the planning mid-ventilation (MidV) CT by an initial bone registration of the vertebrae and then tissue registration of the lipiodol. For comparison, projections of each 4D-CBCT were combined to synthesize 3D-CBCT without phase-sorting. Using the lipiodolized tumor, uncertainties of the treatment setup estimated from the absolute and relative lipiodol position to bone were analyzed separately for 4D- and 3D-CBCT. Qualitatively, 3D-CBCT showed better lipiodol contrast than 4D-CBCT primarily because of a tenfold increase of projections used for reconstruction. Motion artifact was observed to subside in 4D-CBCT compared to 3D-CBCT. Group mean, systematic and random errors estimated from 4D- and 3D-CBCT agreed to within 1 mm in the cranio-caudal (CC) and 0.5 mm in the anterior-posterior (AP) and left-right (LR) directions. Systematic and random errors are largest in the CC direction, amounting to 4.7 mm and 3.7 mm from 3D-CBCT and 5.6 mm and 3.8 mm from 4D-CBCT, respectively. Safety margin calculated from 3D-CBCT and 4D-CBCT differed by 2.1, 0.1 and 0.0 mm in the CC, AP, and LR directions. 3D-CBCT is an adequate alternative to 4D-CBCT when lipoid is used for localizing HCC during free-breathing SBRT. Similar margins are anticipated with 3D- and 4D-CBCT.

  19. Meta-analysis of interstitial pneumonia in studies evaluating iodine-131-labeled lipiodol for hepatocellular carcinoma using exact likelihood approach.

    PubMed

    Oger, Emmanuel; Lavenu, Audrey; Bellissant, Eric; Garin, Etienne; Polard, Elisabeth

    2011-09-01

    Iodine-131-labeled lipiodol is currently licensed for unresectable hepatocellular carcinoma with portal thrombosis. It is thought to be well tolerated. Cases of interstitial pneumonia have been reported, but their frequency (≈2%) has not been well estimated. Quantifying adverse drug event frequency requires an appropriate statistical approach because standard methods are biased. To estimate the frequency of interstitial pneumonia in patients with hepatocellular carcinoma receiving iodine-131-labeled lipiodol, we conducted a systematic review of English articles using MEDLINE and EMBASE. All types of articles were considered except case reports. Primary outcome measure was symptomatic interstitial pneumonia based on investigators' judgment. All pooled analyses were based on a random effects meta-analysis model using an exact likelihood approach based on the binomial within-study distribution. Ten studies, including 142 patients, used low activity per dose, ranging from 0.3 to 1.1 GBq. No respiratory adverse event was noticed in these studies. Eighteen studies, including 542 patients, evaluated higher activity per dose, around 2.2 GBq; 24 cases of interstitial pneumonia were reported in these studies. Estimated frequency of interstitial pneumonia was 1.6% (95%CI, 0.4-6.4%) after one high dose and 4.1% (95%CI, 1.0-16.0%) after two or more high doses. The frequency of interstitial pneumonia appears higher and more precise than previously estimated. The risk appears to be related to the number of injections and the dose level per injection. Generalized linear mixed models using the exact binomial within-study distribution initially described to summarize data on diagnostic evaluation could be relevant for drug-related adverse reaction frequency assessment. Copyright © 2011 John Wiley & Sons, Ltd.

  20. Intracerebral Glycine Administration Impairs Energy and Redox Homeostasis and Induces Glial Reactivity in Cerebral Cortex of Newborn Rats.

    PubMed

    Moura, Alana Pimentel; Parmeggiani, Belisa; Grings, Mateus; Alvorcem, Leonardo de Moura; Boldrini, Rafael Mello; Bumbel, Anna Paula; Motta, Marcela Moreira; Seminotti, Bianca; Wajner, Moacir; Leipnitz, Guilhian

    2016-11-01

    Accumulation of glycine (GLY) is the biochemical hallmark of glycine encephalopathy (GE), an aminoacidopathy characterized by severe neurological dysfunction that may lead to early death. In the present study, we evaluated the effect of a single intracerebroventricular administration of GLY on bioenergetics, redox homeostasis, and histopathology in brain of neonatal rats. Our results demonstrated that GLY decreased the activities of the respiratory chain complex IV and creatine kinase, induced reactive species generation, and diminished glutathione (GSH) levels 1, 5, and 10 days after GLY injection in cerebral cortex of 1-day-old rats. GLY also increased malondialdehyde (MDA) levels 5 days after GLY infusion in this brain region. Furthermore, GLY differentially modulated the activities of superoxide dismutase, catalase, and glutathione peroxidase depending on the period tested after GLY administration. In contrast, bioenergetics and redox parameters were not altered in brain of 5-day-old rats. Regarding the histopathological analysis, GLY increased S100β staining in cerebral cortex and striatum, and GFAP in corpus callosum of 1-day-old rats 5 days after injection. Finally, we verified that melatonin prevented the decrease of complex IV and CK activities and GSH concentrations, and the increase of MDA levels and S100β staining caused by GLY. Based on our findings, it may be presumed that impairment of redox and energy homeostasis and glial reactivity induced by GLY may contribute to the neurological dysfunction observed in GE.

  1. Neuroplastic Sensorimotor Resting State Network Reorganization in Children With Hemiplegic Cerebral Palsy Treated With Constraint-Induced Movement Therapy.

    PubMed

    Manning, Kathryn Y; Menon, Ravi S; Gorter, Jan Willem; Mesterman, Ronit; Campbell, Craig; Switzer, Lauren; Fehlings, Darcy

    2016-02-01

    Using resting state functional magnetic resonance imaging (MRI), we aim to understand the neurologic basis of improved function in children with hemiplegic cerebral palsy treated with constraint-induced movement therapy. Eleven children including 4 untreated comparison subjects diagnosed with hemiplegic cerebral palsy were recruited from 3 clinical centers. MRI and clinical data were gathered at baseline and 1 month for both groups, and 6 months later for the case group only. After constraint therapy, the sensorimotor resting state network became more bilateral, with balanced contributions from each hemisphere, which was sustained 6 months later. Sensorimotor resting state network reorganization after therapy was correlated with a change in the Quality of Upper Extremity Skills Test score at 1 month (r = 0.79, P = .06), and Canadian Occupational Performance Measure scores at 6 months (r = 0.82, P = .05). This clinically correlated resting state network reorganization provides further evidence of the neuroplastic mechanisms underlying constraint-induced movement therapy. © The Author(s) 2015.

  2. FNIRS-based evaluation of cortical plasticity in children with cerebral palsy undergoing constraint-induced movement therapy

    NASA Astrophysics Data System (ADS)

    Cao, Jianwei; Khan, Bilal; Hervey, Nathan; Tian, Fenghua; Delgado, Mauricio R.; Clegg, Nancy J.; Smith, Linsley; Roberts, Heather; Tulchin-Francis, Kirsten; Shierk, Angela; Shagman, Laura; MacFarlane, Duncan; Liu, Hanli; Alexandrakis, George

    2015-03-01

    Sensorimotor cortex plasticity induced by constraint-induced movement therapy (CIMT) in six children (10.2 ± 2.1 years old) with hemiplegic cerebral palsy (CP) was assessed by functional near-infrared spectroscopy (fNIRS). The activation laterality index and time-to-peak/duration during a finger tapping task were quantified before, immediately after, and six months after CIMT. Five age-matched healthy children (9.8 ± 1.3 years old) were also imaged at the same time points to provide comparative activation metrics for normal controls. In children with CP the activation time-to-peak/duration for all sensorimotor centers displayed significant normalization immediately after CIMT that persisted six months later. In contrast to this longer term improvement in localized activation response, the laterality index that depended on communication between sensorimotor centers improved immediately after CIMT, but relapsed six months later.

  3. 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

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

    PubMed Central

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

    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

  5. 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

  6. Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype.

    PubMed

    Tarantini, Stefano; Valcarcel-Ares, Noa M; Yabluchanskiy, Andriy; Springo, Zsolt; Fulop, Gabor A; Ashpole, Nicole; Gautam, Tripti; Giles, Cory B; Wren, Jonathan D; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2017-03-14

    Clinical and experimental studies show that aging exacerbates hypertension-induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin-like growth factor 1 (IGF-1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF-1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver-specific knockdown of IGF-1 (Igf1(f/f)  + TBG-Cre-AAV8) and control mice by angiotensin II plus l-NAME treatment. In IGF-1-deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging, increased oxidative stress-mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension-induced cerebrovascular oxidative stress and MMP activation were increased in IGF-1-deficient mice. We found that IGF-1 deficiency impaired hypertension-induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF-1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that upregulate IGF-1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress, and MMP activation may be useful for the prevention of CMHs, protecting cognitive function in high-risk elderly patients.

  7. CT localization for a patient with a ground-glass opacity pulmonary nodule expecting thoracoscopy: a mixture of lipiodol and India ink

    PubMed Central

    Kim, Kyung Soo; Beck, Kyongmin Sarah; Lee, Kyo Young

    2017-01-01

    Small and deeply seated pure ground-glass opacity (GGO) pulmonary nodules (PNs) are not discernible during video-assisted thoracoscopic surgery (VATS). Moreover, pathologists have difficulty in detecting these nodules due to insufficient localization. We percutaneously injected a mixture of lipiodol and India ink during preoperative CT-guided localization in a 52-year-old female patient presenting with a pure GGO PN. A black-pigmented tattoo lesion was clearly identified, and thoracoscopic wedge resection was performed without difficulty. Pathologic results were also discernible, thus allowing the target lesion to be identified without interruption for microscopic analysis. We introduce a novel method using a mixture of lipiodol and India ink with satisfactory results for preoperative localization of GGO PNs prior to VATS. PMID:28523176

  8. Chronic Cerebral Ischemia Induces Downregulation of A1 Adenosine Receptors During White Matter Damage in Adult Mice.

    PubMed

    Cheng, Pengfei; Ren, Yifei; Bai, Shunjie; Wu, Yu; Xu, Yi; Pan, Junxi; Chen, Jin; Zhu, Xiaofeng; Qi, Zhiguo; Shao, Weihua; Tang, Weiju; Liu, Meiling; Xie, Peng; Huang, Wen

    2015-11-01

    The role of A1 adenosine receptors (A1ARs) in the white matter under chronic cerebral ischemic conditions remains unclear. Here, we used right unilateral common carotid artery occlusion (rUCCAO) to construct a chronic cerebral ischemic mouse model. A1AR expression and proteolipid protein (PLP, a marker of white matter myelination) in the corpus callosum were observed by immunoreaction and immunohistochemistry, respectively. Pro-inflammatory interleukin-1β (IL-1β) and anti-inflammatory interleukin-10 (IL-10) levels were determined by ELISA. The Morris water maze test was employed to detect cognitive impairment. A1AR expression significantly decreased in the rUCCAO group as compared with the sham control group on weeks 2, 4, and 6, respectively. IL-10 levels in the rUCCAO group significantly declined on week 6, while there was no significant change in IL-1β expression. PLP expression significantly decreased in the rUCCAO group on weeks 2, 4, and 6. Moreover, latency time for the Morris water maze test significantly increased in the rUCCAO group on weeks 4 and 6, while the number of platform location crossing significantly decreased in the rUCCAO group on weeks 2, 4, and 6. In conclusion, this study provides the first evidence that chronic cerebral ischemia appears to induce A1AR downregulation and inhibition of IL-10 production, which may play key roles in the neuropathological mechanisms of ischemic white matter lesions. These data will facilitate future studies in formulating effective therapeutic strategies for ischemic white matter lesions.

  9. Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia.

    PubMed

    Hermann, Dirk M; Zechariah, Anil; Kaltwasser, Britta; Bosche, Bert; Caglayan, Ahmet B; Kilic, Ertugrul; Doeppner, Thorsten R

    2015-11-01

    According to the French paradox, red wine consumption reduces the incidence of vascular diseases even in the presence of highly saturated fatty acid intake. This phenomenon is widely attributed to the phytoalexin resveratrol, a red wine ingredient. Experimental studies suggesting that resveratrol has neuroprotective properties mostly used prophylactic delivery strategies associated with short observation periods. These studies did not allow conclusions to be made about resveratrol's therapeutic efficacy post-stroke. Herein, we systematically analyzed effects of prophylactic, acute and post-acute delivery of resveratrol (50mg/kg) on neurological recovery, tissue survival, and angioneurogenesis after focal cerebral ischemia induced by intraluminal middle cerebral artery occlusion in mice. Over an observation period of four weeks, only prolonged post-acute resveratrol delivery induced sustained neurological recovery as assessed by rota rod, tight rope and corner turn tests. Although prophylactic and acute resveratrol delivery reduced infarct volume and enhanced blood-brain-barrier integrity at 2 days post-ischemia by elevating resveratrol's downstream signal sirtuin-1, increasing cell survival signals (phosphorylated Akt, heme oxygenase-1, Bcl-2) and decreasing cell death signals (Bax, activated caspase-3), a sustained reduction of infarct size on day 28 was not observed in any of the three experimental conditions. Instead, enhanced angiogenesis and neurogenesis were noted in animals receiving post-acute resveratrol delivery, which were associated with elevated concentrations of GDNF and VEGF in the brain. Thus, sustained neurological recovery induced by resveratrol depends on successful brain remodeling rather than structural neuroprotection. The recovery promoting effect of delayed resveratrol delivery opens promising perspectives for stroke therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on glutamate-induced neuronal cell death and ischemia-induced cerebral infarct.

    PubMed

    Lee, Bo Kyung; Lee, Dong Ha; Park, Sok; Park, Sung Lyea; Yoon, Jae-Seok; Lee, Min Goo; Lee, Sunkyung; Yi, Kyu Yang; Yoo, Sung Eun; Lee, Kyung Hee; Kim, You-Sun; Lee, Soo Hwan; Baik, Eun Joo; Moon, Chang-Hyun; Jung, Yi-Sook

    2009-01-12

    We investigated the effects of a novel Na(+)/H(+) exchanger-1 (NHE-1) inhibitor KR-33028 on glutamate excitotoxicity in cultured neuron cells in vitro and cerebral infarct in vivo by comparing its potency with that of zoniporide, a well-known, highly potent NHE-1 inhibitor. KR-33028 inhibited NHE-1 activation in a concentration-dependent manner (IC(50)=2.2 nM), with 18-fold greater potency than that of zoniporide (IC(50)=40.7 nM). KR-33028 significantly attenuated glutamate-induced LDH release with approximately 100 times lower EC(25) than that of zoniporide in cortical neurons in vitro (EC(25) of 0.007 and 0.81 microM, respectively), suggesting its 100-fold greater potency than zoniporide in producing anti-necrotic effect. In addition, the EC(50) of KR-33028 for anti-apoptotic effect was 100 times lower than that of zoniporide shown by TUNEL positivity (0.005 and 0.62 microM, respectively) and caspase-3 activity (0.01 and 2.64 microM, respectively). Furthermore, the EC(50) value of KR-33028 against glutamate-induced intracellular Ca(2+) overload was also 100 times lower than that of zoniporide (EC(50) of 0.004 and 0.65 microM, respectively). In the in vivo cerebral infarct model (60 min middle cerebral artery occlusion followed by 24 h reperfusion), KR-33028 reduced infarct size in a dose-dependent manner. Its ED(25) value, however, was quite similar to that of zoniporide (ED(25) of 0.072 and 0.097 mg/kg, respectively). Hence these results suggest that the novel NHE-1 inhibitor, KR-33028, could be an efficient therapeutic tool to protect neuronal cells against ischemic injury.

  11. Cadmium-Induced Apoptosis in Primary Rat Cerebral Cortical Neurons Culture Is Mediated by a Calcium Signaling Pathway

    PubMed Central

    Xu, Hui; Sun, Ya; Hu, Fei-fei; Bian, Jian-chun; Liu, Xue-zhong; Gu, Jian-hong; Liu, Zong-ping

    2013-01-01

    Cadmium (Cd) is an extremely toxic metal, capable of severely damaging several organs, including the brain. Studies have shown that Cd disrupts intracellular free calcium ([Ca2+]i) homeostasis, leading to apoptosis in a variety of cells including primary murine neurons. Calcium is a ubiquitous intracellular ion which acts as a signaling mediator in numerous cellular processes including cell proliferation, differentiation, and survival/death. However, little is known about the role of calcium signaling in Cd-induced apoptosis in neuronal cells. Thus we investigated the role of calcium signaling in Cd-induced apoptosis in primary rat cerebral cortical neurons. Consistent with known toxic properties of Cd, exposure of cerebral cortical neurons to Cd caused morphological changes indicative of apoptosis and cell death. It also induced elevation of [Ca2+]i and inhibition of Na+/K+-ATPase and Ca2+/Mg2+-ATPase activities. This Cd-induced elevation of [Ca2+]i was suppressed by an IP3R inhibitor, 2-APB, suggesting that ER-regulated Ca2+ is involved. In addition, we observed elevation of reactive oxygen species (ROS) levels, dysfunction of cytochrome oxidase subunits (COX-I/II/III), depletion of mitochondrial membrane potential (ΔΨm), and cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP) during Cd exposure. Z-VAD-fmk, a pan caspase inhibitor, partially prevented Cd-induced apoptosis and cell death. Interestingly, apoptosis, cell death and these cellular events induced by Cd were blocked by BAPTA-AM, a specific intracellular Ca2+ chelator. Furthermore, western blot analysis revealed an up-regulated expression of Bcl-2 and down-regulated expression of Bax. However, these were not blocked by BAPTA-AM. Thus Cd toxicity is in part due to its disruption of intracellular Ca2+ homeostasis, by compromising ATPases activities and ER-regulated Ca2+, and this elevation in Ca2+ triggers the activation of the Ca2+-mitochondria apoptotic signaling pathway. This

  12. Pilot Study of the Efficacy of Constraint-Induced Movement Therapy for Infants and Toddlers with Cerebral Palsy

    PubMed Central

    Lowes, Linda Pax; Mayhan, Marianne; Orr, Teresa; Batterson, Nancy; Tonneman, Jill Alyce; Meyer, Angela; Alfano, Lindsay; Wang, Wei; Whalen, Cara N; Nelin, Mary Ann; Lo, Warren David; Case-Smith, Jane

    2014-01-01

    The evidence for Constraint-Induced Movement Therapy (CIMT) effectiveness for infants and toddlers with unilateral cerebral palsy is minimal. We performed a pilot study of CIMT using one-month usual care, one-month intervention, and one-month maintenance (return to usual care) phases on five infants (7- to 18-month old). For the CIMT phase, the infants received 2 hr of occupational therapy and 1 hr of parent-implemented home program for five days/week. The infants were casted for the rst 23 days, and bimanual therapy was provided for the last three days. Fine motor skills for the more affected arm and gross motor skills improved significantly during the CIMT; these gains were maintained at one-month follow-up. Individual infant data show mixed effects. This pilot study provides initial evidence that CIMT is feasible for infants with unilateral cerebral palsy, and presents preliminary data for CIMT on fine and gross motor performance. PMID:23848499

  13. 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.

  14. Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle.

    PubMed

    Simakova, Maria N; Bisen, Shivantika; Dopico, Alex M; Bukiya, Anna N

    2017-09-01

    Statins constitute the most commonly prescribed drugs to decrease cholesterol (CLR). CLR is an important modulator of alcohol-induced cerebral artery constriction (AICAC). Using rats on a high CLR diet (2% CLR) we set to determine whether atorvastatin administration (10mg/kg daily for 18-23weeks) modified AICAC. Middle cerebral arteries were pressurized in vitro at 60mmHg and AICAC was evoked by 50mM ethanol, that is within the range of blood alcohol detected in humans following moderate-to-heavy drinking. AICAC was evident in high CLR+atorvastatin group but not in high CLR diet+placebo. Statin exacerbation of AICAC persisted in de-endothelialized arteries, and was blunted by CLR enrichment in vitro. Fluorescence imaging of filipin-stained arteries showed that atorvastatin decreased vascular smooth muscle (VSM) CLR when compared to placebo, this difference being reduced by CLR enrichment in vitro. Voltage- and calcium-gated potassium channels of large conductance (BK) are known VSM targets of ethanol, with their beta1 subunit being necessary for ethanol-induced channel inhibition and resulting AICAC. Ethanol-induced BK inhibition in excised membrane patches from freshly isolated myocytes was exacerbated in the high CLR diet+atorvastatin group when compared to high CLR diet+placebo. Unexpectedly, atorvastatin decreased the amount and function of BK beta1 subunit as documented by immunofluorescence imaging and functional patch-clamp studies. Atorvastatin exacerbation of ethanol-induced BK inhibition disappeared upon artery CLR enrichment in vitro. Our study demonstrates for the first time statin's ability to exacerbate the vascular effect of a widely consumed drug of abuse, this exacerbation being driven by statin modulation of ethanol-induced BK channel inhibition in the VSM via CLR-mediated mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Serduc, Raphaël; van de Looij, Yohan; Francony, Gilles; Verdonck, Olivier; van der Sanden, Boudewijn; Laissue, Jean; Farion, Régine; Bräuer-Krisch, Elke; Siegbahn, Erik Albert; Bravin, Alberto; Prezado, Yolanda; Segebarth, Christoph; Rémy, Chantal; Lahrech, Hana

    2008-03-01

    Cerebral edema is one of the main acute complications arising after irradiation of brain tumors. Microbeam radiation therapy (MRT), an innovative experimental radiotherapy technique using spatially fractionated synchrotron x-rays, has been shown to spare radiosensitive tissues such as mammal brains. The aim of this study was to determine if cerebral edema occurs after MRT using diffusion-weighted MRI and microgravimetry. Prone Swiss nude mice's heads were positioned horizontally in the synchrotron x-ray beam and the upper part of the left hemisphere was irradiated in the antero-posterior direction by an array of 18 planar microbeams (25 mm wide, on-center spacing 211 mm, height 4 mm, entrance dose 312 Gy or 1000 Gy). An apparent diffusion coefficient (ADC) was measured at 7 T 1, 7, 14, 21 and 28 days after irradiation. Eventually, the cerebral water content (CWC) was determined by microgravimetry. The ADC and CWC in the irradiated (312 Gy or 1000 Gy) and in the contralateral non-irradiated hemispheres were not significantly different at all measurement times, with two exceptions: (1) a 9% ADC decrease (p < 0.05) was observed in the irradiated cortex 1 day after exposure to 312 Gy, (2) a 0.7% increase (p < 0.05) in the CWC was measured in the irradiated hemispheres 1 day after exposure to 1000 Gy. The results demonstrate the presence of a minor and transient cellular edema (ADC decrease) at 1 day after a 312 Gy exposure, without a significant CWC increase. One day after a 1000 Gy exposure, the CWC increased, while the ADC remained unchanged and may reflect the simultaneous presence of cellular and vasogenic edema. Both types of edema disappear within a week after microbeam exposure which may confirm the normal tissue sparing effect of MRT. For more information on this article, see medicalphysicsweb.org

  16. Ethanol induces rapid lipid peroxidation and activation of nuclear factor-kappa B in cerebral vascular smooth muscle: relation to alcohol-induced brain injury in rats.

    PubMed

    Altura, Burton M; Gebrewold, Asefa; Zhang, Aimin; Altura, Bella T

    2002-06-07

    The present study was designed to test the hypothesis that acute administration of alcohol (ethanol) to primary cultured cerebral vascular smooth muscle cells will cause lipid peroxidation, inhibition of IkappaB phosphorylation, and inhibition of nuclear transcription factor-kappa B (NF-kappaB). Ethanol (10, 25, 100 mM) resulted in concentration-dependent rises in malondialdehyde in as little as 30-45 min after exposure to the alcohol, rising to levels 2.5-10x normal after 18-24 h. Using EMSA assays and specific antibodies, ethanol caused three DNA-binding proteins (p50, p65, c-Rel) to rise in nuclear extracts in a concentration-dependent manner. Using a rabbit antibody, IkappaB phosphorylation (and degradation) was stimulated by ethanol (in a concentration-dependent manner) and inhibited by a low concentration of the NF-kappaB inhibitor, pyrrolidine dithiocarbamate. These new biochemical and molecular data indicate that ethanol, even in physiologic concentrations, can elicit rapid lipid peroxidation and activation of NF-kappaB in cerebral vascular muscle cells. The present results when viewed in light of other recently published data suggest that ethanol-induced lipid peroxidation and activation of nuclear transcription factors probably play important roles in alcohol-induced brain-vascular damage, neurobehavioral actions and stroke.

  17. Chromaffin cell grafts to rat cerebral cortex reverse lesion-induced memory deficits.

    PubMed

    Welner, S A; Koty, Z C; Boksa, P

    1990-09-10

    Adrenal chromaffin cells were isolated from donor adult rats and transplanted to the cerebral cortex of bilaterally nucleus basalis magnocellularis-lesioned rats. Chromaffin cell grafts to lesioned animals completely reversed the spatial memory deficit seen in lesioned alone animals on a T-maze alternation task. Although chromaffin cell grafts have been used previously to reverse motor abnormalities arising from defective nigro-striatal aminergic transmission, the present report is the first evidence that chromaffin cell transplants can reverse deficits in memory function. Grafts also enhanced cortical acetylcholinesterase staining.

  18. Logistic Regression Analyses for Predicting Clinically Important Differences in Motor Capacity, Motor Performance, and Functional Independence after Constraint-Induced Therapy in Children with Cerebral Palsy

    ERIC Educational Resources Information Center

    Wang, Tien-ni; Wu, Ching-yi; Chen, Chia-ling; Shieh, Jeng-yi; Lu, Lu; Lin, Keh-chung

    2013-01-01

    Given the growing evidence for the effects of constraint-induced therapy (CIT) in children with cerebral palsy (CP), there is a need for investigating the characteristics of potential participants who may benefit most from this intervention. This study aimed to establish predictive models for the effects of pediatric CIT on motor and functional…

  19. Effects of Home-Based Constraint-Induced Therapy versus Dose-Matched Control Intervention on Functional Outcomes and Caregiver Well-Being in Children with Cerebral Palsy

    ERIC Educational Resources Information Center

    Lin, Keh-chung; Wang, Tien-ni; Wu, Ching-yi; Chen, Chia-ling; Chang, Kai-chieh; Lin, Yu-chan; Chen, Yi-ju

    2011-01-01

    This study compared home-based constraint-induced therapy (CIT) with a dose-matched home-based control intervention for children with cerebral palsy (CP). The differences in unilateral and bilateral motor performance, daily functions, and quality of parental well-being (i.e., the stress level of their parents) were evaluated. The study included 21…

  20. Logistic Regression Analyses for Predicting Clinically Important Differences in Motor Capacity, Motor Performance, and Functional Independence after Constraint-Induced Therapy in Children with Cerebral Palsy

    ERIC Educational Resources Information Center

    Wang, Tien-ni; Wu, Ching-yi; Chen, Chia-ling; Shieh, Jeng-yi; Lu, Lu; Lin, Keh-chung

    2013-01-01

    Given the growing evidence for the effects of constraint-induced therapy (CIT) in children with cerebral palsy (CP), there is a need for investigating the characteristics of potential participants who may benefit most from this intervention. This study aimed to establish predictive models for the effects of pediatric CIT on motor and functional…

  1. Motor Learning Curve and Long-Term Effectiveness of Modified Constraint-Induced Movement Therapy in Children with Unilateral Cerebral Palsy: A Randomized Controlled Trial

    ERIC Educational Resources Information Center

    Geerdink, Yvonne; Aarts, Pauline; Geurts, Alexander C.

    2013-01-01

    The goal of this study was to determine the progression of manual dexterity during 6 weeks (54 h) (modified) constraint-induced movement therapy ((m)CIMT) followed by 2 weeks (18 h) bimanual training (BiT) in children with unilateral spastic cerebral palsy (CP), to establish whether and when a maximal training effect was reached and which factors…

  2. Motor Learning Curve and Long-Term Effectiveness of Modified Constraint-Induced Movement Therapy in Children with Unilateral Cerebral Palsy: A Randomized Controlled Trial

    ERIC Educational Resources Information Center

    Geerdink, Yvonne; Aarts, Pauline; Geurts, Alexander C.

    2013-01-01

    The goal of this study was to determine the progression of manual dexterity during 6 weeks (54 h) (modified) constraint-induced movement therapy ((m)CIMT) followed by 2 weeks (18 h) bimanual training (BiT) in children with unilateral spastic cerebral palsy (CP), to establish whether and when a maximal training effect was reached and which factors…

  3. Effects of Nigella sativa on apoptosis and GABAA receptor density in cerebral cortical and hippocampal neurons in pentylenetetrazol induced kindling in rats.

    PubMed

    Meral, I; Esrefoglu, M; Dar, K A; Ustunova, S; Aydin, M S; Demirtas, M; Arifoglu, Y

    2016-11-01

    We investigated the effects of Nigella sativa on apoptosis and gamma-aminobutyric acid (GABAA) receptor density in cerebral cortical and hippocampal neurons in a pentylenetetrazol (PTZ)-induced kindling model in rats. The PTZ kindling model was produced by injecting PTZ in subconvulsive doses to rats on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22 and 24 of the study into animals of PTZ treated (PTZ) and PTZ + N. sativa treated (PTZ + NS) groups. Clonic and tonic seizures were induced by injecting a convulsive dose of PTZ on day 26 of the study. Rats in the PTZ + NS group were treated also with a 10 mg/kg methanolic extract of N. sativa 2 h before each PTZ injection. Rats in the control group were treated with 4 ml/kg saline. The number of neurons that expressed GABAA receptors in the hippocampus and cerebral cortex of rats in the PTZ and PTZ + NS groups increased significantly. There was no significant difference in the number of GABAA receptors between the PTZ and PTZ + NS groups. GABAA receptor density of the neurons in the cerebral cortex, but not hippocampus, was increased in PTZ group compared to controls. We observed a significant increase in the number of apoptotic neurons in the cerebral cortex of rats of both the PTZ and PTZ + NS groups compared to controls. We observed a significant decrease in the number of the apoptotic neurons in the cerebral cortex of rats in the PTZ + NS group compared to the PTZ group. N. sativa treatment ameliorated the PTZ induced neurodegeneration in the cerebral cortex as reflected by neuronal apoptosis and neuronal GABAA receptor frequency.

  4. T cell immunity to glatiramer acetate ameliorates cognitive deficits induced by chronic cerebral hypoperfusion by modulating the microenvironment.

    PubMed

    Chen, Li; Yao, Yang; Wei, Changjuan; Sun, Yanan; Ma, Xiaofeng; Zhang, Rongxin; Xu, Xiaolin; Hao, Junwei

    2015-09-22

    Vascular dementia (VaD) is a progressive and highly prevalent disorder. However, in a very large majority of cases, a milieu of cellular and molecular events common for multiple neurodegenerative diseases is involved. Our work focused on whether the immunomodulating effect of glatiramer acetate (GA) could restore normalcy to the microenvironment and ameliorate cognitive decline induced by chronic cerebral hypoperfusion. We assessed cognitive function by rats' performance in a Morris water maze (MWM), electrophysiological recordings and by pathologic changes. The results suggest that GA reduced cognitive deficits by reestablishing an optimal microenvironment such as increasing expression of the brain-derived neurotrophic factor (BDNF) and modulating the Th1/Th2 cytokine balance in the hippocampus. When microenvironmental homeostasis is restored, cholinergic activity becomes involved in ameliorating cellular damage. Since vaccination with GA can boost "protective autoimmunity" in this way, a similar strategy may have therapeutic potential for alleviating VaD disease.

  5. Functional and morphological changes in cultured neurons of rat cerebral cortex induced by long-term application of aluminum.

    PubMed

    Kawahara, M; Muramoto, K; Kobayashi, K; Kuroda, Y

    1992-12-30

    Aluminum is an environmental neurotoxin and a suspected risk factor for Alzheimer's disease. The neurotoxicity of aluminum on cultured neurons of rat cerebral cortex was investigated using an assay system for synapse formation and immunohistochemistry. The frequency of spontaneous oscillations of intracellular Ca2+, which is correlated to the number of synapses, was decreased after exposure to 100 microM of aluminum chloride for 22 days. Long-term application of aluminum (48 days) caused aggregation of cell bodies and fasciculation of processes. Processes and cell bodies were strongly stained by antibody to tau protein, which is one of the main components of Alzheimer's neurofibrillary tangles. It is suggested that the characteristics of the degeneration of cultured neurons induced by aluminum show some similarities to the pathology observed in brains with Alzheimer's disease.

  6. Cerebral blood flow during paroxysmal EEG activation induced by sleep in patients with complex partial seizures

    SciTech Connect

    Gozukirmizi, E.; Meyer, J.S.; Okabe, T.; Amano, T.; Mortel, K.; Karacan, I.

    1982-01-01

    Cerebral blood flow (CBF) measurements were combined with sleep polysomnography in nine patients with complex partial seizures. Two methods were used: the 133Xe method for measuring regional (rCBF) and the stable xenon CT method for local (LCBF). Compared to nonepileptic subjects, who show diffuse CBF decreases during stages I-II, non-REM sleep onset, patients with complex partial seizures show statistically significant increases in CBF which are maximal in regions where the EEG focus is localized and are predominantly seen in one temporal region but are also propagated to other cerebral areas. Both CBF methods gave comparable results, but greater statistical significance was achieved by stable xenon CT methodology. CBF increases are more diffuse than predicted by EEG paroxysmal activity recorded from scalp electrodes. An advantage of the 133Xe inhalation method was achievement of reliable data despite movement of the head. This was attributed to the use of a helmet which maintained the probes approximated to the scalp. Disadvantages were poor resolution (7 cm3) and two-dimensional information. The advantage of stable xenon CT method is excellent resolution (80 mm3) in three dimensions, but a disadvantage is that movement of the head in patients with seizure disorders may limit satisfactory measurements.

  7. Dexmedetomidine Protects against Transient Global Cerebral Ischemia/Reperfusion Induced Oxidative Stress and Inflammation in Diabetic Rats

    PubMed Central

    Xing, Xichun; Wang, Qi; Li, Wenzhi

    2016-01-01

    Background Transient global cerebral ischemia/reperfusion (I/R) is a major perioperative complication, and diabetes increases the response of oxidative stress and inflammation induced by I/R. The objective of this study was to determine the protective effect of dexmedetomidine against transient global cerebral ischemia/reperfusion induced oxidative stress and inflammation in diabetic rats. Methods Sixty-four rats were assigned into four experimental groups: normoglycemia, normoglycemia + dexmedetomidine, hyperglycemia, and hyperglycemia + dexmedetomidine and all subsequent neurological examinations were evaluated by a blinded observer. Damage to the brain was histologically assessed using the TUNEL staining method while western blotting was used to investigate changes in the expression levels of apoptosis-related proteins as well as the microglia marker, ionized calcium-binding adapter molecule 1 (Iba1). Water content in the brain was also analyzed. In addition, hippocampal concentrations of malondialdehyde (MDA) and Nox2 (a member of the Nox family of NADPH oxidases), and the activity of superoxide dismutase and catalase were analyzed. Finally, changes in serum concentrations of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were detected. Results Results showed that diabetes increased brain water content, the number of apoptotic neurons, early neurological deficit scores, oxidative stress (MDA and Nox2) and inflammation (pro-inflammatory cytokines including TNF-α and IL-6) levels following transient global I/R injury, but that these symptoms were attenuated following administration of dexmedetomidine. Conclusions These findings suggest that dexmedetomidine can significantly alleviate damage resulting from I/R, and this mechanism may be related to a reduction in both oxidative stress and inflammation which is normally associated with I/R. PMID:26982373

  8. Reversible short-term and delayed long-term cognitive impairment induced by chronic mild cerebral hypoperfusion in rats.

    PubMed

    Thong-asa, Khwanjai; Chompoopong, Supin; Tantisira, Mayuree H; Tilokskulchai, Kanokwan

    2013-08-01

    Chronic cerebral hypoperfusion induced by aging in combination with vascular disorder potentially contributes to the development of vascular dementia. This study aimed to investigate the age-related changes in spatial performances in chronic mild cerebral hypoperfusion induced by permanent right common carotid artery occlusion (rCCAO) in rats. Four-month-old male Sprague-Dawley rats (n = 20) were randomly assigned into sham and rCCAO groups. Spatial performances of young adult rats (age 4-8 months) were evaluated repeatedly by the radial arm water maze at 6 days, and 1, 2 and 4 months after surgery. The spatial performance was re-assessed by the Morris water maze when the rats were 18 months old. The present results revealed that the rCCAO rats developed progressive deficit in spatial learning and memory, starting from day 6 and significant deficit was found at 2 months after rCCAO (p < 0.05). However, the spatial performance of the rCCAO rats was recovered at 4 months after surgery. Testing of the cognitive flexibility of the aged rCCAO rats (18 months old), indicated that the learning flexibility of the aged rCCAO rats was significantly impaired. This deficit was found in parallel with pronounced white matter damage in the corpus callosum and internal capsule and significant cell death in the dorsal hippocampus. Our results suggested that vascular risk insult in young adult rats resulted in spatial learning deficit which could be completely compensated later on. However, such previous vascular risk could be exacerbated by advancing age and subsequently lead to a deficit in cognitive flexibility with white matter damage and significant neuronal death in the dorsal hippocampus.

  9. Current Options for the Management of Aneurysmal Subarachnoid Hemorrhage-Induced Cerebral Vasospasm: A Comprehensive Review of the Literature

    PubMed Central

    Dabus, Guilherme; Nogueira, Raul G.

    2013-01-01

    Objectives Cerebral vasospasm is one of the leading causes of morbi-mortality following aneurysmal subarachnoid hemorrhage. The aim of this article is to discuss the current status of vasospasm therapy with emphasis on endovascular treatment. Methods A comprehensive review of the literature obtained by a PubMed search. The most relevant articles related to medical, endovascular and alternative therapies were selected for discussion. Results Current accepted medical options include the oral nimodipine and ‘triple-H’ therapy (hypertension, hypervolemia and hemodilution). Nimodipine remains the only modality proven to reduce the incidence of infarction. Although widely used, ‘triple-H’ therapy has not been demonstrated to significantly change overall outcome after cerebral vasospasm. Indeed, both induced hypervolemia and hemodilution may have deleterious effects, and more recent physiologic data favor normovolemia with induced hypertension or optimization of cardiac output. Endovascular options include percutaneous transluminal balloon angioplasty (PTA) and intra-arterial (IA) infusion of vasodilators. Multiple case reports and case series have been encountered in the literature using different drug regimens with diverse mechanisms of action. Compared with PTA, IA drug infusion has the advantages of distal penetration and a better safety profile. Its main disadvantages are the more frequent need for repeat treatments and its systemic hemodynamic repercussions. Alternative options using intraventricular/cisternal drug therapy and flow augmentation strategies have also shown possible benefits; however, their use is not yet as well established. Conclusion Blood pressure or cardiac output optimization should be the mainstay of hyperdynamic therapy. Endovascular treatment appears to have a positive impact on neurological outcome compared with the natural history of the disease. The role of intraventricular therapy and flow augmentation strategies in association

  10. The Effect of Long-Term Environmental Enrichment in Chronic Cerebral Hypoperfusion-Induced Memory Impairment in Rats.

    PubMed

    Park, Jong-Min; Seong, Ho-Hyun; Jin, Han-Byeol; Kim, Youn-Jung

    2017-05-01

    Vascular dementia (VaD) is the second most common cause of dementia. It occurs when the cerebral blood supply is reduced by disarrangement of the circulatory system. Environmental enrichment (EE) has been associated with cognitive improvement, motor function recovery, and anxiety relief with respect to various neurodegenerative diseases and emotional stress models. The purpose of this study was to determine whether long-term EE influenced cognitive impairment in a rat model of chronic hypoperfusion induced by permanent occlusion of bilateral common carotid arteries (BCCAo). The Y-maze and Morris water maze tests were performed to evaluate the rats' cognitive functions. Also, the protein expression of brain-derived neurotrophic factor (BDNF), phosphorylated cAMP-calcium response element binding protein (pCREB), and vascular endothelial growth factor (VEGF) were confirmed by Western blot. The microvessels and angiogenesis-associated proteins in the hippocampal region were investigated using immunohistochemistry. The VaD + EE group showed significantly better cognitive functions than the VaD group in both the Y-maze and MWM tests. In addition, the VaD + EE group showed significantly increased expression of BDNF, pCREB, and VEGF in the hippocampus compared to the VaD group. Rats in the VaD + EE group also had increased length of microvessels and VEGF expression in the hippocampus. These results suggest that long-term EE exerts neuroprotective effects against cognitive impairment induced by chronic cerebral hypoperfusion through the enhancement of BDNF, pCREB, and VEGF expression and indicate that EE may be a good nursing intervention in vascular dementia patients.

  11. Synergistic protective effect of astragaloside IV-tetramethylpyrazine against cerebral ischemic-reperfusion injury induced by transient focal ischemia.

    PubMed

    Yang, Jiehong; Li, Jinhui; Lu, Jing; Zhang, Yuyan; Zhu, Zhenhong; Wan, Haitong

    2012-03-06

    Astragaloside IV and tetramethylpyrazine have been extensively used in the cardio-cerbrovascular diseases of medicine as a chief ingredient of glycoside or alkaloid formulations for the treatment of stroke and myocardial ischemia diseases. To investigate the effects of astragaloside IV (ASG IV) and tetramethylpyrazine (TMPZ) on cerebral ischemia-reperfusion (IR) injury model in rat model. Rats were randomly divided into the following five groups: sham group, IR group and treatment group including ASG IV, ASG IV-TMPZ and nimodipine treatment. The therapeutic effect was evaluated by micro-positron emission tomography (Micro-PET) using (18)F-fluoro-2-deoxy-d-glucose. The neurological examination, infarct volume and the levels of oxidative stress- and cell apoptosis-related molecules were assessed. Micro-PET imaging showed that glucose metabolism in the right hippocampus was significantly decreased in the IR group compared to the sham group (P<0.01). ASG IV and ASG IV-TMPZ treatments reversed the decreased glucose metabolism in the model group (P<0.05 and P<0.01, respectively). IR induced the increase of Caspase-3 mRNA levels, MDA content and iNOS activity, but it caused the decrease of SOD activity and Bcl-2 expression compared the sham group (P<0.01). ASG IV-TMPZ and ASG IV reversed the IR-induced changes of these parameters, i.e. the down regulation of Caspase-3 mRNA, MDA content and iNOS activity, and the up regulation of SOD activity and Bcl-2 expression (P<0.05). This study showed that ASG IV-TMPZ played a pivotal synergistic protective role against focal cerebral ischemic reperfusion damage in a rat experimental model. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  12. Medium- and long-term effects of repeated bicuculline-induced seizures in developing rats on local cerebral energy metabolism.

    PubMed

    Doriat, J F; Koziel, V; Humbert, A C; Daval, J L

    1998-07-27

    To assess long-term metabolic consequences of recurrent ictal events arising during development, seizures were repeatedly generated in rats at different stages of cerebral maturation. Seizures were induced by i.p. injections of bicuculline for three consecutive days, starting from postnatal day 5 (P5), when the brain is very immature, or from P15, a period at which the brain is more structurally organized. Local cerebral metabolic rates for glucose were measured in 74 structures at P15, P25 and in adults (P60), by the autoradiographic method using 2-D-[14C]deoxyglucose. Repeated seizures in P5 to P7 pups led to a reduction (16-34%) of glucose consumption at P15, mainly significant in sensory, motor and functionally non-specific areas as well as in cerebellar nuclei. Selective decreases in metabolic activity were still recorded in adults, mostly in auditory system (20%) and cerebellar nuclei (27%). Seizures generated from P15 to P17 led to an overall mortality rate of 62% (versus 22% at P5 to P7). Surviving animals exhibited reduced metabolic rates for glucose (by 7-27%) at P25, significant in 23 structures, and depicting pronounced changes in limbic, hypothalamic, sensory and white matter areas, whereas brain functional activity finally returned to basal values at P60. Therefore, while younger rats seemed to better tolerate repeated bicuculline-induced seizures than older animals, the reverse was true for long-term metabolic effects, and the more immature the brain when seizures arise, the more persistent the functional consequences.

  13. Honokiol suppresses TNF-α-induced neutrophil adhesion on cerebral endothelial cells by disrupting polyubiquitination and degradation of IκBα.

    PubMed

    Chen, Po-Jen; Wang, Yu-Ling; Kuo, Liang-Mou; Lin, Chwan-Fwu; Chen, Chun-Yu; Tsai, Yung-Fong; Shen, Jiann-Jong; Hwang, Tsong-Long

    2016-05-23

    Adhesion molecules expressed on cerebral endothelial cells (ECs) mediate leukocyte recruitment and play a significant role in cerebral inflammation. Increased levels of adhesion molecules on the EC surface induce leukocyte infiltration into inflammatory areas and are thus hallmarkers of inflammation. Honokiol, isolated from the Chinese medicinal herb Magnolia officinalis, has various pharmacological activities, including anti-inflammatory effects, yet the nature of honokiol targeting molecules remains to be revealed. Here, we investigated the inhibitory effect of honokiol on neutrophil adhesion and vascular cell adhesion molecule-1 (VCAM-1) expression, which underlie its molecular target, and mechanisms for inactivating nuclear factor κ enhancer binding protein (NF-κB) in mouse cerebral ECs. Honokiol inhibited tumour necrosis factor-α (TNF-α)-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs. The inflammatory transcription factor NF-κB was downregulated by honokiol. Honokiol significantly blocked TNF-α-induced NF-κB p65 nuclear translocation and degradation of the proteasome-dependent inhibitor of NF-κB α (IκBα). From docking model prediction, honokiol directly targeted the ubiquitin-ubiquitin interface of Lys48-linked polychains. Moreover, honokiol prevented the TNF-α-induced Lys48-linked polyubiquitination, including IκBα-polyubiquitin interaction. Honokiol has protective anti-inflammatory effects on TNF-α-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs, at least in part by directly inhibiting ubiquitination-mediated IκBα degradation and then preventing NF-κB nuclear translocation.

  14. Autophagy protects human brain microvascular endothelial cells against methylglyoxal-induced injuries, reproducible in a cerebral ischemic model in diabetic rats.

    PubMed

    Fang, Lili; Li, Xue; Zhong, Yinbo; Yu, Jing; Yu, Lina; Dai, Haibin; Yan, Min

    2015-10-01

    Cerebral microvascular endothelial cells (ECs) are crucial for brain vascular repair and maintenance, but their physiological function may be impaired during ischemic stroke and diabetes. Methylglyoxal (MGO), a reactive dicarbonyl produced during glucose metabolism, could exacerbate ischemia-induced EC injury and dysfunction. We investigated the protective effect of autophagy on cultured human brain microvascular endothelial cells (HBMEC) that underwent MGO treatment. A further study was conducted to explore the underlying mechanisms of the protective effect. Autophagic activity was assessed by evaluating protein levels, using western blot. 3-methyladenine (3-MA), bafilomycin A1, ammonium chloride (AC), Beclin 1 siRNA, and chloroquine (CQ) were used to cause autophagy inhibition. Alarmar blue assay and lactate dehydrogenase release assay were used to evaluate cell viability. Streptozotocin was administered to induce type I diabetes in rats and post-permanent middle cerebral artery occlusion was performed to elicit cerebral ischemia. Blood-brain barrier permeability was also assessed. Our study found that MGO reduced HBMEC cell viability in a concentration- and time-dependent manner, and triggered the responsive autophagy activation. Autophagy inhibitors bafilomycin A1, AC, 3-MA, and BECN1 siRNA exacerbated MGO-induced HBMEC injury. FAK phosphorylation inhibitor PF573228 inhibited MGO-triggered autophagy and enhanced lactate dehydrogenase release. Meanwhile, similar autophagy activation in brain vascular ECs was observed during permanent middle cerebral artery occlusion-induced cerebral ischemia in diabetic rats, while chloroquine-induced autophagy inhibition enhanced blood-brain barrier permeability. Taken together, our study indicates that autophagy triggered by MGO defends HBMEC against injuries.

  15. Cerebral venous sinus thrombosis with cerebral hemorrhage during early pregnancy

    PubMed Central

    Nie, Quanmin; Guo, Pin; Ge, Jianwei; Qiu, Yongming

    2015-01-01

    Cerebral venous sinus thrombosis (CVST) rarely induces cerebral hemorrhage, and CVST with cerebral hemorrhage during early pregnancy is extremely rare. Upon literature review, we are able to find only one case of CVST with cerebral hemorrhage in early pregnancy. In this paper, we report another case of a 27-year-old patient who developed CVST with cerebral hemorrhage in her fifth week of pregnancy. Although the optimal treatment for this infrequent condition remains controversial, we adopted anticoagulation as the first choice of treatment and obtained favorable results. PMID:25630781

  16. Effectiveness of constraint-induced movement therapy on upper-extremity function in children with cerebral palsy: a systematic review and meta-analysis of randomized controlled trials.

    PubMed

    Chen, Yu-Ping; Pope, Stephanie; Tyler, Dana; Warren, Gordon L

    2014-10-01

    To systematically examine the research literature on the effectiveness of constraint-induced movement therapy on improving arm function in children with cerebral palsy, and to assess the association between the study effect size and the characteristics of the patients and intervention protocol. A systematic literature search was conducted in PubMed, PsycINFO, Cochrane, CINAHL, Web of Science, and TRIP Database up to May 2014. Studies employing randomized controlled trial design, children with cerebral palsy, comparing constraint-induced movement therapy with another intervention with a focus on arm function, and upper-extremity measures were included in this review. Methodological quality was evaluated using the Physiotherapy Evidence-based Database (PEDro) scale. The literature search resulted in 27 randomized controlled trial studies with good methodological quality that compared constraint-induced movement therapy with other intervention therapy. Overall, constraint-induced movement therapy provided a medium beneficial effect (d = 0.546; p < 0.001) when compared with conventional therapy. For the subgroup analyses, presence of a dose-equivalent comparison group, intervention location, and time of follow-up were significant factors. Studies examining constraint-induced movement therapy effect without a dose-equivalent comparison group showed a large effect in children with cerebral palsy, but studies with a dose-equivalent group only showed a small effect. Children who received home-based constraint-induced movement therapy had a better improvement in arm function than those who received constraint-induced movement therapy elsewhere. The research literature supports constraint-induced movement therapy as an effective intervention to improve arm function in children with cerebral palsy. © The Author(s) 2014.

  17. Cognitive Improvement Induced by Environment Enrichment in Chronic Cerebral Hypoperfusion Rats: a Result of Upregulated Endogenous Neuroprotection?

    PubMed

    Yang, Ying; Zhang, Junjian; Xiong, Li; Deng, Min; Wang, Jing; Xin, Jiawei; Liu, Hui

    2015-06-01

    Environment enrichment (EE) has been demonstrated to improve the cognitive impairment that is induced by chronic cerebral hypoperfusion (CCH), but the underlying mechanism has not yet been elucidated. This study aimed to investigate the role of endogenous neuroprotection in EE-induced cognitive improvement in rats with CCH. Permanent bilateral common carotid artery occlusions (2-vessel occlusions (2VOs)) were performed to induce CCH in male adult Wistar rats. Four weeks after the surgeries, the rats were exposed to enriched environments for 4 weeks (6 h/day). Subsequently, we assessed the effects of EE on cognitive function, brain histone acetylation levels, neuroprotection-related transcription factors (i.e., cAMP response element-binding protein (CREB), phospho-CREB (p-CREB), hypoxia-inducible factor 1 (HIF-1) α, and nuclear regulatory factor 2 (Nrf2)), and oxidative stress and histological changes in the brain. After 2VO, the rats exposed to the EE treatment exhibited increased acetylation of histone 4 and increased p-CREB and Nrf2 protein levels in the brain. HIF-1α levels were increased after 2VO and reduced after EE treatment. The oxidative damage, histopathological changes in the brain, and spatial learning and memory impairments induced by 2VO were subsequently restored after EE treatment. These data indicate that EE promotes the acetylation of histone 4, regulates some neuroprotection-related transcription factors, attenuates oxidative damage, and protects against the histopathological damage to the brain induced by CCH. Together, the effects of EE in CCH rats might contribute to the recovery of spatial learning and memory.

  18. cPKCγ membrane translocation is involved in herkinorin-induced neuroprotection against cerebral ischemia/reperfusion injury in mice

    PubMed Central

    Gui, Xiaochen; Cui, Xu; Wei, Haiping; Feng, Guang; Zhang, Xuezheng; He, Yongjin; Li, Junfa; Li, Tianzuo

    2016-01-01

    Herkinorin is an opiate analgesic with limited adverse effects, functioning as a primary selective atypical opioid µ agonist. The present study aimed to identify whether herkinorin has a positive effect on ischemic/reperfusion (I/R) injury. Adult male C57BL/6 mice were randomly divided into five groups: i) Naïve, ii) sham, iii) I/R, iv) I/R with dimethyl sulfoxide (I/R+D) and v) I/R with herkinorin (I/R+H). The I/R injury model was induced by occluding the middle cerebral artery for 1 h followed by 24 h or 7 days of reperfusion. Neurobehavioral scores and sensorimotor functions were examined 24 h and 7 days following reperfusion. In addition, infarct volumes were examined at these time points using a 2,3,5-triphenyltetrazolium chloride assay. Herkinorin treatment improved neurobehavioral and sensorimotor functional recovery from I/R-induced brain injury. There was a significant decrease in infarct volume in the I/R+H group at 24 h or 7 days following reperfusion compared with the I/R and I/R+D groups. Western blotting suggested that the decrease in conventional protein kinase C γ (cPKCγ) membrane translocation in the peri-infarct region may be attenuated by herkinorin pretreatment. These results indicated that herkinorin may be beneficial in I/R-induced mouse brain injury, and this may be attributed to the membrane translocation of cPKCγ following activation. PMID:27922694

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

    PubMed Central

    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

    2017-01-01

    ABSTRACT 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 CO2 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. PMID:28103118

  20. Network and external perturbation induce burst synchronisation in cat cerebral cortex

    NASA Astrophysics Data System (ADS)

    Lameu, Ewandson L.; Borges, Fernando S.; Borges, Rafael R.; Batista, Antonio M.; Baptista, Murilo S.; Viana, Ricardo L.

    2016-05-01

    The brain of mammals are divided into different cortical areas that are anatomically connected forming larger networks which perform cognitive tasks. The cat cerebral cortex is composed of 65 areas organised into the visual, auditory, somatosensory-motor and frontolimbic cognitive regions. We have built a network of networks, in which networks are connected among themselves according to the connections observed in the cat cortical areas aiming to study how inputs drive the synchronous behaviour in this cat brain-like network. We show that without external perturbations it is possible to observe high level of bursting synchronisation between neurons within almost all areas, except for the auditory area. Bursting synchronisation appears between neurons in the auditory region when an external perturbation is applied in another cognitive area. This is a clear evidence that burst synchronisation and collective behaviour in the brain might be a process mediated by other brain areas under stimulation.

  1. Cortical reorganization induced by virtual reality therapy in a child with hemiparetic cerebral palsy.

    PubMed

    You, Sung H; Jang, Sung Ho; Kim, Yun-Hee; Kwon, Yong-Hyun; Barrow, Irene; Hallett, Mark

    2005-09-01

    Virtual reality (VR) therapy is a new, neurorehabilitation intervention aimed at enhancing motor performance in children with hemiparetic cerebral palsy (CP). This case report investigated the effects of VR therapy on cortical reorganization and associated motor function in an 8-year-old male with hemiparetic CP. Cortical activation and associated motor development were measured before and after VR therapy using functional magnetic resonance imaging (fMRI) and standardized motor tests. Before VR therapy, the bilateral primary sensorimotor cortices (SMCs) and ipsilateral supplementary motor area (SMA) were predominantly activated during affected elbow movement. After VR therapy, the altered activations disappeared and the contralateral SMC was activated. This neuroplastic change was associated with enhanced functional motor skills including reaching, self-feeding, and dressing. These functions were not possible before the intervention. To our knowledge, this is the first fMRI study in the literature that provides evidence for neuroplasticity after VR therapy in a child with hemiparetic CP.

  2. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6.

    PubMed Central

    Campbell, I L; Abraham, C R; Masliah, E; Kemper, P; Inglis, J D; Oldstone, M B; Mucke, L

    1993-01-01

    Cytokines are thought to be important mediators in physiologic and pathophysiologic processes affecting the central nervous system (CNS). To explore this hypothesis, transgenic mice were generated in which the cytokine interleukin 6 (IL-6), under the regulatory control of the glial fibrillary acidic protein gene promoter, was overexpressed in the CNS. A number of transgenic founder mice and their offspring exhibited a neurologic syndrome the severity of which correlated with the levels of cerebral IL-6 expression. Transgenic mice with high levels of IL-6 expression developed severe neurologic disease characterized by runting, tremor, ataxia, and seizure. Neuropathologic manifestations included neuro-degeneration, astrocytosis, angiogenesis, and induction of acute-phase-protein production. These findings indicate that cytokines such as IL-6 can have a direct pathogenic role in inflammatory, infectious, and neurodegenerative CNS diseases. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:7694279

  3. Effect of ST36 Acupuncture on Hyperventilation-Induced CO2 Reactivity of the Basilar and Middle Cerebral Arteries and Heart Rate Variability in Normal Subjects

    PubMed Central

    Jung, Woo-Sang; Cho, Ki-Ho; Kim, Young-Suk; Ko, Chang-Nam; Park, Jung-Mi; Moon, Sang-Kwan

    2014-01-01

    This study was conducted to verify the effect of acupuncture on cerebral haemodynamics to provide evidence for the use of acupuncture treatment as a complementary therapy for the high-risk stroke population. The effect of ST36 acupuncture treatment on the hyperventilation-induced CO2 reactivity of the basilar and middle cerebral arteries was studied in 10 healthy male volunteers (mean age, 25.2 ± 1.5 years) using a transcranial Doppler sonography with an interval of 1 week between measurements, and a portable ECG monitoring system was used to obtain ECG data simultaneously. The CO2 reactivity of the basilar and middle cerebral arteries increased significantly after ST36 acupuncture treatment, whereas the mean arterial blood pressure and pulse rate did not change significantly. The high-frequency power significantly increased after ST36 acupuncture treatment, and the percentage increase of high-frequency power correlated significantly with the percentage increase in the CO2 reactivity of the contralateral middle cerebral artery. These data suggest that ST36 acupuncture treatment increases CO2 reactivity, indicating improvement of vasodilatory potential of the cerebral vasculature to compensate for fluctuations caused by changes in external conditions. The increase in parasympathetic tone by ST36 acupuncture treatment is responsible for this therapeutic effect. PMID:25132861

  4. Matrix Metalloproteinase-12 Induces Blood-Brain Barrier Damage After Focal Cerebral Ischemia.

    PubMed

    Chelluboina, Bharath; Klopfenstein, Jeffrey D; Pinson, David M; Wang, David Z; Vemuganti, Raghu; Veeravalli, Krishna Kumar

    2015-12-01

    Matrix metalloproteinases (MMPs) have a central role in compromising the integrity of the blood-brain barrier (BBB). The role of MMP-12 in brain damage after ischemic stroke remains unknown. The main objective of the current study is to investigate the effect of MMP-12 suppression at an early time point before reperfusion on the BBB damage in rats. Sprague-Dawley rats were subjected to middle cerebral artery occlusion and reperfusion. MMP-12 shRNA-expressing plasmids formulated as nanoparticles were administered at a dose of 1 mg/kg body weight. The involvement of MMP-12 on BBB damage was assessed by performing various techniques, including Evans blue dye extravasation, 2,3,5-triphenyltetrazolium chloride staining, immunoblot, gelatin zymography, and immunofluorescence analysis. MMP-12 is upregulated ≈31-, 47-, and 66-fold in rats subjected 1-, 2-, or 4-hour ischemia, respectively, followed by 1-day reperfusion. MMP-12 suppression protected the BBB integrity by inhibiting the degradation of tight-junction proteins. Either intravenous or intra-arterial delivery of MMP-12 shRNA-expressing plasmid significantly reduced the percent Evans blue dye extravasation and infarct size. Furthermore, MMP-12 suppression reduced the endogenous levels of other proteases, such as tissue-type plasminogen activator and MMP-9, which are also known to be the key players involved in BBB damage. These results demonstrate the adverse role of MMP-12 in acute brain damage that occurs after ischemic stroke and, thereby, suggesting that MMP-12 suppression could be a promising therapeutic target for cerebral ischemia. © 2015 American Heart Association, Inc.

  5. Subfailure Overstretch Induces Persistent Changes in the Passive Mechanical Response of Cerebral Arteries

    PubMed Central

    Bell, E. David; Sullivan, Jacob W.; Monson, Kenneth L.

    2015-01-01

    Cerebral blood vessels are critical in maintaining the health of the brain, but their function can be disrupted by traumatic brain injury (TBI). Even in cases without hemorrhage, vessels are deformed with the surrounding brain tissue. This subfailure deformation could result in altered mechanical behavior. This study investigates the effect of overstretch on the passive behavior of isolated middle cerebral arteries (MCAs), with the hypothesis that axial stretch beyond the in vivo length alters this response. Twenty nine MCA sections from 11 ewes were tested. Vessels were subjected to a baseline test consisting of an axial stretch from a buckled state to 1.05* in vivo stretch (λIV) while pressurized at 13.3 kPa. Specimens were then subjected to a target level of axial overstretch between 1.05*λIV (λz = 1.15) and 1.52*λIV (λz = 1.63). Following overstretch, baseline tests were repeated immediately and then every 10 min, for 60 min, to investigate viscoelastic recovery. Injury was defined as an unrecoverable change in the passive mechanical response following overstretch. Finally, pressurized MCAs were pulled axially to failure. Post-overstretch response exhibited softening such that stress values at a given level of stretch were lower after injury. The observed softening also generally resulted in increased non-linearity of the stress-stretch curve, with toe region slope decreasing and large deformation slope increasing. There was no detectable change in reference configuration or failure values. As hypothesized, the magnitude of these alterations increased with overstretch severity, but only once overstretch exceeded 1.2*λIV (p < 0.001). These changes were persistent over 60 min. These changes may have significant implications in repeated TBI events and in increased susceptibility to stroke post-TBI. PMID:25674561

  6. Cerebral haemodynamic response to acute intracranial hypertension induced by head-down tilt.

    PubMed

    Bosone, Daniele; Ozturk, Vesile; Roatta, Silvestro; Cavallini, Anna; Tosi, Piera; Micieli, Giuseppe

    2004-01-01

    The aim of this study was to evaluate, in a context of general inhibition of the sympathetic nervous system, the cerebral haemodynamic response to -30 degrees head-down tilt (HDT), a manoeuvre that produces an increase in intracranial arterial pressure. Nineteen healthy subjects were studied according to the following protocol: 10 min lying in supine position, 10 min HDT, 10 min recovery. Inhibition of the sympathetic system was confirmed by the decrease in heart rate (-3.6 bpm) and arterial blood pressure (-5.9 mmHg, p<0.05) in the late phase of the test. Blood velocity and blood pusatility index initially increased (+3.2 cm s(-1) and +9% respectively, p<0.01) then returned towards baseline before the end of HDT, while the cerebrovascular resistance index (=arterial blood pressure/blood velocity) dropped significantly and remained below control level (-7%, p<0.01) throughout the test. The changes in both these indices were opposite to those reported in several sympathetic activation tests, such as the handgrip and cold pressor tests. Conversely, arterial pressure at cranial level increased during HDT (as it also does during sympathetic activation tests), due to the development of a hydrostatic pressure gradient between heart and brain levels. Therefore, the effects observed on the pulsatility and resistance indices are not secondary to the increase in intracranial arterial pressure. It is suggested that the changes in these cerebrovascular indices are mediated by a reduction of sympathetic tone that presumably involves the cerebral as well as the peripheral vascular bed.

  7. Reduction of β-radiation exposure during preparation of 188Re-labelled Lipiodol for hepatocellular carcinoma treatment.

    PubMed

    Lepareur, Nicolas; Laffont, Sophie; Ardisson, Valérie; Noiret, Nicolas; Garin, Etienne

    2012-02-01

    Rhenium-188 (188Re) is of widespread interest for treating various diseases because of its attractive physical and chemical properties. The routine preparation of therapeutic doses of 188Re-labelled tracers can result in significant radiation exposure to the operator. We studied the impact of automating the preparation of 188Re-Lipiodol on the radiochemist's exposure, as well as the importance of the model of syringe shielding. To monitor radiation exposure continuously readable electronic personal dosimeters were used. Thermoluminescence dosimeters were fixed to the probable most exposed fingers of the radiochemist during preparation of the radiotracer and during the syringing. Dose rates were measured using a Babyline. Automation of the synthesis reduced personal dose equivalents from 2.60±4.35 to 1.61±1.20 µSv/GBq [Hp(10)] and from 38.37±55.28 to 21.84±16.14 µSv/GBq [Hp(0.07)]. Dose to the extremities was also reduced (-80% for the right hand; -58% for the left one). The Lemer-Pax PSWG syringe shield led to a slightly lower dose to the hands compared with the Medisystem (1.1±0.27 vs. 1.34±0.6 mSv/GBq for the right finger). Automation of the synthesis leads to a significant decrease in radiation exposure to the operator. The Lemer-Pax PSWG syringe shield provides better hand protection than the smaller Medisystem Mediclic.

  8. Chemoembolization of unresectable hepatocellular carcinoma: Decreased toxicity with slow-release doxorubicin‑eluting beads compared with lipiodol.

    PubMed

    Recchia, Francesco; Passalacqua, Giovanni; Filauri, Pietro; Doddi, Marco; Boscarato, Pietro; Candeloro, Giampiero; Necozione, Stefano; Desideri, Giovambattista; Rea, Silvio

    2012-05-01

    Chemoembolization with lipiodol (TACE) improves survival of selected patients with unresectable hepatocellular carcinoma (HCC), but results in substantial toxicity. To improve treatment tolerance, we conducted this phase II study using doxorubicin-loaded beads (DC Beads®) delivered by selective transcatheter arterial chemoembolization (DEB-TACE). We compared the results with those obtained with TACE in our historical controls. Thirty-five patients were recruited with diagnoses of HCC. Patients received DEB-TACE with doxorubicin loaded on DC Beads. Computed tomography of the upper abdomen was performed one month after DEB-TACE. Historical controls were a group of 70 patients with matched characteristics treated with TACE. After a median follow-up of 14.1 months (range, 6-36 months), 22 patients (63%) had an objective response. There was a statistically significant decrease in liver enzymes (p<0.001), lactate dehydrogenase, (p<0.001) in DEB-TACE-treated patients compared to TACE-treated patients. DEB-TACE with doxorubicin-loaded DC Beads, a safe and reliable treatment for HCC, leads to decreased toxicity compared to TACE.

  9. Neuroprotective effects of focal brain cooling on photochemically-induced cerebral infarction in rats: analysis from a neurophysiological perspective.

    PubMed

    He, Yeting; Fujii, Masami; Inoue, Takao; Nomura, Sadahiro; Maruta, Yuichi; Oka, Fumiaki; Shirao, Satoshi; Owada, Yuji; Kida, Hiroyuki; Kunitsugu, Ichiro; Yamakawa, Toshitaka; Tokiwa, Tatsuji; Yamakawa, Takeshi; Suzuki, Michiyasu

    2013-02-25

    Although systemic hypothermia provides favorable outcomes in stroke patients, it has only been adopted in a limited number of patients because of fatal complications. To resolve these issues, focal brain cooling (FBC) has recently drawn attention as a less-invasive treatment for brain injuries. Therefore, we investigated whether FBC has a favorable effect on focal cerebral ischemia (FCI). Male-adult-Wistar rats were used. Under general anesthesia, a small burr hole was made and FCI was induced in the primary sensorimotor area (SI-MI) using photothrombosis. An additional craniotomy was made over the SI-MI and FBC was performed at a temperature of 15°C for 5h. Electrocorticograms (ECoG) were recorded on the border cortex of the ischemic focus. Thereafter, rats were sacrificed and the infarct area was measured. In another experiment, rats were allowed to recover for 5 days after cooling and neurobehavioral function was evaluated. FBC suppressed all ECoG frequency bands during and after cooling (p<0.05), except for the delta frequency band in the precooling versus rewarming periods. The injured areas in the cooling and non-cooling groups were 0.99±0.30 and 1.71±0.54 mm(2), respectively (p<0.03). The grip strength at 2 days after surgery was preserved in the cooling group (p<0.05). We report the novel finding that epileptiform discharges were suppressed in the ischemic border, the infarct area was reduced and neurobehaviour was preserved by FBC. These results indicate that FBC is neuroprotective in the ischemic brain and has demonstrated therapeutic potential for cerebral infarction. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Correlates of delayed neuronal damage and neuroprotection in a rat model of cardiac-arrest-induced cerebral ischemia.

    PubMed

    Li, M M; Payne, R S; Reid, K H; Tseng, M T; Rigor, B M; Schurr, A

    1999-04-24

    Numerous studies over the past three decades have used rodent models of cerebral ischemia. To measure the postischemic outcome, the majority of these studies used histopathology as the method of choice both quantitatively and qualitatively. No functional measure of postischemic outcome has been proved to correlate well with the histopathological one. The rat chest compression model of cardiac-arrest-induced global cerebral ischemia was used in the present study. Two separate measures of neuronal damage at 7 days postischemia were performed: (a) histologically, by counting normal pyramidal cell bodies in the mid-CA1 hippocampal region of the rat brain, in hematoxylin-eosin-stained, paraffin-embedded 6-microm sections, and (b) electrophysiologically, by counting the number of 400 microm hippocampal slices in which it was possible to evoke a normal (>/=10 mV) CA1 population spike by orthodromic stimulation of the Schaffer collaterals. The correlation between these two measures was tested in the following groups of rats: (a) control, untreated group, (b) MK-801-treated groups (0.03 to 1.0 mg/kg given i.p. shortly after ischemia), (c) diltiazem-treated (DILT) groups 1.0 to 30 mg/kg, given i.p. shortly after ischemia, and (d) a group treated with a combination of the two drugs together (0.1 mg/kg MK-801+3.0 mg/kg DILT given i.p. shortly after ischemia). The two measures of postischemic outcome were highly correlated in all groups studied. Both MK-801 and DILT exhibited a dose-dependent neuroprotective effect. When administered together, a synergy between the neuroprotective effect of MK-801 and DILT was observed. At the doses used, minimal or no side effects of either MK-801 or DILT were observed. Copyright 1999 Elsevier Science B.V.

  11. Changes in cerebral [(18)F]-FDG uptake induced by acute alcohol administration in a rat model of alcoholism.

    PubMed

    Gispert, Juan D; Figueiras, Francisca P; Vengeliene, Valentina; Herance, José R; Rojas, Santiago; Spanagel, Rainer

    2017-06-01

    Several [(18)F]-FDG positron emission tomography (PET) studies in alcoholics have consistently reported decreases in overall brain glucose metabolism at rest and following acute alcohol administration. However, changes in cerebral glucose utilization associated with the transition to addiction are not well understood and require longitudinal translational imaging studies in animal models of alcoholism. Here, we studied brain glucose uptake in alcohol drinking rats in order to provide convergent evidence to what has previously been reported in human studies. Brain glucose metabolism was measured by [(18)F]-FDG microPET imaging in different male Wistar rat groups: short-term drinking (three months), long-term drinking (twelve months) and alcohol-naïve. Global and regional cerebral glucose uptake was measured at rest and following acute alcohol administration. We showed that alcohol significantly reduced the whole-brain glucose metabolism. This effect was most pronounced in the parietal cortex and cerebellum. Alcohol-induced decreases in brain [(18)F]-FDG uptake was most apparent in alcohol-naïve rats, less intense in short-term drinkers and absent in long-term drinkers. The latter finding indicates the occurrence of tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrast, some regions, like the ventral striatum and entorhinal cortex, showed enhanced metabolic activity, an effect that did not undergo tolerance during long-term alcohol consumption. Our findings are comparable to those described in human studies using the same methodology. We conclude that [(18)F]-FDG PET studies in rat models of alcoholism provide good translation and can be used for future longitudinal studies investigating alterations in brain function during different stages of the addiction cycle. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Systemic administration of l-kynurenine sulfate induces cerebral hypoperfusion transients in adult C57Bl/6 mice.

    PubMed

    Varga, Dániel Péter; Menyhárt, Ákos; Puskás, Tamás; Bari, Ferenc; Farkas, Eszter; Kis, Zsolt; Vécsei, László; Toldi, József; Gellért, Levente

    2017-11-01

    The kynurenine pathway is a cascade of enzymatic steps generating biologically active compounds. l-kynurenine (l-KYN) is a central metabolite of tryptophan degradation. In the mammalian brain, l-KYN is partly converted to kynurenic acid (KYNA), which exerts multiple effects on neurotransmission. Recently, l-KYN or one of its derivatives were attributed a direct role in the regulation of the systemic circulation. l-KYN dilates arterial blood vessels during sepsis in rats, while it increases cerebral blood flow (CBF) in awake rabbits. Therefore, we hypothesized that acute elevation of systemic l-KYN concentration may exert potential effects on mean arterial blood pressure (MABP) and on resting CBF in the mouse brain. C57Bl/6 male mice were anesthetized with isoflurane, and MABP was monitored in the femoral artery, while CBF was assessed through the intact parietal bone with the aid of laser speckle contrast imaging. l-KYN sulfate (l-KYNs) (300mg/kg, i.p.) or vehicle was administered intraperitoneally. Subsequently, MABP and CBF were continuously monitored for 2.5h. In the control group, MABP and CBF were stable (69±4mmHg and 100±5%, respectively) throughout the entire data acquisition period. In the l-KYNs-treated group, MABP was similar to that, of control group (73±6mmHg), while hypoperfusion transients of 22±6%, lasting 7±3min occurred in the cerebral cortex over the first 60-120min following drug administration. In conclusion, the systemic high-dose of l-KYNs treatment destabilizes resting CBF by inducing a number of transient hypoperfusion events. This observation indicates the careful consideration of the dose of l-KYN administration by interpreting the effect of kynurenergic manipulation on brain function. By planning clinical trials basing on kynurenergic manipulation possible vascular side effects should also be considered. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Increased pressure-induced tone in rat parenchymal arterioles vs. middle cerebral arteries: role of ion channels and calcium sensitivity.

    PubMed

    Cipolla, Marilyn J; Sweet, Julie; Chan, Siu-Lung; Tavares, Matthew J; Gokina, Natalia; Brayden, Joseph E

    2014-07-01

    Brain parenchymal arterioles (PAs) are high-resistance vessels that branch off pial arteries and perfuse the brain parenchyma. PAs are the target of cerebral small vessel disease and have been shown to have greater pressure-induced tone at lower pressures than pial arteries. We investigated mechanisms by which brain PAs have increased myogenic tone compared with middle cerebral arteries (MCAs), focusing on differences in vascular smooth muscle (VSM) calcium and ion channel function. The amount of myogenic tone and VSM calcium was measured using Fura 2 in isolated and pressurized PAs and MCAs. Increases in intraluminal pressure caused larger increases in tone and cytosolic calcium in PAs compared with MCAs. At 50 mmHg, myogenic tone was 37 ± 5% for PAs vs. 6.5 ± 4% for MCAs (P < 0.01), and VSM calcium was 200 ± 20 nmol/l in PAs vs. 104 ± 15 nmol/l in MCAs (P < 0.01). In vessels permeabilized with Staphylococcus aureus α-toxin, PAs were not more sensitive to calcium, suggesting calcium sensitization was not at the level of the contractile apparatus. PAs were 30-fold more sensitive to the voltage-dependent calcium channel (VDCC) inhibitor nifedipine than MCAs (EC50 for PAs was 3.5 ± 0.4 vs. 82.1 ± 2.1 nmol/l for MCAs;P < 0.01); however, electrophysiological properties of the VDCC were not different in VSM. PAs had little to no response to the calcium-activated potassium channel inhibitor iberiotoxin, whereas MCAs constricted ∼15%. Thus increased myogenic tone in PAs appears related to differences in ion channel activity that promotes VSM membrane depolarization but not to a direct sensitization of the contractile apparatus to calcium.

  14. Salvia miltiorrhiza extract protects white matter and the hippocampus from damage induced by chronic cerebral hypoperfusion in rats.

    PubMed

    Kim, Min-Soo; Bang, Ji Hye; Lee, Jun; Kim, Hyeon Woo; Sung, Sang Hyun; Han, Jung-Soo; Jeon, Won Kyung

    2015-11-23

    Salvia miltiorrhiza (SM), an herbal plant, is traditionally used in the treatment of cardiovascular and cerebrovascular diseases in Asian countries. SM has multiple biological effects including anti-inflammatory activity. The present study is aimed at investigating the effects of SM extract in rats with chronic cerebral hypoperfusion. Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). The rats were divided into 3 groups: sham-control, BCCAo treated with vehicle, and BCCAo treated with SM extract. Vehicle or SM extract (200 mg/kg) were administered daily by oral gavage beginning on day 21 after BCCAo and continuing to day 42. Immunohistochemical analyses were used to measure Iba-1-positive microglia and myelin basic protein (MBP) in white matter and hippocampal tissue. In addition, the expression levels of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, and the toll-like receptor (TLR) pathway in the hippocampus, were analyzed by western blot. Administration of SM extract attenuated the activation of microglial cells in the white matter and hippocampus after BCCAo. SM extract also prevented neuroinflammation after BCCAo by reducing hippocampal levels of TNF-α, IL-1β, and IL-6, and increasing the reduced levels of MBP in the white matter and hippocampus. Further, the administration of SM extract alleviated the up-regulation of hippocampal TLR4 and myeloid differentiation primary response gene 88 (MyD88) in rats with chronic BCCAo. Our findings suggest that SM may be a promising therapeutic candidate in vascular dementia because of its protective effects against damage to the white matter and hippocampus after BCCAo.

  15. 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

  16. Up-regulation of ryanodine receptor expression increases the calcium-induced calcium release and spontaneous calcium signals in cerebral arteries from hindlimb unloaded rats.

    PubMed

    Morel, Jean-Luc; Dabertrand, Fabrice; Porte, Yves; Prevot, Anne; Macrez, Nathalie

    2014-08-01

    Microgravity induces a redistribution of blood volume. Consequently, astronauts' body pressure is modified so that the upright blood pressure gradient is abolished, thereby inducing a modification in cerebral blood pressure. This effect is mimicked in the hindlimb unloaded rat model. After a duration of 8 days of unloading, Ca2+ signals activated by depolarization and inositol-1,4,5-trisphosphate intracellular release were increased in cerebral arteries. In the presence of ryanodine and thapsigargin, the depolarization-induced Ca2+ signals remained increased in hindlimb suspended animals, indicating that Ca2+ influx and Ca2+-induced Ca2+ release mechanism were both increased. Spontaneous Ca2+ waves and localized Ca2+ events were also investigated. Increases in both amplitude and frequency of spontaneous Ca2+ waves were measured in hindlimb suspension conditions. After pharmacological segregation of Ca2+ sparks and Ca2+ sparklets, their kinetic parameters were characterized. Hindlimb suspension induced an increase in the frequencies of both Ca2+ localized events, suggesting an increase of excitability. Labeling with bodipy compounds suggested that voltage-dependent Ca2+ channels and ryanodine receptor expressions were increased. Finally, the expression of the ryanodine receptor subtype 1 (RyR1) was increased in hindlimb unloading conditions. Taken together, these results suggest that RyR1 expression and voltage-dependent Ca2+ channels activity are the focal points of the regulation of Ca2+ signals activated by vasoconstriction in rat cerebral arteries with an increase of the voltage-dependent Ca2+ influx.

  17. 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.

  18. 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 Central

    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. PMID:27922691

  19. Silver nanoparticles induced neurotoxicity through oxidative stress in rat cerebral astrocytes is distinct from the effects of silver ions.

    PubMed

    Sun, Cheng; Yin, Nuoya; Wen, Ruoxi; Liu, Wei; Jia, Yanxia; Hu, Ligang; Zhou, Qunfang; Jiang, Guibin

    2016-01-01

    The rapid development of silver nanoparticles (AgNPs) based products has raised increasing concerns in view of their potential hazardous risks to the environment and human health. The roles of the released silver ions in AgNPs induced cytotoxicities are being hotly debated. Using rat cerebral astrocytes, the neurotoxicological effects of AgNPs and silver ions were investigated. Acute toxicity based on Alamar Blue assay showed that silver ions were considerably more toxic than AgNPs. Comparative studies indicated that AgNPs increased caspase activities and induced cell apoptosis under cytotoxic level of exposures, while silver ions compromised cell membrane integrity and dominantly caused cell necrosis. Cellular internalization of silver provided the basis for the cytotoxicities of these two silver species. In contrast to silver ions, intracellular reactive oxygen species (ROS) generation occurred in time- and concentration-dependent manners in astrocytes upon AgNPs stimulation, which caused subsequent c-Jun N-terminal kinases (JNK) phosphorylation and promoted the programmed cell death. Non-cytotoxic level of AgNPs exposure increased multiple cytokines secretion from the astrocytes, indicating that AgNPs were potentially involved in neuroinflammation. This effect was independent of silver ions as well. The distinct toxicological effects caused by AgNPs and silver ions provided the solid proofs for the particle-specific effects which should be concerned regarding the accurate assessment of AgNPs exposure risks.

  20. Gallium nitride induces neuronal differentiation markers in neural stem/precursor cells derived from rat cerebral cortex.

    PubMed

    Chen, Chi-Ruei; Li, Yi-Chen; Young, Tai-Horng

    2009-09-01

    In the present study, gallium nitride (GaN) was used as a substrate to culture neural stem/precursor cells (NSPCs), isolated from embryonic rat cerebral cortex, to examine the effect of GaN on the behavior of NSPCs in the presence of basic fibroblast growth factor (bFGF) in serum-free medium. Morphological studies showed that neurospheres maintained their initial shape and formed many long and thick processes with the fasciculate feature on GaN. Immunocytochemical characterization showed that GaN could induce the differentiation of NSPCs into neurons and astrocytes. Compared to poly-d-lysine (PDL), the most common substrate used for culturing neurons, there was considerable expression of synapsin I for differentiated neurons on GaN, suggesting GaN could induce the differentiation of NSPCs towards the mature differentiated neurons. Western blot analysis showed that the suppression of glycogen synthase kinase-3beta (GSK-3beta) activity was one of the effects of GaN-promoted NSPC differentiation into neurons. Finally, compared to PDL, GaN could significantly improve cell survival to reduce cell death after long-term culture. These results suggest that GaN potentially has a combination of electric characteristics suitable for developing neuron and/or NSPC chip systems.

  1. Intranasal insulin improves cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV)-induced memory impaired rats.

    PubMed

    Rajasekar, N; Nath, Chandishwar; Hanif, Kashif; Shukla, Rakesh

    2017-03-15

    Insulin/insulin receptor signaling is involved in cognitive functions. Clinical studies have shown that intranasal insulin administration improves memory functions. However, the molecular mechanisms associated with improvement in memory functions are largely unexplored. Therefore, we investigated the protective effect of intranasal insulin in intracerebroventricular (ICV) streptozotocin (STZ) induced memory impairment in rats. Rats were injected with STZ (3mg/kg, ICV) bilaterally twice, on days 1 and 3 and intranasal insulin (2IU/rat/day) was given for 14days. Memory was assessed by Morris water maze test. Cerebral blood flow (CBF) was measured by laser-Doppler flowmetry. The biochemical and molecular studies were done in cortex and hippocampus of rat brain. STZ (ICV) administration caused memory impairment along with the reduction of CBF, ATP level, and Nrf-2 expression. Treatment with intranasal insulin significantly improved memory functions as well as restored CBF, ATP content and Nrf-2 expression in STZ injected rats. STZ administration stimulated oxidative-nitrosative stress as evidenced by a significant increase in ROS, malondialdehyde, NO level and inducible nitric oxide synthase expression and the decrease in glutathione level; which was normalized by intranasal insulin delivery. STZ-induced cholinergic dysfunction (AChE activity and α7-nAChR expression), and mitochondrial hypofunction was largely prevented by treatment with intranasal insulin. Intranasal insulin delivery successfully restored BDNF level and pCREB expression in STZ injected rats. The study shows the beneficial effects of intranasal insulin against STZ-induced memory impairment, which attributed to improved CBF, cholinergic function, brain energy metabolism, BDNF, Nrf-2 expression and antioxidative action. Copyright © 2016. Published by Elsevier Inc.

  2. Dietary nitrate facilitates an acetazolamide-induced increase in cerebral blood flow during visual stimulation.

    PubMed

    Aamand, Rasmus; Ho, Yi-Ching Lynn; Dalsgaard, Thomas; Roepstorff, Andreas; Lund, Torben E

    2014-02-01

    The carbonic anhydrase (CA) inhibitor acetazolamide (AZ) is used routinely to estimate cerebrovascular reserve capacity in patients, as it reliably increases cerebral blood flow (CBF). However, the mechanism by which AZ accomplishes this CBF increase is not entirely understood. We recently discovered that CA can produce nitric oxide (NO) from nitrite, and that AZ enhances this NO production in vitro. In fact, this interaction between AZ and CA accounted for a large part of AZ's vasodilatory action, which fits well with the known vasodilatory potency of NO. The present study aimed to assess whether AZ acts similarly in vivo in the human cerebrovascular system. Hence, we increased or minimized the dietary intake of nitrate in 20 healthy male participants, showed them a full-field flickering dartboard, and measured their CBF response to this visual stimulus with arterial spin labeling. Doing so, we found a significant positive interaction between the dietary intake of nitrate and the CBF modulation afforded by AZ during visual stimulation. In addition, but contrary to studies conducted in elderly participants, we report no effect of nitrate intake on resting CBF in healthy human participants. The present study provides in vivo support for an enhancing effect of AZ on the NO production from nitrite catalyzed by CA in the cerebrovascular system. Furthermore, our results, in combination with the results of other groups, indicate that nitrate may have significant importance to vascular function when the cerebrovascular system is challenged by age or disease.

  3. Cerebroprotective Effect of Moringa oleifera against Focal Ischemic Stroke Induced by Middle Cerebral Artery Occlusion

    PubMed Central

    Wattanathorn, Jintanaporn; Tong-Un, Terdthai; Muchimapura, Supaporn; Wannanon, Panakaporn; Jittiwat, Jinatta

    2013-01-01

    The protection against ischemic stroke is still required due to the limitation of therapeutic efficacy. Based on the role of oxidative stress in stroke pathophysiology, we determined whether Moringa oleifera, a plant possessing potent antioxidant activity, protected against brain damage and oxidative stress in animal model of focal stroke. M. oleifera leaves extract at doses of 100, 200 and 400 mg·kg−1 was orally given to male Wistar rats (300–350 g) once daily at a period of 2 weeks before the occlusion of right middle cerebral artery (Rt.MCAO) and 3 weeks after Rt.MCAO. The determinations of neurological score and temperature sensation were performed every 7 days throughout the study period, while the determinations of brain infarction volume, MDA level, and the activities of SOD, CAT, and GSH-Px were performed 24 hr after Rt.MCAO. The results showed that all doses of extract decreased infarction volume in both cortex and subcortex. The protective effect of medium and low doses of extract in all areas occurred mainly via the decreased oxidative stress. The protective effect of the high dose extract in striatum and hippocampus occurred via the same mechanism, whereas other mechanisms might play a crucial role in cortex. The detailed mechanism required further exploration. PMID:24367723

  4. An experimental study on laser-induced suturing of venous grafts in cerebral revascularization surgery

    NASA Astrophysics Data System (ADS)

    Puca, Alfredo; Albanese, Alessio; Esposito, Giuseppe; Maira, Giulio; Rossi, Giacomo; Pini, Roberto

    2005-04-01

    To test laser-assisted high flow bypass in cerebral revascularization procedures, we set up an experimental model on rabbits which included harvesting a jugular vein graft and its implantation on the common carotid artery through a double end-to-side anastomosis. The study was carried out on 25 New Zealand rabbits by performing on each animal the proximal anastomosis using conventional suturing, while the distal one was obtained by means of low-power diode laser welding in association with the topical application of Indocyanine Green (ICG) solution to enhance local absorption of the laser light. After the procedure, the animals were subjected to a follow-up from 2 to 9 days. Bypass patency was evaluated by means of Doppler study. The vascular segments were excised and evaluated by histological and immunohistochemical examinations. Utilization of the diode laser was associated with a substantial shortening of the operative time, as well as with a more active endothelial regeneration process at the anastomotic site.

  5. Cerebral microvascular rarefaction induced by whole brain radiation is reversible by systemic hypoxia in mice

    PubMed Central

    Warrington, Junie P.; Csiszar, Anna; Johnson, Daniel A.; Herman, Terence S.; Ahmad, Salahuddin; Lee, Yong Woo

    2011-01-01

    Whole brain radiation therapy (WBRT) leads to cognitive impairment in 40–50% of brain tumor survivors following treatment. Although the etiology of cognitive deficits post-WBRT remains unclear, vascular rarefaction appears to be an important component of these impairments. In this study, we assessed the effects of WBRT on the cerebrovasculature and the effects of systemic hypoxia as a potential mechanism to reverse the microvascular rarefaction. Transgenic mice expressing green fluorescent protein driven by the Acta2 (smooth muscle actin) promoter for blood vessel visualization were randomly assigned to control or radiated groups. Animals received a clinical series of 4.5 Gy WBRT two times weekly for 4 wk followed by 1 mo of recovery. Subsequently, mice were subjected to 11% (hypoxia) or 21% (normoxia) oxygen for 1 mo. Capillary density in subregions of the hippocampus revealed profound vascular rarefaction that persisted despite local tissue hypoxia. Nevertheless, systemic hypoxia was capable of completely restoring cerebrovascular density. Thus hippocampal microvascular rarefaction post-WBRT is not capable of stimulating angiogenesis and can be reversed by chronic systemic hypoxia. Our results indicate a potential shift in sensitivity to angiogenic stimuli and/or the existence of an independent pathway of regulating cerebral microvasculature. PMID:21186274

  6. Tetrahydrobiopterin in antenatal brain hypoxia-ischemia-induced motor impairments and cerebral palsy.

    PubMed

    Vasquez-Vivar, Jeannette; Shi, Zhongjie; Luo, Kehuan; Thirugnanam, Karthikeyan; Tan, Sidhartha

    2017-10-01

    Antenatal brain hypoxia-ischemia, which occurs in cerebral palsy, is considered a significant cause of motor impairments in children. The mechanisms by which antenatal hypoxia-ischemia causes brain injury and motor deficits still need to be elucidated. Tetrahydrobiopterin is an important enzyme cofactor that is necessary to produce neurotransmitters and to maintain the redox status of the brain. A genetic deficiency of this cofactor from mutations of biosynthetic or recycling enzymes is a well-recognized factor in the development of childhood neurological disorders characterized by motor impairments, developmental delay, and encephalopathy. Experimental hypoxia-ischemia causes a decline in the availability of tetrahydrobiopterin in the immature brain. This decline coincides with the loss of brain function, suggesting this occurrence contributes to neuronal dysfunction and motor impairments. One possible mechanism linking tetrahydrobiopterin deficiency, hypoxia-ischemia, and neuronal injury is oxidative injury. Evidence of the central role of the developmental biology of tetrahydrobiopterin in response to hypoxic ischemic brain injury, especially the development of motor deficits, is discussed. Copyright © 2017. Published by Elsevier B.V.

  7. Chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis causes selective recognition impairment in adult mice.

    PubMed

    Patel, Arati; Moalem, Alimohammad; Cheng, Hank; Babadjouni, Robin M; Patel, Kaleena; Hodis, Drew M; Chandegara, Deep; Cen, Steven; He, Shuhan; Liu, Qinghai; Mack, William J

    2017-10-01

    Chronic cerebral hypoperfusion (CCH) can result in vascular dementia and small vessel white matter ischemic injury. These findings have previously been demonstrated in a murine experimental model of CCH secondary to bilateral common carotid artery stenosis (BCAS). This study sought to elucidate the effects of CCH on recognition memory as assessed by the novel object recognition (NOR) test and histological analysis of the hippocampus and perirhinal cortex. Studies were performed on ten-week-old male mice using bilateral 0.18 mm microcoils to narrow the carotid arteries in accordance with prior publications. Following surgery, BCAS (n = 6) and sham (n = 6) mice were evaluated using NOR and 8-arm radial maze testing paradigms. Tissue damage was assessed using H&E staining on a parallel cohort of mice (n = 6 BCAS, n = 7 sham). In the NOR paradigm, BCAS mice demonstrated significant deficits in short-term memory. Consistent with prior studies, BCAS mice also performed significantly worse on 8-arm radial maze testing. BCAS mice exhibited significantly more neuronal injury in the perirhinal cortex when compared to sham-operated mice. However, no significant differences in neuronal damage were observed in the CA1 region of the hippocampus. Experimental CCH secondary to BCAS results in recognition memory deficits on NOR testing. Damage to the perirhinal cortex, rather than to the hippocampus, may underlie this impairment.

  8. Computer-aided detection of radiation-induced cerebral microbleeds on susceptibility-weighted MR images☆

    PubMed Central

    Bian, Wei; Hess, Christopher P.; Chang, Susan M.; Nelson, Sarah J.; Lupo, Janine M.

    2013-01-01

    Recent interest in exploring the clinical relevance of cerebral microbleeds (CMBs) has motivated the search for a fast and accurate method to detect them. Visual inspection of CMBs on MR images is a lengthy, arduous task that is highly prone to human error because of their small size and wide distribution throughout the brain. Several computer-aided CMB detection algorithms have recently been proposed in the literature, but their diagnostic accuracy, computation time, and robustness are still in need of improvement. In this study, we developed and tested a semi-automated method for identifying CMBs on minimum intensity projected susceptibility-weighted MR images that are routinely used in clinical practice to visually identify CMBs. The algorithm utilized the 2D fast radial symmetry transform to initially detect putative CMBs. Falsely identified CMBs were then eliminated by examining geometric features measured after performing 3D region growing on the potential CMB candidates. This algorithm was evaluated in 15 patients with brain tumors who exhibited CMBs on susceptibility-weighted images due to prior external beam radiation therapy. Our method achieved heightened sensitivity and acceptable amount of false positives compared to prior methods without compromising computation speed. Its superior performance and simple, accelerated processing make it easily adaptable for detecting CMBs in the clinic and expandable to a wide array of neurological disorders. PMID:24179783

  9. [Intraventricular yohimbine infusion induces noradrenergic changes in motor cerebral injured rats and enhances motor recovery].

    PubMed

    González-Piña, Rigoberto; Alfaro-Rodríguez, Alfonso; Bueno-Nava, Antonio; Ávila-Luna, Alberto

    2013-01-01

    It has been proposed that noradrenaline is one of the neurotransmitters involved in the functional recovery. In this sense, it has been proposed that the alpha-2 noradrenergic receptors play an important role in the functional reinstatement. the aim of this work was to study the role of the alpha-2 noradrenergic receptors on the noradrenaline contents in cerebellum and pons of rats iron-injured in the motor cortex. Fifteen male Wistar rats were allocated in three groups: control (n = 5) with intracortical infusion of saline (0.9%), injured (n = 5) with intracortical infusion of dextran iron and intraventricular infusion of saline, and injured + yohimbine (alpha-2 receptor antagonist; n = 5) that received an intracortical infusion of dextran iron and also an intraventricular infusion of yohimbine. Motor behavior was assessed by means of the beam-walking paradigm. Three days after surgeries, the animals were sacrificed and the left and right sides of the pons and the cerebellar hemispheres were extracted. Tissues were prepared for noradrenaline analysis by means of high performance liquid chromatography. We observed that the yohimbine-treated animals had a noradrenaline increase in the right side of the pons and a decrease in the right cerebellar hemisphere. It is concluded that the blockage of the alpha-2 receptors leads to an increase of noradrenaline in the locus coeruleus, which retards the effects of the cerebral injury.

  10. Local cerebral hyperthermia induces spontaneous thrombosis and arteriolar constriction in the pia mater of the mouse

    NASA Astrophysics Data System (ADS)

    El-Sabban, Farouk; Fahim, Mohamed A.

    1995-06-01

    The effect of local cerebral hyperthermia on responses of pial microvessels of the mouse was investigated. A set protocol was followed, involving the performance of a craniotomy on anaesthetized animals and using intravital microscope-television closed circuitry. Controlled hyperthermic exposure was applied regionally by heating the brain surface with irrigating artificial cerebrospinal fluid. Microvascular responses such as changes in diameter, thrombosis and embolism were monitored and video-taped observations were further viewed and analysed. When both brain surface and core body temperatures were kept at 37° C, no changes in pial microvessels were noted. With core body temperature kept at 37° C and at a brain surface temperature of 43.1° C, passing emboli and arteriolar constriction were observed. A few minutes later, visible thrombosis was prevalent. Further spontaneous thrombo-embolic activity continued and at the end of a 50-min hyperthermic exposure, arterioles attained a constriction of 37%. Thrombus formation was sometimes massive enough to occlude fully the microvessel. The protocol followed in this study can be adopted to other small animal species and for a variety of experimental procedures involving hyperthermia and the pial microcirculation.

  11. Cerebroprotective effect of Moringa oleifera against focal ischemic stroke induced by middle cerebral artery occlusion.

    PubMed

    Kirisattayakul, Woranan; Wattanathorn, Jintanaporn; Tong-Un, Terdthai; Muchimapura, Supaporn; Wannanon, Panakaporn; Jittiwat, Jinatta

    2013-01-01

    The protection against ischemic stroke is still required due to the limitation of therapeutic efficacy. Based on the role of oxidative stress in stroke pathophysiology, we determined whether Moringa oleifera, a plant possessing potent antioxidant activity, protected against brain damage and oxidative stress in animal model of focal stroke. M. oleifera leaves extract at doses of 100, 200 and 400 mg·kg(-1) was orally given to male Wistar rats (300-350 g) once daily at a period of 2 weeks before the occlusion of right middle cerebral artery (Rt.MCAO) and 3 weeks after Rt.MCAO. The determinations of neurological score and temperature sensation were performed every 7 days throughout the study period, while the determinations of brain infarction volume, MDA level, and the activities of SOD, CAT, and GSH-Px were performed 24 hr after Rt.MCAO. The results showed that all doses of extract decreased infarction volume in both cortex and subcortex. The protective effect of medium and low doses of extract in all areas occurred mainly via the decreased oxidative stress. The protective effect of the high dose extract in striatum and hippocampus occurred via the same mechanism, whereas other mechanisms might play a crucial role in cortex. The detailed mechanism required further exploration.

  12. [Prothrombotic states and cerebral ischemia].

    PubMed

    Barinagarrementeria, F; González-Duarte, A; Cantú-Brito, C

    1998-01-01

    Hematological disorders per se represent unusual causes of cerebral ischemia, explaining in young people 4% of strokes. Hematological disorders that induce a thrombotic tendency contribute to overall ischemic stroke risk and may directly cause cerebral ischemia in patients without other risk factors. The frequency of cerebral infarctions caused by prothrombotic states is not known. This review will focus on disorders such as prothrombotic coagulopaties, including resistance to activated protein C and antiphospholipid syndrome as cause of cerebral infarction. Cerebral venous thrombosis and cerebral infarction from arterial origin are the most common form of neurological involvement. Pathophysiological mechanism of stroke in these patients are multiple and can include as in antiphospholipid syndrome embolism from valves abnormalities related to hematological disturbance, as well as thrombosis of extracranial or intracranial vessels. Is clear, however, that prothrombotic states could explains a high percentage of cases of those so called cryptogenic cerebral infarction in young people.

  13. Cerebral Aneurysms

    MedlinePlus

    ... cerebral aneurysm may be required to restore deteriorating respiration and reduce abnormally high pressure within the brain. ... cerebral aneurysm may be required to restore deteriorating respiration and reduce abnormally high pressure within the brain. ...

  14. Cerebral Palsy

    MedlinePlus

    ... ol (Spanish) Recommend on Facebook Tweet Share Compartir Cerebral palsy (CP) is a group of disorders that affect ... resource—it highlights the ADDM Network’s data on cerebral palsy in a way that is useful for stakeholders ...

  15. Cerebral Palsy

    MedlinePlus

    Cerebral palsy is a group of disorders that affect a person's ability to move and to maintain balance ... do not get worse over time. People with cerebral palsy may have difficulty walking. They may also have ...

  16. Acute simvastatin treatment restores cerebral functional capillary density and attenuates angiotensin II-induced microcirculatory changes in a model of primary hypertension.

    PubMed

    Freitas, Felipe; Estato, Vanessa; Reis, Patricia; Castro-Faria-Neto, Hugo C; Carvalho, Vinícius; Torres, Rafael; Lessa, Marcos A; Tibiriçá, Eduardo

    2017-09-02

    We investigated the acute effects of simvastatin on cerebral microvascular rarefaction and dysfunction in spontaneously hypertensive rats (SHRs). Male Wistar Kyoto rats (WKY) and SHRs were divided into 4 groups of 8 animals each: WKY-CTL and SHR-CTL, treated with 0.9% saline; and WKY+SIM and SHR+SIM, treated with simvastatin (30 mg/kg/day) for 3 days by gavage. Cerebral functional capillary density (FCD) was assessed by intravital fluorescence videomicroscopy. Microvascular cerebral blood flow (mCBF) before and after administration within the cranial window of angiotensin II (1 μM) was investigated using laser speckle contrast imaging. Cerebral FCD was reduced in SHR-CTL compared to WKY-CTL (p<0.05). Simvastatin increased cerebral FCD in SHRs compared to SHR-CTL (p<0.05). The mCBF was reduced in SHR-CTL compared to WKY-CTL (p<0.05), and simvastatin increased mCBF compared with SHR-CTL (p<0.05). Angiotensin II elicited a reduction of mCBF in SHR-CTL and increased mCBF in WKY-CTL (SHR-CTL -13.53±2% vs. WKY-CTL +13.74±4%; p<0.001), which was attenuated in SHRs treated with simvastatin (SHR+SIM -6.7±1% vs. SHR-CTL -13.53±2%; p<0.01). The antihypertensive effect of simvastatin is associated with an improvement in cerebral microvascular perfusion and capillary density that may help to prevent hypertension-induced cerebrovascular damage independent of cholesterol lowering. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  17. Hypoxia-inducible factor and vascular endothelial growth factor are expressed more frequently in embolized than in nonembolized cerebral arteriovenous malformations.

    PubMed

    Sure, Ulrich; Battenberg, Elmar; Dempfle, Astrid; Tirakotai, Wuttipong; Bien, Siegfried; Bertalanffy, Helmut

    2004-09-01

    In previous studies, we documented a marked neoangiogenesis and endothelial proliferation in cerebral arteriovenous malformations (AVMs) that were embolized before surgery compared with those that were not embolized. We hypothesized that embolization caused a local hypoxia that promotes neoangiogenesis as a possible pathomechanism. To support this hypothesis, we now examined the angiogenesis-related proteins in a larger cohort of patients. In addition, we investigated hypoxia-inducible factor-1 alpha as a possible protein operative during neoangiogenesis of cerebral AVMs. Paraffin-embedded specimens of 56 AVMs obtained from surgical resection and 14 brain tissue controls were immunohistochemically stained with antibodies to proliferating cell nuclear antigen, MIB-1, vascular endothelial growth factor, Flk1, and hypoxia-inducible factor-1 alpha by standard protocols. In AVMs treated with embolization before surgery (n = 35, 63%), the expression of hypoxia-inducible factor-1 alpha (P = 0.0101) and vascular endothelial growth factor (P = 0.0007) was significantly higher (Fisher's exact test) than in patients who did not have previous endovascular treatment. Differences in the expression of Flk-1 (P = 0.0798) and proliferating cell nuclear antigen (P = 0.0423) were in the same direction but were not significant when corrected for multiple testing. Our results provide circumstantial evidence that a partial occlusion of cerebral AVMs might induce local hypoxia-related neoangiogenesis. To support these data, future animal studies should be performed.

  18. Ventricular fibrillation-induced cardiac arrest in the rat as a model of global cerebral ischemia

    PubMed Central

    Dave, Kunjan R.; Della-Morte, David; Saul, Isabel; Prado, Ricardo; Perez-Pinzon, Miguel A.

    2013-01-01

    Cardiopulmonary arrest remains one of the leading causes of death and disability in Western countries. Although ventricular fibrillation (VF) models in rodents mimic the “square wave” type of insult (rapid loss of pulse and pressure) commonly observed in adult humans at the onset of cardiac arrest (CA), they are not popular because of the complicated animal procedure, poor animal survival and thermal injury. Here we present a modified, simple, reliable, ventricular fibrillation-induced rat model of CA that will be useful in studying mechanisms of CA-induced delayed neuronal death as well as the efficacy of neuroprotective drugs. CA was induced in male Sprague Dawley rats using a modified method of von Planta et al. In brief, VF was induced in anesthetized, paralyzed, mechanically ventilated rats by an alternating current delivered to the entrance of the superior vena cava into the heart. Resuscitation was initiated by administering a bolus injection of epinephrine and sodium bicarbonate followed by mechanical ventilation and manual chest compressions and countershock with a 10-J DC current. Neurologic deficit score was higher in the CA group compared to the sham group during early reperfusion periods, suggesting brain damage. Significant damage in CA1 hippocampus (21% normal neurons compared to control animals) was observed following histopathological assessment at seven days of reperfusion. We propose that this method of VF-induced CA in rat provides a tool to study the mechanism of CA-induced neuronal death without compromising heart functions. PMID:24187598

  19. Repeated edaravone treatment reduces oxidative cell damage in rat brain induced by middle cerebral artery occlusion.

    PubMed

    Yamamoto, Yorihiro; Yanagisawa, Makoto; Tak, Nyou Wei; Watanabe, Kazutoshi; Takahashi, Chizuko; Fujisawa, Akio; Kashiba, Misato; Tanaka, Masahiko

    2009-01-01

    The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) has been used to treat acute brain infarction in Japan since 2001. To obtain direct evidence that edaravone serves as an antioxidant in vivo, four groups of rats were prepared: (i) an ischemia/reperfusion (I/R) group receiving 2 h occlusion-reperfusion of the middle cerebral artery; (ii) a single administration group treated by intravenous infusion of edaravone (3 mg/kg) immediately after I/R; (iii) a repeated treatment group receiving twice daily edaravone administration for 14 days; and (iv) a sham operation group without occlusion. Repeated treatment with edaravone significantly improved the neurological symptoms and impairment of motor function as compared to the I/R group, while single administration demonstrated limited efficacy. No significant differences in plasma antioxidants such as ascorbate, urate, and vitamin E, or in redox status of coenzyme Q(9) were observed among the four groups. In contrast, the plasma content of oleic acid in the total free fatty acids (percentage 18:1) was significantly increased in the I/R group for 7 days as compared to the sham operation group. Oleic acid was produced from stearic acid by the action of stearoyl-CoA desaturase to compensate for the oxidative loss of polyunsaturated fatty acids. The above results suggest that cellular oxidative damage in the rat brain is evident for at least 7 days after I/R. Repeated treatment suppressed the percentage 18:1 increment, while the single administration did not, which is consistent with the limited efficacy of single administration.

  20. Effects of ellagic acid pretreatment on renal functions disturbances induced by global cerebral ischemic-reperfusion in rat

    PubMed Central

    Nejad, Khojasteh Hoseiny; Gharib-Naseri, Mohammad Kazem; Sarkaki, Alireza; Dianat, Mahin; Badavi, Mohammad; Farbood, Yaghoub

    2017-01-01

    Objective(s): Global cerebral ischemia-reperfusion (GCIR) causes disturbances in brain functions as well as other organs such as kidney. Our aim was to evaluate the protective effects of ellagic acid (EA) on certain renal disfunction after GCIR. Materials and Methods: Adult male Wistar rats (n=32, 250-300 g) were used. GCIR was induced by bilateral vertebral and common carotid arteries occlusion (4-VO). Animal groups were: 1) received DMSO/saline (10%) as solvent of EA, 2) solvent + GCIR, 3) EA + GCIR, and 4) EA. Under anesthesia with ketamine/xylazine, GCIR was induced (20 and 30 min respectively) in related groups. EA (100 mg/kg, dissolved in DMSO/saline (10%) or solvent was administered (1.5 ml/kg) orally for 10 consecutive days to the related groups. EEG was recorded from NTS in GCIR treated groups. Results: Our data showed that: a) EEG in GCIR treated groups was flattened. b) GCIR reduced GFR (P<0.01) and pretreatment with EA attenuated this reduction. c) BUN was increased by GCIR (P<0.001) and pretreatment with EA improved the BUN to normal level. d) Serum creatinine concentration was elevated by GCIR but not significantly, however, in EA+GCIR group serum creatinine was reduced (P<0.05). e) GCIR induced proteinuria (P<0.05) but, EA was unable to reduced proteinuria. Conclusion: Results indicate that GCIR impairs certain renal functions and EA as an antioxidant can improve these functions. Our results suggest the possible usefulness of ellagic acid in patients with brain stroke. PMID:28133528

  1. Effects of ellagic acid pretreatment on renal functions disturbances induced by global cerebral ischemic-reperfusion in rat.

    PubMed

    Nejad, Khojasteh Hoseiny; Gharib-Naseri, Mohammad Kazem; Sarkaki, Alireza; Dianat, Mahin; Badavi, Mohammad; Farbood, Yaghoub

    2017-01-01

    Global cerebral ischemia-reperfusion (GCIR) causes disturbances in brain functions as well as other organs such as kidney. Our aim was to evaluate the protective effects of ellagic acid (EA) on certain renal disfunction after GCIR. Adult male Wistar rats (n=32, 250-300 g) were used. GCIR was induced by bilateral vertebral and common carotid arteries occlusion (4-VO). Animal groups were: 1) received DMSO/saline (10%) as solvent of EA, 2) solvent + GCIR, 3) EA + GCIR, and 4) EA. Under anesthesia with ketamine/xylazine, GCIR was induced (20 and 30 min respectively) in related groups. EA (100 mg/kg, dissolved in DMSO/saline (10%) or solvent was administered (1.5 ml/kg) orally for 10 consecutive days to the related groups. EEG was recorded from NTS in GCIR treated groups. Our data showed that: a) EEG in GCIR treated groups was flattened. b) GCIR reduced GFR (P<0.01) and pretreatment with EA attenuated this reduction. c) BUN was increased by GCIR (P<0.001) and pretreatment with EA improved the BUN to normal level. d) Serum creatinine concentration was elevated by GCIR but not significantly, however, in EA+GCIR group serum creatinine was reduced (P<0.05). e) GCIR induced proteinuria (P<0.05) but, EA was unable to reduced proteinuria. Results indicate that GCIR impairs certain renal functions and EA as an antioxidant can improve these functions. Our results suggest the possible usefulness of ellagic acid in patients with brain stroke.

  2. On tracking the course of cerebral oxygen saturation and pilot performance during gravity-induced loss of consciousness.

    PubMed

    Tripp, Lloyd D; Warm, Joel S; Matthews, Gerald; Chiu, Peter Y; Bracken, R Bruce

    2009-12-01

    The aim of this study was to track the course of cerebral tissue oxygen saturation (rSO2) and pilot performance during an episode of gravity-induced loss of consciousness (GLOC). GLOC, a major problem facing pilots of high-performance aircraft, is brought about by a sudden reduction in rSO2 as a result of increased +Gz force. It consists of 24 s of complete functional impairment followed by a prolonged period of performance recovery. This study tested the hypothesis that delayed recovery in GLOC is caused by a slow return of rSO2 following removal of the g-force that induced the episode. GLOC was induced in U.S. Air Force personnel via a centrifuge with math and tracking tasks emulating flight performance. A near-infrared spectroscopy unit provided the rSO2 measure. Declines in rSO2 from baseline pinpointed when pilots would cease active flight control and when GLOC would set in. Counter to expectation, rSO2 returned to baseline levels shortly after the centrifuge came to a complete stop following GLOC onset. Nevertheless, performance deficits continued for 49.45 s thereafter. The prolonged performance recovery time in GLOC cannot be attributed to delays in the return of rSO2. This finding explains why previous ergonomic efforts to shorten the duration of GLOC episodes by increasing the rate of return of rSO2 have not been fruitful. Evidently, another approach is needed. Such an approach might use the close linkage between loss of rSO2, performance deterioration, and GLOC onset to develop a warning system that would permit pilots to take effective action to avoid GLOC incapacitation.

  3. Radiation-Induced Changes in Normal-Appearing White Matter in Patients With Cerebral Tumors: A Diffusion Tensor Imaging Study

    SciTech Connect

    Nagesh, Vijaya Tsien, Christina I.; Chenevert, Thomas L.; Ross, Brian D.; Lawrence, Theodore S.; Junick, Larry; Cao Yue

    2008-03-15

    Purpose: To quantify the radiation-induced changes in normal-appearing white matter before, during, and after radiotherapy (RT) in cerebral tumor patients. Methods and Materials: Twenty-five patients with low-grade glioma, high-grade glioma, or benign tumor treated with RT were studied using diffusion tensor magnetic resonance imaging. The biologically corrected doses ranged from 50 to 81 Gy. The temporal changes were assessed before, during, and to 45 weeks after the start of RT. The mean diffusivity of water (), fractional anisotropy of diffusion, diffusivity perpendicular ({lambda}{sub perpendicular}) and parallel ({lambda}{sub parallel}) to white matter fibers were calculated in normal-appearing genu and splenium of the corpus callosum. Results: In the genu and splenium, fractional anisotropy decreased and , {lambda}{sub parallel}, {lambda}{sub -perpendicular} increased linearly and significantly with time (p < 0.01). At 45 weeks after the start of RT, {lambda}{sub -perpendicular} had increased {approx}30% in the genu and splenium, and {lambda}{sub parallel} had increased 5% in the genu and 9% in the splenium, suggesting that demyelination is predominant. The increases in {lambda}{sub perpendicular} and {lambda}{sub parallel} were dose dependent, starting at 3 weeks and continuing to 32 weeks from the start of RT. The dose-dependent increase in {lambda}{sub perpendicular} and {lambda}{sub parallel} was not sustained after 32 weeks, indicating the transition from focal to diffuse effects. Conclusion: The acute and subacute changes in normal-appearing white matter fibers indicate radiation-induced demyelination and mild structural degradation of axonal fibers. The structural changes after RT are progressive, with early dose-dependent demyelination and subsequent diffuse dose-independent demyelination and mild axonal degradation. Diffusion tensor magnetic resonance imaging is potentially a biomarker for the assessment of radiation-induced white matter injury.

  4. Chronic cerebral hypoperfusion induces long-lasting cognitive deficits accompanied by long-term hippocampal silent synapses increase in rats.

    PubMed

    Wang, Zhiqiang; Fan, Jin; Wang, Jian; Li, Yuxia; Duan, Dan; Du, Guo; Wang, Qingsong

    2016-03-15

    Synaptic dysfunction underlies cognitive deficits induced by chronic cerebral hypoperfusion (CCH). There are silent synapses in neural circuits, but the effect of CCH on silent synapses is unknown. The present study was designed to explore learning and memory deficits and dynamic changes in silent synapses by direct visualization in a rat model of CCH. Adult male Sprague-Dawley rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) to reproduce CCH. Learning and memory effects were examined at 1, 4, 12, and 24 weeks after BCCAO. In addition, immunofluorescent confocal microscopy was used to detect AMPA and N-methyl-d-aspartate receptors colocalized with synaptophysin, and Golgi-Cox staining was used to observe dendritic spine density. We found that BCCAO rats exhibited recognition memory deficits from 4 weeks; spatial learning and memory, as well as working memory impairment began at 1 week and persistent to 24 weeks after surgery. Following BCCAO, the percentage of silent synapses increased by 29.81-55.08% compared with the controls at different time points (P<0.001). Compared with control groups, dendritic spine density in the CA1 region of BCCAO groups significantly decreased (P<0.001). Thus, the present study suggests that CCH can induce long-lasting cognitive deficits and long-term increase in the number of silent synapses. Furthermore, the decrease in dendritic spine density was correlated with the decrease in the number of functional synapses. The results suggest a potential mechanism by which CCH can induce learning and memory deficits.

  5. cPKCγ membrane translocation is involved in herkinorin‑induced neuroprotection against cerebral ischemia/reperfusion injury in mice.

    PubMed

    Gui, Xiaochen; Cui, Xu; Wei, Haiping; Feng, Guang; Zhang, Xuezheng; He, Yongjin; Li, Junfa; Li, Tianzuo

    2017-01-01

    Herkinorin is an opiate analgesic with limited adverse effects, functioning as a primary selective atypical opioid µ agonist. The present study aimed to identify whether herkinorin has a positive effect on ischemic/reperfusion (I/R) injury. Adult male C57BL/6 mice were randomly divided into five groups: i) Naïve, ii) sham, iii) I/R, iv) I/R with dimethyl sulfoxide (I/R+D) and v) I/R with herkinorin (I/R+H). The I/R injury model was induced by occluding the middle cerebral artery for 1 h followed by 24 h or 7 days of reperfusion. Neurobehavioral scores and sensorimotor functions were examined 24 h and 7 days following reperfusion. In addition, infarct volumes were examined at these time points using a 2,3,5‑triphenyltetrazolium chloride assay. Herkinorin treatment improved neurobehavioral and sensorimotor functional recovery from I/R‑induced brain injury. There was a significant decrease in infarct volume in the I/R+H group at 24 h or 7 days following reperfusion compared with the I/R and I/R+D groups. Western blotting suggested that the decrease in conventional protein kinase C γ (cPKCγ) membrane translocation in the peri‑infarct region may be attenuated by herkinorin pretreatment. These results indicated that herkinorin may be beneficial in I/R‑induced mouse brain injury, and this may be attributed to the membrane translocation of cPKCγ following activation.

  6. Facilitation handlings induce increase in electromyographic activity of muscles involved in head control of cerebral palsy children.

    PubMed

    Simon, Anelise de Saldanha; do Pinho, Alexandre Severo; Grazziotin Dos Santos, Camila; Pagnussat, Aline de Souza

    2014-10-01

    This study aimed to investigate the electromyographic (EMG) activation of the main cervical muscles involved in the head control during two postures widely used for the facilitation of head control in children with Cerebral Palsy (CP). A crossover trial involving 31 children with clinical diagnosis of CP and spastic quadriplegia was conducted. Electromyography was used to measure muscular activity in randomized postures. Three positions were at rest: (a) lateral decubitus, (b) ventral decubitus on the floor and (c) ventral decubitus on the wedge. Handlings for facilitating the head control were performed using the hip joint as key point of control in two postures: (a) lateral decubitus and (b) ventral decubitus on wedge. All children underwent standardized handlings, performed by the same researcher with experience in the neurodevelopmental treatment. EMG signal was recorded from muscles involved in the head control (paraspinal and sternocleidomastoid muscles) in sagittal, frontal and transverse planes, at the fourth cervical vertebra (C4), tenth thoracic vertebra (T10) and sternocleidomastoid muscle (SCM) levels. The results showed a significant increase in muscle activation when handling was performed in the lateral decubitus at C4 (P<0.001), T10 (P<0.001) and SCM (P=0.02) levels. A significant higher muscle activation was observed when handling was performed in lateral decubitus when compared to ventral decubitus at C4 level (P<0.001). Handling in ventral decubitus also induced an increase in EMG activation at T10 (P=0.018) and SCM (P=0.004) levels but not at C4 level (P=0.38). In conclusion, handlings performed in both positions may induce the facilitation of head control, as evaluated by the activity of cervical and upper trunk muscles. Handling performed in lateral decubitus may induce a slightly better facilitation of head control. These findings contribute to evidence-based physiotherapy practice for the rehabilitation of severely spastic quadriplegic CP

  7. Simultaneous Imaging of Radiation-Induced Cerebral Microbleeds, Arteries and Veins, Using a Multiple Gradient Echo Sequence at 7 Tesla

    PubMed Central

    Bian, Wei; Banerjee, Suchandrima; Kelly, Douglas A.C.; Hess, Christopher P.; Larson, Peder E.Z.; Chang, Susan M.; Nelson, Sarah J.; Lupo, Janine M.

    2016-01-01

    Background The purpose of this study was to implement and evaluate the utility of a multi-echo sequence at 7 Tesla (T) for simultaneous time-of-flight (TOF) MR-angiography (MRA) and susceptibility-weighted imaging (SWI) of radiation-induced cerebral microbleeds (CMBs), intracranial arteries, and veins. Methods A four-echo gradient-echo sequence was implemented on a 7T scanner. The first echo was used to create TOF-MRA images, while the remaining echoes were combined to visualize CMBs and veins on SWI images. The sequence was evaluated on eight brain tumor patients with known radiation-induced CMBs. Single-echo images were also acquired to visually and quantitatively compare the contrast-to-noise ratio (CNR) of small- and intermediate-vessels between acquisitions. The number of CMBs detected with each acquisition was also quantified. Statistical significance was determined using a Wilcoxon signed-rank test. Results Compared with the single-echo sequences, the CNR of small and intermediate arteries increased 7.6% (P < 0.03) and 9.5% (P = 0.06), respectively, while the CNR of small and intermediate veins were not statistically different between sequences (P = 0.95 and P = 0.46, respectively). However, these differences were not discernible by visual inspection. Also the multi-echo sequence detected 18.3% more CMBs (P < 0.008) due to higher slice resolution. Conclusion The proposed 7T multi-echo sequence depicts arteries, veins, and CMBs on a single image to facilitate quantitative evaluation of radiation-induced vascular injury. PMID:25471321

  8. Changes in serum iodine concentration, urinary iodine excretion and thyroid function after hysterosalpingography using an oil-soluble iodinated contrast medium (lipiodol).

    PubMed

    Kaneshige, Terumi; Arata, Naoko; Harada, Shohei; Ohashi, Toshinori; Sato, Shiori; Umehara, Nagayoshi; Saito, Takakazu; Saito, Hidekazu; Murashima, Atsuko; Sago, Haruhiko

    2015-03-01

    Reports of hypothyroidism after hysterosalpingography (HSG) using lipiodol are emerging. The present study was designed to investigate the changes in serum iodine concentration (SIC), urinary iodine concentration/creatinine excretion (UI/Cr), and thyroid function before and after HSG using lipiodol. The prospective observation study included 22 infertile euthyroid women with no previous history of thyroid disease. All underwent HSG between April 2007 and August 2008 at our institution. We examined SIC, UI/Cr, and thyroid function before HSG, and at 4, 8, 12, and 24 weeks, and 9-12 months after HSG. The median value of SIC and UI/Cr peaked at 4 weeks after HSG and remained at significantly high levels at 8, 12, and 24 weeks post-HSG compared with pre-HSG. In sync with the increase of iodine, the mean level of TSH significantly increased at 4, 8, 12, and 24 weeks post-HSG compared with pre-HSG. After 24 weeks, differences in SIC, UI/Cr, and TSH levels before and after HSG became nonsignificant. The mean value of free triiodothyronine and free thyroxine showed no significant difference at any of the time points compared with pre-HSG. Three cases (13.6%) showed transient high TSH (>5 μIU/L) with normal thyroid hormones at 4 or 8 weeks after HSG. Thyroid monitoring should be conducted in the first 4-8 weeks after HSG using lipiodol and attention to thyroid dysfunction should be paid for up to 6 months after the procedure due to the possibility of excess iodine.

  9. Preparation of the core-shell structure adriamycin lipiodol microemulsions and their synergistic anti-tumor effects with diethyldithiocarbamate in vivo.

    PubMed

    Daocheng, Wu; Mingxi, Wan

    2010-11-01

    We prepared the core-shell structure adriamycin lipiodol microemulsions (ADM-CSLMs) and evaluated their in vivo antitumor effects in combination with Diethyldithiocarbamate (DDC). Two types of ADM-CSLMs, adriamycin liposome-lipiodol microemulsion(ADM-LLM) and adriamycin microsphere lipiodol microemulsion (ADM-MLM), were prepared through the emulsification method. The drug loading and encapsulation efficiency of ADM-CSLMs were measured by the high-performance liquid chromatograph (HPLC). The size and shape of the ADM-CSLMs were determined by an atom force microscopy (AFM), a transmission electron microscopy (TEM), and a particle size analyzer, respectively. The synergistic effects of DDC and ADM-CSLMs for cancer treatment of carcinoma drug-resistance cell was evaluated by the MTT method, the activation of superoxide dismutase (SOD) was detected by chemiluminescence, and the ADM accumulation in cells was measured by flow cytometry. Walker-256 carcinoma was transplanted to the livers of the male SD rats, ADM-CSLMs were administrated to the livers of the rats by intervention hepatic artery embolization through microsurgery. The tumor growth and animal survival were evaluated. The results show that the average diameter of ADM-LLM and ADM-MLM were 4.23 ± 1.2 μm and 4.67 ± 1.4 μm, respectively, and their ADM encapsulation efficiency were 83.7% and 87.2% with respect to loading efficiency of 82 μg/ml and 91 μg/ml. The tumor growth and animal survival in two of the ADM-CSLMs combined with DDC groups were significantly higher than that of ADM only treatment, ADM liposome combined with DDC (P < 0.01), as well as the ADM microsphere combined with DDC (P < 0.01). Therefore, ADM-CSLMs are useful carriers for the treatment of carcinoma and their anti-tumor effect can be enhanced by DDC in a suitable concentration.

  10. Intra-Arterial Rhenium-188 Lipiodol in the Treatment of Inoperable Hepatocellular Carcinoma: Results of an IAEA-Sponsored Multination Study

    SciTech Connect

    Bernal, Patricia; Raoul, Jean-Luc Vidmar, Gaj; Sereegotov, Erdenechimeg; Sundram, Felix X.; Kumar, Ajay; Jeong, Jae Min; Pusuwan, Pawana; Divgi, Chaitanya; Zanzonico, Pat; Stare, Janez; Buscombe, John; Chau Trinh Thi Minh; Saw, Maung Maung; Chen Shaoliang; Ogbac, Ruben; Padhy, Ajit K.

    2007-12-01

    Purpose: Intra-arterial injections (IAI) of 131I-lipiodol is effective in treating hepatocellular carcinoma patients, but is expensive and requires a 7-day hospitalization in a radioprotection room. 188Re is inexpensive, requires no patient isolation, and can be used with lipiodol. Methods and Materials: This International Atomic Energy Agency-sponsored phase II trial aimed to assess the safety and the efficacy of a radioconjugate 188Re + lipiodol (188Re-Lip) in a large cohort of hepatocellular carcinoma patients from developing countries. A scout dose is used to determine the maximal tolerated dose (lungs <12 Gy, normal liver <30 Gy, bone marrow <1.5 Gy) and then the delivery of the calculated activity. Efficacy was assessed using response evaluation criteria in solid tumor (RECIST) and alpha-feto-protein ({alpha}FP) levels and severe adverse events were graded using the Common Toxicity Criteria of the National Cancer Institute scale v2.0. Results: The trial included 185 patients from eight countries. The procedure was feasible in all participating centers. One treatment was given to 134 patients; 42, 8, and 1 received two, three, and four injections, respectively. The injected activity during the first treatment was 100 mCi. Tolerance was excellent. We observed three complete responses and 19 partial responses (22% of evaluable patients, 95% confidence interval 16-35%); 1- and 2-year survivals were 46% and 23%. Some factors affected survival: country of origin, existence of a cirrhosis, Cancer of the Liver Italian Program score, tumor dose, absence of progression, and posttreatment decrease in {alpha}FP level. Conclusions: IAI of 188Re-Lip in developing countries is feasible, safe, cost-effective, and deserves a phase III trial.

  11. A Water-Ethanol Extract from the Willow Bracket Mushroom, Phellinus igniarius (Higher Basidiomycetes), Reduces Transient Cerebral Ischemia-Induced Neuronal Death.

    PubMed

    Kim, Jin Hee; Choi, Bo Young; Kim, Hyun Jung; Kim, In Yeol; Lee, Bo Eun; Sohn, Min; Park, Hyoung Jin; Suh, Sang Won

    2015-01-01

    This study investigated the potential neuroprotective effect of a mushroom extract from Phellinus igniarius (Piwep) after transient cerebral ischemia. Ph. Igniarius, which has a history of traditional medicinal use, contains immunomodulatory compounds that have been described to have effects on the human immune system. Using a model of transient cerebral ischemia induced by both common carotid artery occlusion and hypovolemia, a water-ethanol extract precipitate of Ph. Igniarius (Piwep) was delivered intraperitoneally immediately after the insult and was injected subsequently every other day for the experimental course. Neuronal death was examined by Fluoro-Jade B staining 1 week after the insult. Piwep injection lead to decreased hippocampal neuronal death, suppression of oxidative injury, activation of microglia, and disruption of the blood-brain barrier. We conclude that Piwep potently inhibits hippocampal neuronal death following ischemia and may have a high therapeutic potential for ameliorating stroke-induced neuron death in the clinical setting.

  12. 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.

  13. Evaluation of near infrared spectroscopy for detecting the β blocker-induced decrease in cerebral oxygenation during hemodilution in a swine model.

    PubMed

    Kurita, Tadayoshi; Morita, Koji; Sato, Shigehito

    2015-12-01

    β blockers reduce cerebral oxygenation after acute hemodilution and may contribute to the incidence of stroke when used perioperatively. The goal of the study was to investigate whether cerebral tissue oxygenation using near infrared spectroscopy can detect the β blocker-induced decrease in cerebral oxygenation depending on the severity of hemodilution and/or the dose of β blockers. Animals were anesthetized with 2% isoflurane and randomly assigned to a landiolol or esmolol group. After baseline measurement, landiolol or esmolol was administered at 40 µg/kg/min for 20 min, increased to 200 µg/kg/min for 20 min, and then stopped. Hemodynamic and arterial variables and the tissue oxygenation index (TOI) were recorded at each β blocker dose. Two stages of hemodilution were sequentially induced by repeated hemorrhage of 600 ml (33% of estimated blood volume) and infusion of the same volume of hydroxyethylstarch. During each stage, landiolol or esmolol was similarly administered and measurements were made. Landiolol and esmolol both dose-dependently decreased heart rate, mean arterial pressure and cardiac output, depending on the severity of hemodilution. Landiolol at 40 µg/kg/min was almost equivalent in potency to 200 µg/kg/min esmolol for decreasing HR before hemodilution. Based on the TOI, short-acting β blockers reduced cerebral oxygenation in a dose-dependent manner during hemodilution, and oxygenation returned to the baseline level after drug infusion was stopped. TOI may be useful for identification of a decrease in cerebral oxygenation for patients receiving β blockade during surgery associated with major bleeding.

  14. Cyclooxygenase-2 inhibitors differentially attenuate pentylenetetrazol-induced seizures and increase of pro- and anti-inflammatory cytokine levels in the cerebral cortex and hippocampus of mice.

    PubMed

    Temp, Fernanda Rossatto; Marafiga, Joseane Righes; Milanesi, Laura Hautrive; Duarte, Thiago; Rambo, Leonardo Magno; Pillat, Micheli Mainardi; Mello, Carlos Fernando

    2017-09-05

    Seizures increase prostaglandin and cytokine levels in the brain. However, it remains to be determined whether cyclooxygenase-2 (COX-2) derived metabolites play a role in seizure-induced cytokine increase in the brain and whether anticonvulsant activity is shared by all COX-2 inhibitors. In this study we investigated whether three different COX-2 inhibitors alter pentylenetetrazol (PTZ)-induced seizures and increase of interleukin-1β (IL-1β), interleukin-6 (IL-6), interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) levels in the hippocampus and cerebral cortex of mice. Adult male albino Swiss mice received nimesulide, celecoxib or etoricoxib (0.2, 2 or 20mg/kg in 0.1% carboxymethylcellulose (CMC) in 5% Tween 80, p.o.). Sixty minutes thereafter the animals were injected with PTZ (50mg/kg, i.p.) and the latency to myoclonic jerks and to generalized tonic-clonic seizures were recorded. Twenty minutes after PTZ injection animals were killed and cytokine levels were measured. PTZ increased cytokine levels in the cerebral cortex and hippocampus. While celecoxib and nimesulide attenuated PTZ -induced increase of proinflammatory cytokines in the cerebral cortex, etoricoxib did not. Nimesulide was the only COX-2 inhibitors that attenuated PTZ-induced seizures. This effect coincided with an increase of IL-10 levels in the cerebral cortex and hippocampus, constituting circumstantial evidence that IL-10 increase may be involved in the anticonvulsant effect of nimesulide. Copyright © 2017. Published by Elsevier B.V.

  15. Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus.

    PubMed

    Kim, D H; Lee, H E; Kwon, K J; Park, S J; Heo, H; Lee, Y; Choi, J W; Shin, C Y; Ryu, J H

    2015-01-22

    Throughout adulthood, neurons are continuously replaced by new cells in the dentate gyrus (DG) of the hippocampus, and this neurogenesis is increased by various neuronal injuries including ischemic stroke and seizure. While several mechanisms of this injury-induced neurogenesis have been elucidated, the initiation factor remains unclear. Here, we investigated which signal(s) trigger(s) ischemia-induced cell proliferation and neurogenesis in the hippocampal DG region. We found that early apoptotic cell death of the immature neurons occurred in the DG region following transient forebrain ischemia/reperfusion in mice. Moreover, early immature neuronal death in the DG initiated transient forebrain ischemia/reperfusion-induced neurogenesis through glycogen synthase kinase-3β/β-catenin signaling, which was mediated by microglia-derived insulin-like growth factor-1 (IGF-1). Additionally, we observed that the blockade of immature neuronal cell death, early microglial activation, or IGF-1 signaling attenuated ischemia-induced neurogenesis. These results suggest that early immature neuronal cell death initiates ischemia-induced neurogenesis through microglial IGF-1 in mice.

  16. Inhibitory effect of melatonin on cerebral endothelial cells dysfunction induced by methamphetamine via NADPH oxidase-2.

    PubMed

    Jumnongprakhon, Pichaya; Govitrapong, Piyarat; Tocharus, Chainarong; Tocharus, Jiraporn

    2016-11-01

    Melatonin is a hormone that mostly produced from the pineal gland, and it performs as a strong neuroprotectant to both neuron and glial cells against methamphetamine (METH)-induced neurotoxicity. Recently, it has been found that METH also damages the blood brain barrier (BBB) structure and function. However, the protective mechanism of melatonin on the BBB impairment caused by METH has not been investigated. In this study, the primary rat brain microvascular endothelium cells (BMVECs) isolated from neonatal rats was used to investigate the protective effect of melatonin on METH-induced BBB impairment and the underlying mechanism. The results demonstrated that melatonin decreased the level of reactive oxygen species (ROS), reactive nitrogen species (RNS), and apoptosis induced by METH via NADPH oxidase (NOX)-2 since apocynin, a NOX-2 inhibitor abolished those changes. In addition, melatonin was found to improve cell integrity by increasing the transendothelial electric resistance (TEER) values, and up-regulate the tight junction proteins ZO-1, occludin, and claudin-5, thereby decreasing the paracellular permeability caused by METH mediated by NOX-2. Our data suggest that METH induces BBB impairment by mediating NOX-2 activity, and then induces oxidative and nitrative stress, as well as apoptosis, which causes the impairment of cell integrity, and that melatonin reduces these negative effects of METH by mediating via MT1/2 receptors. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Endothelial progenitor cells and neural progenitor cells synergistically protect cerebral endothelial cells from Hypoxia/reoxygenation-induced injury via activating the PI3K/Akt pathway.

    PubMed

    Wang, Jinju; Chen, Yusen; Yang, Yi; Xiao, Xiang; Chen, Shuzhen; Zhang, Cheng; Jacobs, Bradley; Zhao, Bin; Bihl, Ji; Chen, Yanfang

    2016-02-03

    Protection of cerebral endothelial cells (ECs) from hypoxia/reoxygenation (H/R)-induced injury is an important strategy for treating ischemic stroke. In this study, we investigated whether co-culture with endothelial progenitor cells (EPCs) and neural progenitor cells (NPCs) synergistically protects cerebral ECs against H/R injury and the underlying mechanism. EPCs and NPCs were respectively generated from inducible pluripotent stem cells. Human brain ECs were used to produce an in vitro H/R-injury model. Data showed: 1) Co-culture with EPCs and NPCs synergistically inhibited H/R-induced reactive oxygen species (ROS) over-production, apoptosis, and improved the angiogenic and barrier functions (tube formation and permeability) in H/R-injured ECs. 2) Co-culture with NPCs up-regulated the expression of vascular endothelial growth factor receptor 2 (VEGFR2). 3) Co-culture with EPCs and NPCs complementarily increased vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) levels in conditioned medium, and synergistically up-regulated the expression of p-Akt/Akt and p-Flk1/VEGFR2 in H/R-injured ECs. 4) Those effects could be decreased or abolished by inhibition of both VEGFR2 and tyrosine kinase B (TrkB) or phosphatidylinositol-3-kinase (PI3K). Our data demonstrate that EPCs and NPCs synergistically protect cerebral ECs from H/R-injury, via activating the PI3K/Akt pathway which mainly depends on VEGF and BDNF paracrine.

  18. N-Butylphthalide (NBP) ameliorated cerebral ischemia reperfusion-induced brain injury via HGF-regulated TLR4/NF-κB signaling pathway.

    PubMed

    Zhang, Ping; Guo, Zhen-Fang; Xu, Yu-Ming; Li, Yu-Sheng; Song, Jing-Gui

    2016-10-01

    N-Butylphthalide (NBP) has been known to have potential neuroprotective effects in Alzheimer's disease and stroke animal models. Hepatocyte-growth factor (HGF), with strong angiogenic properties, exerted protective role in brain injury. The present study was aimed to investigate the possible anti-inflammatory effects of NBP on the brain injury of rats with cerebral ischemia reperfusion (IR) and astrocytes activation induced by lipopolysaccharide (LPS) treatment. Our results showed that cerebral IR induced brain damage with down-regulation of HGF and astrocytes activation. NBP treatment significantly increased HGF expression and activated cMet/PI3K/AKT signaling pathway, stimulating mTOR activity and suppressing apoptosis in brain tissues. Also NBP inhibited pro-inflammatory cytokines expression, including IL-6, IL-1β, and TNFα, via TLR4/NF-κB suppression. Anti-HGF treatment enhanced TLR4 expression while HGF could suppress TLR4 activation and its down-streaming signals, attenuating inflammation finally. Notably, NBP up-regulated HGF and down-regulated TLR4 expression significantly in the astrocytes combined with the treatment of TLR4 inhibitor than the cells only treated with TLR4 inhibitor, suggesting that NBP could further suppress TLR4 activation, suggesting that NBP might impede TLR4 through up-regulating HGF expression. These results suggested that NBP treatment significantly ameliorated cerebral IR-induced brain injury by inhibiting TLR4/NF-κB-associated inflammation regulated by HGF.

  19. Effect of therapist-based constraint-induced therapy at home on motor control, motor performance and daily function in children with cerebral palsy: a randomized controlled study.

    PubMed

    Chen, Chia-ling; Kang, Lin-ju; Hong, Wei-Hsien; Chen, Fei-Chuan; Chen, Hsieh-Ching; Wu, Ching-yi

    2013-03-01

    To determine the effect of therapist-based constraint-induced therapy at home on motor performance, daily function and reaching control for children with cerebral palsy. A single-blinded, randomized controlled trial. Forty-seven children (23 boys; 24 girls) with unilateral cerebral palsy, aged 6-12 years, were randomized to constraint-induced therapy (n = 24) or traditional rehabilitation (n = 23). Constraint-induced therapy involved intensive functional training of the more affected arm while the less affected arm was restrained. Traditional rehabilitation involved functional unilateral and bilateral arm training. Both groups received individualized therapist-based interventions at home for 3.5-4 hours/day, two days a week for four weeks. Motor performance and daily function were measured by the Peabody Developmental Motor Scale, Second Edition and the Pediatric Motor Activity Log. Reaching control was assessed by the kinematics of reaction time, movement time, movement unit and peak velocity. There were larger effects in favour of constraint-induced therapy on motor performance, daily function, and some aspects of reaching control compared with traditional rehabilitation. Children receiving constraint-induced therapy demonstrated higher scores for Peabody Developmental Motor Scale, Second Edition - Grasping (pretest mean ± SD, 39.9 ± 3.1; posttest, 44.1 ± 2.8; P < 0.001), Pediatric Motor Activity Log (pretest, 1.8 ± 0.3; posttest, 2.5 ± 0.3; P < 0.001) and shorter reaction time, normalized movement time (P < 0.001) and higher peak velocity (P = 0.004) of reaching movement. Constraint-induced therapy induced better grasping performance, daily function, and temporal and spatiotemporal control of reaching in children with unilateral cerebral palsy than traditional rehabilitation.

  20. PPARγ agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria.

    PubMed

    Serghides, Lena; McDonald, Chloe R; Lu, Ziyue; Friedel, Miriam; Cui, Cheryl; Ho, Keith T; Mount, Howard T J; Sled, John G; Kain, Kevin C

    2014-03-01

    Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ adjunctive therapy administered to mice at the onset of CM signs, was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase and the neurotrophic factors brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM.

  1. Intravenous Administration of Cilostazol Nanoparticles Ameliorates Acute Ischemic Stroke in a Cerebral Ischemia/Reperfusion-Induced Injury Model

    PubMed Central

    Nagai, Noriaki; Yoshioka, Chiaki; Ito, Yoshimasa; Funakami, Yoshinori; Nishikawa, Hiroyuki; Kawabata, Atsufumi

    2015-01-01

    It was reported that cilostazol (CLZ) suppressed disruption of the microvasculature in ischemic areas. In this study, we have designed novel injection formulations containing CLZ nanoparticles using 0.5% methylcellulose, 0.2% docusate sodium salt, and mill methods (CLZnano dispersion; particle size 81 ± 59 nm, mean ± S.D.), and investigated their toxicity and usefulness in a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice). The pharmacokinetics of injections of CLZnano dispersions is similar to that of CLZ solutions prepared with 2-hydroxypropyl-β-cyclodextrin, and no changes in the rate of hemolysis of rabbit red blood cells, a model of cell injury, were observed with CLZnano dispersions. In addition, the intravenous injection of 0.6 mg/kg CLZnano dispersions does not affect the blood pressure and blood flow, and the 0.6 mg/kg CLZnano dispersions ameliorate neurological deficits and ischemic stroke in MCAO/reperfusion mice. It is possible that the CLZnano dispersions will provide effective therapy for ischemic stroke patients, and that injection preparations of lipophilic drugs containing drug nanoparticles expand their therapeutic usage. PMID:26690139

  2. Changes in diffusion tensor tractographic findings associated with constraint-induced movement therapy in young children with cerebral palsy.

    PubMed

    Kwon, Jeong-Yi; Chang, Won Hyuk; Chang, Hyun Jung; Yi, Sook-Hee; Kim, Min-Young; Kim, Eun-Hye; Kim, Yun-Hee

    2014-12-01

    The objective of the study was to determine whether constraint-induced movement therapy (CIMT) could lead to changes in diffusion tensor tractography (DTT) associated with clinical improvement in young children with unilateral cerebral palsy (CP). A standardized pediatric CIMT protocol (4weeks, 120h of constraint) was used on 10 children with unilateral CP who were younger than 5years. DTT was performed in five participants before and after the intervention. Clinical outcome was measured by using the Pediatric Motor Activity Log (PMAL), Quality of Upper Extremity Skills Test (QUEST), and self-care domain of the Pediatric Evaluation of Disability Inventory. In two patients, the affected corticospinal tract (CST) visible on pretreatment DTT became more prominent on posttreatment DTT. In one patient, the affected CST was not visible on pretreatment DTT, but was visible on posttreatment DTT. All the clinical outcomes significantly improved in the CIMT group compared with the control group. Changes in the PMAL how often scale (PMAL-HO) score significantly differed between the CIMT and control groups. Changes in the properties of the affected CST on DTT were accompanied with improved arm function after CIMT in the children with CP. CIMT might lead to CST reorganization in young children with CP. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  3. The use of EEG to measure cerebral changes during computer-based motion-sickness-inducing tasks

    NASA Astrophysics Data System (ADS)

    Strychacz, Christopher; Viirre, Erik; Wing, Shawn

    2005-05-01

    Motion sickness (MS) is a stressor commonly attributed with causing serious navigational and performance errors. The distinct nature of MS suggests this state may have distinct neural markers distinguishable from other states known to affect performance (e.g., stress, fatigue, sleep deprivation, high workload). This pilot study used new high-resolution electro-encephalograph (EEG) technologies to identify distinct neuronal activation changes that occur during MS. Brain EEG activity was monitored while subjects performed a ball-tracking task and viewed stimuli on a projection screen intended to induce motion sickness/spatial disorientation. Results show the presence of EEG spectral changes in all subjects who developed motion sickness when compared to baseline levels. These changes included: 1) low frequency (1 to 10 Hz) changes that may reflect oculomotor movements rather than intra-cerebral sources; 2) increased spectral power across all frequencies (attributable to increased scalp conductivity related to sweating), 3) local increases of power spectra in the 20-50 Hz range (likely attributable to external muscles on the skull) and; 4) a central posterior (occipital) independent component that shows suppression of a 20 Hz peak in the MS condition when compared to baseline. Further research is necessary to refine neural markers, characterize their origin and physiology, to distinguish between motion sickness and other states and to enable markers to be used for operator state monitoring and the designing of interventions for motion sickness.

  4. Astrocytic adaptation during cerebral angiogenesis follows the new vessel formation induced through chronic hypoxia in adult mouse cortex

    NASA Astrophysics Data System (ADS)

    Masamoto, Kazuto; Kanno, Iwao

    2014-03-01

    We examined longitudinal changes of the neuro-glia-vascular unit during cerebral angiogenesis induced through chronic hypoxia in the adult mouse cortex. Tie2-GFP mice in which the vascular endothelial cells expressed green fluorescent proteins (GFP) were exposed to chronic hypoxia, while the spatiotemporal developments of the cortical capillary sprouts and the neighboring astrocytic remodeling were characterized with repeated two-photon microscopy. The capillary sprouts appeared at early phases of the hypoxia adaptation (1-2 weeks), while the morphological changes of the astrocytic soma and processes were not detected in this phase. In the later phases of the hypoxia adaptation (> 2 weeks), the capillary sprouts created a new connection with existing capillaries, and its neighboring astrocytes extended their processes to the newly-formed vessels. The findings show that morphological adaptation of the astrocytes follow the capillary development during the hypoxia adaptation, which indicate that the newly-formed vessels provoke cellular interactions with the neighboring astrocytes to strengthen the functional blood-brain barrier.

  5. Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients.

    PubMed

    Deprez, Sabine; Amant, Frederic; Yigit, Refika; Porke, Kathleen; Verhoeven, Judith; Van den Stock, Jan; Smeets, Ann; Christiaens, Marie-Rose; Leemans, Alexander; Van Hecke, Wim; Vandenberghe, Joris; Vandenbulcke, Mathieu; Sunaert, Stefan

    2011-03-01

    A subgroup of patients with breast cancer suffers from mild cognitive impairment after chemotherapy. To uncover the neural substrate of these mental complaints, we examined cerebral white matter (WM) integrity after chemotherapy using magnetic resonance diffusion tensor imaging (DTI) in combination with detailed cognitive assessment. Postchemotherapy breast cancer patients (n = 17) and matched healthy controls (n = 18) were recruited for DTI and neuropsychological testing, including the self-report cognitive failure questionnaire (CFQ). Differences in DTI WM integrity parameters [fractional anisotropy (FA) and mean diffusivity (MD)] between patients and healthy controls were assessed using a voxel-based two-sample-t-test. In comparison with healthy controls, the patient group demonstrated decreased FA in frontal and temporal WM tracts and increased MD in frontal WM. These differences were also confirmed when comparing this patient group with an additional control group of nonchemotherapy-treated breast cancer patients (n = 10). To address the heterogeneity observed in cognitive function after chemotherapy, we performed a voxel-based correlation analysis between FA values and individual neuropsychological test scores. Significant correlations of FA with neuropsychological tests covering the domain of attention and processing/psychomotor speed were found in temporal and parietal WM tracts. Furthermore, CFQ scores correlated negatively in frontal and parietal WM. These studies show that chemotherapy seems to affect WM integrity and that parameters derived from DTI have the required sensitivity to quantify neural changes related to chemotherapy-induced mild cognitive impairment. Copyright © 2010 Wiley-Liss, Inc.

  6. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.

    PubMed

    Kleinschnitz, Christoph; Kraft, Peter; Dreykluft, Angela; Hagedorn, Ina; Göbel, Kerstin; Schuhmann, Michael K; Langhauser, Friederike; Helluy, Xavier; Schwarz, Tobias; Bittner, Stefan; Mayer, Christian T; Brede, Marc; Varallyay, Csanad; Pham, Mirko; Bendszus, Martin; Jakob, Peter; Magnus, Tim; Meuth, Sven G; Iwakura, Yoichiro; Zernecke, Alma; Sparwasser, Tim; Nieswandt, Bernhard; Stoll, Guido; Wiendl, Heinz

    2013-01-24

    We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in Rag1(-/-) mice lacking lymphocytes. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with the ischemic brain endothelium via the LFA-1/ICAM-1 pathway and platelets and these findings were confirmed in vitro. Ablation of Tregs reduced microvascular thrombus formation and improved cerebral reperfusion on stroke, as revealed by ultra-high-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Tregs had no functional relevance. We define herein a novel and unexpected role of Tregs in a primary nonimmunologic disease state.

  7. Warming Effect on Miriplatin-Lipiodol Suspension as a Chemotherapeutic Agent for Transarterial Chemoembolization for Hepatocellular Carcinoma: Preliminary Clinical Experience

    SciTech Connect

    Kora, Shinn-ichi; Urakawa, Hiroshi; Mitsufuji, Toshimichi; Osame, Akinobu; Higashihara, Hideyuki; Yoshimitsu, Kengo

    2013-08-01

    PurposeTo retrospectively elucidate the preliminary clinical impact of warmed miriplatin-lipiodol suspension (MPT-LPD) when used as a chemotherapeutic agent for transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).Materials and MethodsBetween June and December 2010, TACE was performed with MPT-LPD at room temperature (RT group), and after January 2011, TACE with MPT-LPD warmed to 40 Degree-Sign C was performed (W group). The intraarterial appearance of MPT-LPD immediately after injection through microcatheters at the second-order branches was compared between the two groups with a 5-point grading system. Local therapeutic effects of HCCs as assessed by follow-up computed tomography (CT) obtained 1-3 months after TACE were compared between the groups with a 4-point grading system (TE1-TE4). After April 2011, angiography-assisted CT was routinely performed at TACE, and HCCs that revealed apparent corona enhancement (CE) were retrospectively selected. The degree of concordance between CE and MPT-LPD accumulation as assessed by CT immediately after TACE was assessed with a 3-point grading scale.ResultsMPT-LPD therapy resulted in a smooth and continuous appearance in the W group (grades 1, 2, 3, 4, and 5 were, respectively, 1, 2, 11, 18, and 4) compared to the RT group (4, 0, 1, 2, and 0). The W group (TE1, TE2, TE3, and TE4 were 1, 9, 11, and 12) revealed better local therapeutic effects than the RT group (6, 3, 9, and 0) (p < 0.05). CE was found in 26 HCC nodules, and concordance between CE and MPT-LPD accumulation was observed in 66 % (grades 1, 2, and 3 were, respectively, 2, 8, and 19).ConclusionWarmed MPT-LPD flowed more smoothly within vascular lumen, passed through tumor sinusoid of HCC, and had better local therapeutic effects at short-term observation than MPT-LPD at room temperature.

  8. High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes.

    PubMed

    Shah, Gul N; Morofuji, Yoichi; Banks, William A; Price, Tulin O

    2013-10-18

    Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration.

  9. High Glucose-Induced Mitochondrial Respiration and Reactive Oxygen Species in Mouse Cerebral Pericytes is Reversed by Pharmacological Inhibition of Mitochondrial Carbonic Anhydrases: Implications for Cerebral Microvascular Disease in Diabetes

    PubMed Central

    Shah, Gul N.; Morofuji, Yoichi; Banks, William A.; Price, Tulin O.

    2013-01-01

    Hyperglycemia-induced oxidative stress leads to diabetes-associated damage to the microvasculature of the brain. Pericytes in close proximity to endothelial cells in the brain microvessels are vital to the integrity of the blood-brain barrier and are especially susceptible to oxidative stress. According to our recently published results, streptozotocin-diabetic mouse brain exhibits oxidative stress and loose pericytes by twelve weeks of diabetes, and cerebral pericytes cultured in high glucose media suffer intracellular oxidative stress and apoptosis. Oxidative stress in diabetes is hypothesized to be caused by reactive oxygen species (ROS) produced during hyperglycemia-induced enhanced oxidative metabolism of glucose (respiration). To test this hypothesis, we investigated the effect of high glucose on respiration rate and ROS production in mouse cerebral pericytes. Previously, we showed that pharmacological inhibition of mitochondrial carbonic anhydrases protects the brain from oxidative stress and pericyte loss. The high glucose-induced intracellular oxidative stress and apoptosis of pericytes in culture were also reversed by inhibition of mitochondrial carbonic anhydrases. Therefore, we extended our current study to determine the effect of these inhibitors on high glucose-induced increases in pericyte respiration and ROS. We now report that both the respiration and ROS are significantly increased in pericytes challenged with high glucose. Furthermore, inhibition of mitochondrial carbonic anhydrases significantly slowed down both the rate of respiration and ROS production. These data provide new evidence that pharmacological inhibitors of mitochondrial carbonic anhydrases, already in clinical use, may prove beneficial in protecting the brain from oxidative stress caused by ROS produced as a consequence of hyperglycemia-induced enhanced respiration. PMID:24076121

  10. Blast Overpressure Waves Induce Transient Anxiety and Regional Changes in Cerebral Glucose Metabolism and Delayed Hyperarousal in Rats

    PubMed Central

    Awwad, Hibah O.; Gonzalez, Larry P.; Tompkins, Paul; Lerner, Megan; Brackett, Daniel J.; Awasthi, Vibhudutta; Standifer, Kelly M.

    2015-01-01

    Physiological alterations, anxiety, and cognitive disorders are strongly associated with blast-induced traumatic brain injury (blast TBI), and are common symptoms in service personnel exposed to blasts. Since 2006, 25,000–30,000 new TBI cases are diagnosed annually in U.S. Service members; increasing evidence confirms that primary blast exposure causes diffuse axonal injury and is often accompanied by altered behavioral outcomes. Behavioral and acute metabolic effects resulting from blast to the head in the absence of thoracic contributions from the periphery were examined, following a single blast wave directed to the head of male Sprague-Dawley rats protected by a lead shield over the torso. An 80 psi head blast produced cognitive deficits that were detected in working memory. Blast TBI rats displayed increased anxiety as determined by elevated plus maze at day 9 post-blast compared to sham rats; blast TBI rats spent significantly more time than the sham controls in the closed arms (p < 0.05; n = 8–11). Interestingly, anxiety symptoms were absent at days 22 and 48 post-blast. Instead, blast TBI rats displayed increased rearing behavior at day 48 post-blast compared to sham rats. Blast TBI rats also exhibited suppressed acoustic startle responses, but similar pre-pulse inhibition at day 15 post-blast compared to sham rats. Acute physiological alterations in cerebral glucose metabolism were determined by positron emission tomography 1 and 9 days post-blast using 18F-fluorodeoxyglucose (18F-FDG). Global glucose uptake in blast TBI rat brains increased at day 1 post-blast (p < 0.05; n = 4–6) and returned to sham levels by day 9. Our results indicate a transient increase in cerebral metabolism following a blast injury. Markers for reactive astrogliosis and neuronal damage were noted by immunoblotting motor cortex tissue from day 10 post-blast in blast TBI rats compared to sham controls (p < 0.05; n = 5–6). PMID:26136722

  11. Blast Overpressure Waves Induce Transient Anxiety and Regional Changes in Cerebral Glucose Metabolism and Delayed Hyperarousal in Rats.

    PubMed

    Awwad, Hibah O; Gonzalez, Larry P; Tompkins, Paul; Lerner, Megan; Brackett, Daniel J; Awasthi, Vibhudutta; Standifer, Kelly M

    2015-01-01

    Physiological alterations, anxiety, and cognitive disorders are strongly associated with blast-induced traumatic brain injury (blast TBI), and are common symptoms in service personnel exposed to blasts. Since 2006, 25,000-30,000 new TBI cases are diagnosed annually in U.S. Service members; increasing evidence confirms that primary blast exposure causes diffuse axonal injury and is often accompanied by altered behavioral outcomes. Behavioral and acute metabolic effects resulting from blast to the head in the absence of thoracic contributions from the periphery were examined, following a single blast wave directed to the head of male Sprague-Dawley rats protected by a lead shield over the torso. An 80 psi head blast produced cognitive deficits that were detected in working memory. Blast TBI rats displayed increased anxiety as determined by elevated plus maze at day 9 post-blast compared to sham rats; blast TBI rats spent significantly more time than the sham controls in the closed arms (p < 0.05; n = 8-11). Interestingly, anxiety symptoms were absent at days 22 and 48 post-blast. Instead, blast TBI rats displayed increased rearing behavior at day 48 post-blast compared to sham rats. Blast TBI rats also exhibited suppressed acoustic startle responses, but similar pre-pulse inhibition at day 15 post-blast compared to sham rats. Acute physiological alterations in cerebral glucose metabolism were determined by positron emission tomography 1 and 9 days post-blast using (18)F-fluorodeoxyglucose ((18)F-FDG). Global glucose uptake in blast TBI rat brains increased at day 1 post-blast (p < 0.05; n = 4-6) and returned to sham levels by day 9. Our results indicate a transient increase in cerebral metabolism following a blast injury. Markers for reactive astrogliosis and neuronal damage were noted by immunoblotting motor cortex tissue from day 10 post-blast in blast TBI rats compared to sham controls (p < 0.05; n = 5-6).

  12. Sensitization of cerebral tissue in nude mice with photodynamic therapy induces ADAM17/TACE and promotes glioma cell invasion

    PubMed Central

    Zheng, Xuguang; Jiang, Feng; Katakowski, Mark; Zhang, Xuepeng; Jiang, Hao; Zhang, Zheng Gang; Chopp, Michael

    2008-01-01

    In the present study, we tested the hypothesis that a mild cerebral tissue injury promotes subsequent glioma invasion via activation of the ADAM17-EGFR-PI3K-Akt pathway. Mild injury was induced by Photodynamic therapy (PDT), which employs tissue-penetrating laser light exposure following systemic administration of a tumor-localizing photosensitizer. Athymic nude mice were treated with sublethal PDT (80J/cm2 with 2mg/kg Photofrin). Hypoxic stress and ADAM17-EGFR-PI3K-Akt were measured using Western blot and immunostaining. Additional groups with/without pro-sublethal PDT were subsequently implanted with U87 glioma tumor cell. Tumor invasion and ADAM17-EGFR-PI3K-Akt pathway in tumor area were measured. After a sublethal dose of PDT, HIF-1α expression was increased by a factor of three in PDT-treated normal brain tissue compared to contralateral control brain tissue. PDT-treated brain tissue exhibited a significant increase in ADAM17, p-EGFR, p-Akt expression compared to non-treated tissue. ADAM17 positive area significantly increased from 1.78% to 10.89%. The percentage of p-EGFR and p-Akt positive cells significantly increased from 9.50% and 14.50% to 21.31% and 32.29%,respectively, PDT treatment significantly increased subsequent implanted U87 glioma cell invasion by 3.68-fold and increased ADAM17, EGFR, p-EGFR, Akt, p-Akt expression by 178%, 43.9%,152.7%, 89.6%,and 164.2%, respectively, compared to control group. Our data showed that a sublethal sensitization of cerebral tissue with PDT significantly increased U87 cell invasion in nude mice, and that glioma cell invasion is highly correlated with activation of the ADAM17-EGFR-PI3K-Akt pathway (r=0.928, 0.775, 0.870, 0.872, and 0.883, respectively), most likely via HIF-1α. PMID:18358600

  13. Mechanical Injury Induces Brain Endothelial-Derived Microvesicle Release: Implications for Cerebral Vascular Injury during Traumatic Brain Injury

    PubMed Central

    Andrews, Allison M.; Lutton, Evan M.; Merkel, Steven F.; Razmpour, Roshanak; Ramirez, Servio H.

    2016-01-01

    It is well established that the endothelium responds to mechanical forces induced by changes in shear stress and strain. However, our understanding of vascular remodeling following traumatic brain injury (TBI) remains incomplete. Recently published studies have revealed that lung and umbilical endothelial cells produce extracellular microvesicles (eMVs), such as microparticles, in response to changes in mechanical forces (blood flow and mechanical injury). Yet, to date, no studies have shown whether brain endothelial cells produce eMVs following TBI. The brain endothelium is highly specialized and forms the blood-brain barrier (BBB), which regulates diffusion and transport of solutes into the brain. This specialization is largely due to the presence of tight junction proteins (TJPs) between neighboring endothelial cells. Following TBI, a breakdown in tight junction complexes at the BBB leads to increased permeability, which greatly contributes to the secondary phase of injury. We have therefore tested the hypothesis that brain endothelium responds to mechanical injury, by producing eMVs that contain brain endothelial proteins, specifically TJPs. In our study, primary human adult brain microvascular endothelial cells (BMVEC) were subjected to rapid mechanical injury to simulate the abrupt endothelial disruption that can occur in the primary injury phase of TBI. eMVs were isolated from the media following injury at 2, 6, 24, and 48 h. Western blot analysis of eMVs demonstrated a time-dependent increase in TJP occludin, PECAM-1 and ICAM-1 following mechanical injury. In addition, activation of ARF6, a small GTPase linked to extracellular vesicle production, was increased after injury. To confirm these results in vivo, mice were subjected to sham surgery or TBI and blood plasma was collected 24 h post-injury. Isolation and analysis of eMVs from blood plasma using cryo-EM and flow cytometry revealed elevated levels of vesicles containing occludin following brain trauma

  14. Comparative Study of Brain CD8+ T Cells Induced by Sporozoites and Those Induced by Blood-Stage Plasmodium berghei ANKA Involved in the Development of Cerebral Malaria

    PubMed Central

    Bagot, Sébastien; Nogueira, Fatima; Collette, Alexis; do Rosario, Virgilio; Lemonier, François; Cazenave, Pierre-André; Pied, Sylviane

    2004-01-01

    To obtain insight into the mechanisms that contribute to the pathogenesis of Plasmodium infections, we developed an improved rodent model that mimics human malaria closely by inducing cerebral malaria (CM) through sporozoite infection. We used this model to carry out a detailed study on isolated T cells recruited from the brains of mice during the development of CM. We compared several aspects of the immune response related to the experimental model of Plasmodium berghei ANKA infection induced by sporozoites in C57BL/6 mice and those related to a blood-stage infection. Our data show that in both models, oligoclonal TCRVβ4+, TCRVβ6+, TCRVβ8.1+, and TCRVβ11+ major histocompatibility complex class I-restricted CD8 T cells were present in the brains of CM+ mice. These CD8+ T cells display an activated phenotype, do not undergo apoptosis, secrete gamma interferon or tumor necrosis factor alpha, and are associated with the development of the neurological syndrome. PMID:15102792

  15. Biphasic Functional Regulation in Hippocampus of Rat with Chronic Cerebral Hypoperfusion Induced by Permanent Occlusion of Bilateral Common Carotid Artery

    PubMed Central

    Lee, In Sun; Han, Jung-Soo; Kim, Bu-Yeo

    2013-01-01

    Background Chronic cerebral hypoperfusion induced by permanent occlusion of the bilateral common carotid artery (BCCAO) in rats has been commonly used for the study of Alzheimer’s disease and vascular dementia. Despite the apparent cognitive dysfunction in rats with BCCAO, the molecular markers or pathways involved in the pathological alternation have not been clearly identified. Methods Temporal changes (sham, 21, 35, 45, 55 and 70 days) in gene expression in the hippocampus of rats after BCCAO were measured using time-course microarray analysis. Gene Ontology (GO) and pathway analyses were performed to identify the functional involvement of temporally regulated genes in BCCAO. Results Two major gene expression patterns were observed in the hippocampus of rats after BCCAO. One pattern, which was composed of 341 early up-regulated genes after the surgical procedure, was dominantly involved in immune-related biological functions (false discovery rate [FDR]<0.01). Another pattern composed of 182 temporally delayed down-regulated genes was involved in sensory perception such as olfactory and cognition functions (FDR<0.01). In addition to the two gene expression patterns, the temporal change of GO and the pathway activities using all differentially expressed genes also confirmed that an immune response was the main early change, whereas sensory functions were delayed responses. Moreover, we identified FADD and SOCS3 as possible core genes in the sensory function loss process using text-based mining and interaction network analysis. Conclusions The biphasic regulatory mechanism first reported here could provide molecular evidence of BCCAO-induced impaired memory in rats as well as mechanism of the development of vascular dementia. PMID:23936146

  16. Acute administration of methionine and/or methionine sulfoxide impairs redox status and induces apoptosis in rat cerebral cortex.

    PubMed

    Soares, Mayara Sandrielly Pereira; Viau, Cassiana Macagnan; Saffi, Jenifer; Costa, Marcelo Zanusso; da Silva, Tatiane Morgana; Oliveira, Pathise Souto; Azambuja, Juliana Hofstatter; Barschak, Alethéa Gatto; Braganhol, Elizandra; S Wyse, Angela T; Spanevello, Roselia Maria; Stefanello, Francieli Moro

    2017-07-04

    High plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO) may occur in several genetic abnormalities. Patients with hypermethioninemia can present neurological dysfunction; however, the neurotoxicity mechanisms induced by these amino acids remain unknown. The aim of the present work was to study the effects of Met and/or MetO on oxidative stress, genotoxicity, cytotoxicity and to evaluate whether the cell death mechanism is mediated by apoptosis in the cerebral cortex of young rats. Forty-eight Wistar rats were divided into groups: saline, Met 0.4 g/Kg, MetO 0.1 g/Kg and Met 0.4 g/Kg + MetO 0.1 g/Kg, and were euthanized 1 and 3 h after subcutaneous injection. Results showed that TBARS levels were enhanced by MetO and Met+MetO 1 h and 3 h after treatment. ROS was increased at 3 h by Met, MetO and Met+MetO. SOD activity was increased in the Met group, while CAT was reduced in all experimental groups 1 h and 3 h after treatment. GPx activity was enhanced 1 h after treatment by Met, MetO and Met+MetO, however it was reduced in the same experimental groups 3 h after administration of amino acids. Caspase-3, caspase-9 and DNA damage was increased and cell viability was reduced by Met, MetO and Met+MetO at 3 h. Also, Met, MetO and Met+MetO, after 3 h, enhanced early and late apoptosis cells. Mitochondrial electrochemical potential was decreased by MetO and Met+MetO 1 h and 3 h after treatment. These findings help understand the mechanisms involved in neurotoxicity induced by hypermethioninemia.

  17. Role of mitophagy regulated by Parkin/DJ-1 in remote ischemic postconditioning-induced mitigation of focal cerebral ischemia-reperfusion.

    PubMed

    Zhou, M; Xia, Z-Y; Lei, S-Q; Leng, Y; Xue, R

    2015-12-01

    We evaluated the role of mitophagy controlled by Parkin/DJ-1 in remote ischemic post conditioning-induced mitigation of focal cerebral ischemia-reperfusion (I/R) injury in rats. Ninety adult male rats were randomly assigned into 5 groups including a sham operation group (S) and ischemia-reperfusion group (I/R). Focal cerebral I/R was induced by right middle cerebral artery occlusion (MCAO). I/R+remote ischemic postconditioning (I/R+RIPoC), I/R+RIPoC+ mitophagy inhibitor Mdivi-1 (I/R+RIPoC+M), and I/R+RIPoC+ normal saline (I/R+RIPoC+NS) groups all received 3 cycles of 10 minutes reperfusion followed by 10 minutes ischemia in bilateral femoral arteries at the beginning of cerebral reperfusion. I/R+RIPoC+M received mitochondrial division inhibitor (Mdivi-1) before ischemia and after 24h of reperfusion, neurological deficit scores (NDSs) were measured and rats were then sacrificed. Brain was removed and size of the infarct was determined. Apoptosis index and LC3-II/I ratio, Parkin/DJ-1 proteins expression, SOD activity, MDA and 15-F2t-Isoprostane content in cerebral ischemic penumbra were studied. Linear correlation between Parkin/DJ-1 proteins expression and LC3-II/I ratio and cerebral infarct size were analyzed. In experimental groups the NDSs, percentage of cerebral infarct size, apoptosis index, LC3-II/I ratio, MDA and 15-F2t-Isoprostane content significantly increased and Parkin/DJ-1 proteins were up-regulated (p<0.05). In I/R+RIPoC and I/R+RIPoC+NS groups, NDSs, percentage of cerebral infarct size, apoptosis index, MDA and 15-F2t-Isoprostane content decreased significantly while LC3-II/I ratio and SOD activity increased compared to I/R group. Parkin/DJ-1 proteins were up-regulated in I/R+RIPoC, I/R+RIPoC+NS and I/R+RIPoC+M groups (p<0.05). LC3-II/I ratio and SOD activity significantly decreased (p<0.05). Parkin/DJ-1 proteins expression didn't changed in I/R+RIPoC+M group (p>0.05). The Parkin/DJ-1 proteins expression were positively correlated with LC3-II/I ratio

  18. Use of human induced pluripotent stem cell-derived neurons as a model for Cerebral Toxoplasmosis.

    PubMed

    Tanaka, Naomi; Ashour, Danah; Dratz, Edward; Halonen, Sandra

    2016-01-01

    Toxoplasma gondii is a ubiquitous protozoan parasite with approximately one-third of the worlds' population chronically infected. In chronically infected individuals, the parasite resides primarily in cysts within neurons in the central nervous system. The chronic infection in immunocompetent individuals has been considered to be asymptomatic but increasing evidence indicates the chronic infection can lead to neuropsychiatric disorders such as Schizophrenia, prenatal depression and suicidal thoughts. A better understanding of the mechanism(s) by which the parasite exerts effects on human behavior is limited due to lack of suitable human neuronal models. In this paper, we report the use of human neurons derived from normal cord blood CD34+ cells generated via genetic reprogramming, as an in vitro model for the study T. gondii in neurons. This culture method resulted in a relatively pure monolayer of induced human neuronal-like cells that stained positive for neuronal markers, MAP2, NFL, NFH and NeuN. These induced human neuronal-like cells (iHNs) were efficiently infected by the Prugniad strain of the parasite and supported replication of the tachyzoite stage and development of the cyst stage. Infected iHNs could be maintained through 5 days of infection, allowing for formation of large cysts. This induced human neuronal model represents a novel culture method to study both tachyzoite and bradyzoite stages of T. gondii in human neurons. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  19. Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia.

    PubMed

    Matsuura, Wataru; Harada, Shinichi; Tokuyama, Shogo

    2016-01-01

    Central post-stroke pain (CPSP), a potential sequela of stroke, is classified as neuropathic pain. Although we recently established a CPSP-like model in mice, the effects of adjuvant analgesics as therapeutic drugs for neuropathic pain in this model are unknown. Hence, the aim of the present study was to assess the usefulness of our model by evaluating the effects of adjuvant analgesics used for treating neuropathic pain in this mouse model of CPSP. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical allodynia was measured after BCAO using the von Frey test. The mechanical allodynia was significantly increased on day 3 after BCAO compared with that during the pre-BCAO assessment. BCAO-induced mechanical allodynia was significantly decreased by intraperitoneal injections of imipramine (a tricyclic antidepressant), mexiletine (an antiarrhythmic), gabapentin (an antiepileptic), or a subcutaneous injection of morphine (an opioid receptor agonist) compared with that following vehicle treatment in BCAO-mice. By contrast, milnacipran (a serotonin and norepinephrine reuptake inhibitor), paroxetine (selective serotonin reuptake inhibitor), carbamazepine (antiepileptic), and indomethacin (nonsteroidal anti-inflammatory drug) did not affect the BCAO-induced mechanical allodynia. Our results show that BCAO in mice may be useful as an animal model of CPSP. In addition, BCAO-induced mechanical allodynia may be suppressed by some adjuvant analgesics used to treat neuropathic pain.

  20. Intra-cerebral cannabidiol infusion-induced neuroprotection is partly associated with the TNF-α/TNFR1/NF-кB pathway in transient focal cerebral ischaemia.

    PubMed

    Khaksar, Sepideh; Bigdeli, Mohammad Reza

    2017-09-05

    Stroke is a neurological disease, which, in addition to high mortality, imposes many financial and mental burdens on families and the society. The main objective of this study was to investigate the effect of cannabidiol (CBD) on one of the major inflammatory pathways in cerebral ischaemia. Using stereotaxic surgery, the cannula was implanted into the right lateral ventricle of rats. CBD (50, 100, and 200 ng/rat; i.c.v.) was administrated for five consecutive days. After pretreatment, the rats were subjected to 60 min of right middle cerebral artery occlusion (MCAO). After 24 h, neurological deficits score, infarct volume, brain oedema, and blood-brain barrier (BBB) permeability in total, core, and penumbra areas were assessed. The expression of tumour necrosis factor alfa (TNF-α), tumour necrosis factor receptor 1 (TNFR1), and nuclear factor-kappa B (NF-кB) in the mentioned regions was also studied. Administration of CBD (100 and 200 ng/rat) caused a significant reduction in infarction, brain oedema, and BBB permeability compared with the vehicle-received group. Down-regulation of TNF-α, TNFR1, and NF-кB expression was also observed by CBD. The results achieved in this study support the idea that CBD has a cerebroprotective effect (partly through suppression of TNF-α, TNFR1, and NF-кB) on ischaemic injury. CBD, cannabidiol; ANOVA, analysis of variance; PVDF, polyvinylidene difluoride; SDS-PAGE, sodium dodecyl sulphate polyacrylamide gel electrophoresis; SEM, standard error of mean.

  1. Hypertonic saline alleviates experimentally induced cerebral oedema through suppression of vascular endothelial growth factor and its receptor VEGFR2 expression in astrocytes.

    PubMed

    Huang, Linqiang; Cao, Wei; Deng, Yiyu; Zhu, Gaofeng; Han, Yongli; Zeng, Hongke

    2016-10-13

    Cerebral oedema is closely related to the permeability of blood-brain barrier, vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) all of which are important blood-brain barrier (BBB) permeability regulatory factors. Zonula occludens 1 (ZO-1) and claudin-5 are also the key components of BBB. Hypertonic saline is widely used to alleviate cerebral oedema. This study aimed to explore the possible mechanisms underlying hypertonic saline that ameliorates cerebral oedema effectively. Middle cerebral artery occlusion (MCAO) model in Sprague-Dawley (SD) rats and of oxygen-glucose deprivation model in primary astrocytes were used in this study. The brain water content (BWC) was used to assess the effect of 10 % HS on cerebral oedema. The assessment of Evans blue (EB) extravasation was performed to evaluate the protective effect of 10 % HS on blood-brain barrier. The quantification of VEGF, VEGFR2, ZO-1 and claudin-5 was used to illustrate the mechanism of 10 % HS ameliorating cerebral oedema. BWC was analysed by wet-to-dry ratios in the ischemic hemisphere of SD rats; it was significantly decreased after 10 % HS treatment (P < 0.05). We also investigated the blood-brain barrier protective effect by 10 % HS which reduced EB extravasation effectively in the peri-ischemic brain tissue. In parallel to the above notably at 24 h following MCAO, mRNA and protein expression of VEGF and VEGFR2 in the peri-ischemic brain tissue was down-regulated after 10 % HS treatment (P < 0.05). Along with this, in vitro studies showed increased VEGF and VEGFR2 mRNA and protein expression in primary astrocytes under hypoxic condition (P < 0.05), but it was suppressed after HS treatment (P < 0.05). In addition, HS inhibited the down-regulation of ZO-1, claudin-5 effectively. The results suggest that 10 % HS could alleviate cerebral oedema possibly through reducing the ischemia induced BBB permeability as a consequence of

  2. Effects of long‑term post‑ischemic treadmill exercise on gliosis in the aged gerbil hippocampus induced by transient cerebral ischemia.

    PubMed

    Ahn, Ji Hyeon; Shin, Myoung Cheol; Park, Joon Ha; Kim, In Hye; Cho, Jeong-Hwi; Lee, Tae-Kyeong; Lee, Jae-Chul; Chen, Bai Hui; Shin, Bich Na; Tae, Hyun-Jin; Park, Jinseu; Choi, Soo Young; Lee, Yun Lyul; Kim, Dae Won; Kim, Yang Hee; Won, Moo-Ho; Cho, Jun Hwi

    2017-06-01

    Therapeutic exercise is an integral component of the rehabilitation of patients who have suffered a stroke. The objective of the present study was to use immunohistochemistry to investigate the effects of post‑ischemic exercise on neuronal damage or death and gliosis in the aged gerbil hippocampus following transient cerebral ischemia. Aged gerbils (male; age, 22‑24 months) underwent ischemia and were subjected to treadmill exercise for 1 or 4 weeks. Neuronal death was detected in the stratum pyramidale of the hippocampal CA1 region and in the polymorphic layer of the dentate gyrus using cresyl violet and Fluoro‑Jade B histofluorescence staining. No significant difference in neuronal death was identified following 1 or 4 weeks of post‑ischemic treadmill exercise. However, post‑ischemic treadmill exercise affected gliosis (the activation of astrocytes and microglia). Glial fibrillary acidic protein‑immunoreactive astrocytes and ionized calcium binding adaptor molecule 1‑immunoreactive microglia were activated in the CA1 and polymorphic layer of the dentate gyrus of the group without treadmill exercise. Conversely, 4 weeks of treadmill exercise significantly alleviated ischemia‑induced astrocyte and microglial activation; however, 1 week of treadmill exercise did not alleviate gliosis. These findings suggest that long‑term post‑ischemic treadmill exercise following transient cerebral ischemia does not influence neuronal protection; however, it may effectively alleviate transient cerebral ischemia‑induced astrocyte and microglial activation in the aged hippocampus.

  3. Neuroprotective effects of Salidroside and its analogue tyrosol galactoside against focal cerebral ischemia in vivo and H2O2-induced neurotoxicity in vitro.

    PubMed

    Shi, Tian-yao; Feng, Shu-fang; Xing, Jiang-hao; Wu, Yu-mei; Li, Xiao-qiang; Zhang, Nan; Tian, Zhen; Liu, Shui-bing; Zhao, Ming-gao

    2012-05-01

    Salidroside (Sal) is a natural antioxidant extracted from the root of Rhodiola rosea L. that elicits neuroprotective effects in vivo and in vitro. Tyrosol galactoside (Tyr), an analog of Sal, was recently synthesized in our laboratory. The purpose of the current study was to investigate and compare the neuroprotective effects of Sal and Tyr against focal cerebral ischemia in vivo and H(2)O(2)-induced neurotoxicity in vitro. Sal and Tyr significantly prevented a cerebral ischemic injury induced by a 2 h middle cerebral artery occlusion and a 24 h reperfusion in rats in vivo. Furthermore, the oxidative insult was markedly attenuated by treatments of Sal and Tyr in the cultured rat cortical neurons after a 30 min exposure to 50 μM of H(2)O(2). Western blot analysis revealed that Sal and Tyr decreased the expression of Bax and restored the balance of pro- and anti-apoptotic proteins. The neuroprotective effects of these two analogues show that Tyr has a better antioxidative action compared with Sal both in vivo and in vitro, and suggest that the antioxidant activity of Sal and Tyr may be partly due to their different substituents in their glycosyl groups. This gives a new insight into the development of therapeutic natural antioxidants against oxidative stress.

  4. Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage.

    PubMed

    Sun, Kai; Fan, Jingyu; Han, Jingyan

    2015-01-01

    Ischemic stroke and ischemia/reperfusion (I/R) injury induced by thrombolytic therapy are conditions with high mortality and serious long-term physical and cognitive disabilities. They have a major impact on global public health. These disorders are associated with multiple insults to the cerebral microcirculation, including reactive oxygen species (ROS) overproduction, leukocyte adhesion and infiltration, brain blood barrier (BBB) disruption, and capillary hypoperfusion, ultimately resulting in tissue edema, hemorrhage, brain injury and delayed neuron damage. Traditional Chinese medicine (TCM) has been used in China, Korea, Japan and other Asian countries for treatment of a wide range of diseases. In China, the usage of compound TCM preparation to treat cerebrovascular diseases dates back to the Han Dynasty. Even thousands of years earlier, the medical formulary recorded many classical prescriptions for treating cerebral I/R-related diseases. This review summarizes current information and underlying mechanisms regarding the ameliorating effects of compound TCM preparation, Chinese materia medica, and active components on I/R-induced cerebral microcirculatory disturbances, brain injury and neuron damage.

  5. Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage

    PubMed Central

    Sun, Kai; Fan, Jingyu; Han, Jingyan

    2015-01-01

    Ischemic stroke and ischemia/reperfusion (I/R) injury induced by thrombolytic therapy are conditions with high mortality and serious long-term physical and cognitive disabilities. They have a major impact on global public health. These disorders are associated with multiple insults to the cerebral microcirculation, including reactive oxygen species (ROS) overproduction, leukocyte adhesion and infiltration, brain blood barrier (BBB) disruption, and capillary hypoperfusion, ultimately resulting in tissue edema, hemorrhage, brain injury and delayed neuron damage. Traditional Chinese medicine (TCM) has been used in China, Korea, Japan and other Asian countries for treatment of a wide range of diseases. In China, the usage of compound TCM preparation to treat cerebrovascular diseases dates back to the Han Dynasty. Even thousands of years earlier, the medical formulary recorded many classical prescriptions for treating cerebral I/R-related diseases. This review summarizes current information and underlying mechanisms regarding the ameliorating effects of compound TCM preparation, Chinese materia medica, and active components on I/R-induced cerebral microcirculatory disturbances, brain injury and neuron damage. PMID:26579420

  6. Improved targeting of 5-[125I/131I]iodo-2‧-deoxyuridine to rat hepatoma by using lipiodol emulsion

    NASA Astrophysics Data System (ADS)

    Yu, Hung-Man; Yeh, Hsin-Pei; Chang, Tien-Kui; Huang, Kuang-Liang; Chuang, Kuo-Tang; Liu, Ren-Shen; Wang, Shyh-Jen; Hwang, Jeng-Jong; Chi, Kwan-Hwa; Chen, Fu-Du; Lin, Wuu-Jyh; Chen, Chin-Hsiung; Wang, Hsin-Ell

    2006-12-01

    This study aims to assess whether emulsion of [ 125/131I]IUdR and lipiodol (IUdR/LP) can improve delivery of IUdR into hepatoma. MethodsIn vitro release profile of IUdR from IUdR/LP to serum was performed. IUdR/LP was injected into N1-S1 hepatoma-bearing SD rat via hepatic artery and IUdR/normal saline (IUdR/NS) was used for comparison. Biodistribution, autoradiography, imaging and tumor DNA incorporation assay were performed. The radioactive metabolites in plasma and urine were analyzed. Radiation doses to tumor and organs were estimated. ResultsIUdR released from lipiodol into serum was fast. There were longer retention, more DNA incorporation and higher radiation dose of IUdR in the tumor by using IUdR/LP. IUdR/LP deposited deep in the hepatomas. Only free iodide was found in the plasma and urine after injection of IUdR/LP. ConclusionsHepatic artery injection of IUdR/LP emulsion could definitely enhance the tumor cell uptake and incorporation to DNA of *IUdR, prolong the tumor retention time and increase radiation dose to tumor. IUdR/LP may be an effective therapeutic agent for the treatment of hepatic tumors.

  7. Reversible cerebral vasoconstriction syndrome in the context of recent cerebral venous thrombosis: Report of a case.

    PubMed

    Bourvis, Nadège; Franc, Julie; Szatmary, Zoltan; Chabriat, Hugues; Crassard, Isabelle; Ducros, Anne

    2016-01-01

    Reversible cerebral constriction syndrome and cerebral venous thrombosis are two rare conditions. Reversible cerebral constriction syndrome affects the cerebral arteries and the pathology is still largely unknown. To date, no physiological link with cerebral venous thrombosis has been reported. We report here the case of a 24-year-old woman who presented a reversible cerebral constriction syndrome in the setting of a cerebral venous thrombosis. Cerebral venous thrombosis had developed in her left lateral venous sinus, within the stent placed one year before, in order to treat an idiopathic intracranial hypertension. The co-occurrence of cerebral venous thrombosis and reversible cerebral constriction syndrome in the same patient raises the issue of a potential link between them. We discuss the potential common trigger factors in this case: recent hormonal therapy; intracranial hypotension iatrogenically induced by lumbar puncture. © International Headache Society 2015.

  8. The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: Contribution of TRPM2 and TRPV1 channels

    PubMed Central

    Akpınar, Hatice; Nazıroğlu, Mustafa; Övey, İshak Suat; Çiğ, Bilal; Akpınar, Orhan

    2016-01-01

    Dexmedetomidine (DEX) may act as an antioxidant through regulation of TRPM2 and TRPV1 channel activations in the neurons by reducing cerebral ischemia-induced oxidative stress and apoptosis. The neuroprotective roles of DEX were tested on cerebral ischemia (ISC) in the cultures of rat primary hippocampal and DRG neurons. Fifty-six rats were divided into five groups. A placebo was given to control, sham control, and ISC groups, respectively. In the third group, ISC was induced. The DEX and ISC+DEX groups received intraperitoneal DEX (40 μg/kg) 3, 24, and 48 hours after ISC induction. DEX effectively reversed capsaicin and cumene hydroperoxide/ADP-ribose-induced TRPV1 and TRPM2 densities and cytosolic calcium ion accumulation in the neurons, respectively. In addition, DEX completely reduced ISC-induced oxidative toxicity and apoptosis through intracellular reactive oxygen species production and depolarization of mitochondrial membrane. The DEX and ISC+DEX treatments also decreased the expression levels of caspase 3, caspase 9, and poly (ADP-ribose) polymerase in the hippocampus and DRG. In conclusion, the current results are the first to demonstrate the molecular level effects of DEX on TRPM2 and TRPV1 activation. Therefore, DEX can have remarkable neuroprotective impairment effects in the hippocampus and DRG of ISC-induced rats. PMID:27872485

  9. The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: Contribution of TRPM2 and TRPV1 channels.

    PubMed

    Akpınar, Hatice; Nazıroğlu, Mustafa; Övey, İshak Suat; Çiğ, Bilal; Akpınar, Orhan

    2016-11-22

    Dexmedetomidine (DEX) may act as an antioxidant through regulation of TRPM2 and TRPV1 channel activations in the neurons by reducing cerebral ischemia-induced oxidative stress and apoptosis. The neuroprotective roles of DEX were tested on cerebral ischemia (ISC) in the cultures of rat primary hippocampal and DRG neurons. Fifty-six rats were divided into five groups. A placebo was given to control, sham control, and ISC groups, respectively. In the third group, ISC was induced. The DEX and ISC+DEX groups received intraperitoneal DEX (40 μg/kg) 3, 24, and 48 hours after ISC induction. DEX effectively reversed capsaicin and cumene hydroperoxide/ADP-ribose-induced TRPV1 and TRPM2 densities and cytosolic calcium ion accumulation in the neurons, respectively. In addition, DEX completely reduced ISC-induced oxidative toxicity and apoptosis through intracellular reactive oxygen species production and depolarization of mitochondrial membrane. The DEX and ISC+DEX treatments also decreased the expression levels of caspase 3, caspase 9, and poly (ADP-ribose) polymerase in the hippocampus and DRG. In conclusion, the current results are the first to demonstrate the molecular level effects of DEX on TRPM2 and TRPV1 activation. Therefore, DEX can have remarkable neuroprotective impairment effects in the hippocampus and DRG of ISC-induced rats.

  10. Traumatic brain injury-induced ependymal ciliary loss decreases cerebral spinal fluid flow.

    PubMed

    Xiong, Guoxiang; Elkind, Jaclynn A; Kundu, Suhali; Smith, Colin J; Antunes, Marcelo B; Tamashiro, Edwin; Kofonow, Jennifer M; Mitala, Christina M; Cole, Jeffrey; Stein, Sherman C; Grady, M Sean; Einhorn, Eugene; Cohen, Noam A; Cohen, Akiva S

    2014-08-15

    Traumatic brain injury (TBI) afflicts up to 2 million people annually in the United States and is the primary cause of death and disability in young adults and children. Previous TBI studies have focused predominantly on the morphological, biochemical, and functional alterations of gray matter structures, such as the hippocampus. However, little attention has been given to the brain ventricular system, despite the fact that altered ventricular function is known to occur in brain pathologies. In the present study, we investigated anatomical and functional alterations to mouse ventricular cilia that result from mild TBI. We demonstrate that TBI causes a dramatic decrease in cilia. Further, using a particle tracking technique, we demonstrate that cerebrospinal fluid flow is diminished, thus potentially negatively affecting waste and nutrient exchange. Interestingly, injury-induced ventricular system pathology resolves completely by 30 days after injury as ependymal cell ciliogenesis restores cilia density to uninjured levels in the affected lateral ventricle.

  11. Traumatic Brain Injury-Induced Ependymal Ciliary Loss Decreases Cerebral Spinal Fluid Flow

    PubMed Central

    Xiong, Guoxiang; Elkind, Jaclynn A.; Kundu, Suhali; Smith, Colin J.; Antunes, Marcelo B.; Tamashiro, Edwin; Kofonow, Jennifer M.; Mitala, Christina. M.; Stein, Sherman C.; Grady, M. Sean; Einhorn, Eugene; Cohen, Noam A.

    2014-01-01

    Abstract Traumatic brain injury (TBI) afflicts up to 2 million people annually in the United States and is the primary cause of death and disability in young adults and children. Previous TBI studies have focused predominantly on the morphological, biochemical, and functional alterations of gray matter structures, such as the hippocampus. However, little attention has been given to the brain ventricular system, despite the fact that altered ventricular function is known to occur in brain pathologies. In the present study, we investigated anatomical and functional alterations to mouse ventricular cilia that result from mild TBI. We demonstrate that TBI causes a dramatic decrease in cilia. Further, using a particle tracking technique, we demonstrate that cerebrospinal fluid flow is diminished, thus potentially negatively affecting waste and nutrient exchange. Interestingly, injury-induced ventricular system pathology resolves completely by 30 days after injury as ependymal cell ciliogenesis restores cilia density to uninjured levels in the affected lateral ventricle. PMID:24749541

  12. Role of thalamic nuclei in the modulation of Fos expression within the cerebral cortex during hypertonic saline-induced muscle nociception.

    PubMed

    Xiao, Y; Lei, J; Ye, G; Xu, H; You, H-J

    2015-09-24

    It has been proposed that thalamic mediodorsal (MD) and ventromedial (VM) nuclei form thalamic 'nociceptive discriminators' in discrimination of nociceptive afferents, and specifically govern endogenous descending facilitation and inhibition. The present study conducted in rats was to explore the role of thalamic MD and VM nuclei in modulation of cerebral neuronal activities by means of detection of spatiotemporal variations of Fos expression within the cerebral cortex. Following a unilateral intramuscular injection of 5.8% saline into the gastrocnemius muscle, Fos expression within the bilateral, different areas of the cerebral cortex except S2 was significantly increased (P<0.05). Particularly, the increases in Fos expression within the cingulate cortex and the insular cortex occurred at 0.5h, 4h and reached the peak level at 4h, 16h, respectively. Electrolytic lesion of the contralateral thalamic MD and VM nuclei significantly blocked the 5.8% saline intramuscularly induced increases in Fos expression within the bilateral cingulate and insular cortices, respectively. Additionally, the 5.8% saline-induced Fos expression in the cingulate cortex and the insular cortex were dose-dependently attenuated by microinjection of μ-opioid antagonist β-funaltrexamine hydrochloride into the thalamic MD and VM nuclei. It is suggested that (1) the neural circuits of 'thalamic MD nucleus - cingulate cortex' and 'thalamic VM nucleus - insular cortex' form two distinct pathways in the endogenous control of nociception, (2) mirror or contralateral pain is hypothesized to be related to cross-talk of neuronal activities within the bilateral cerebral cortices modulated by μ-opioid receptors within the thalamic MD and VM nuclei.

  13. Protective effects of propofol against whole cerebral ischemia/reperfusion injury in rats through the inhibition of the apoptosis-inducing factor pathway.

    PubMed

    Tao, Tao; Li, Chun-Lei; Yang, Wan-Chao; Zeng, Xian-Zhang; Song, Chun-Yu; Yue, Zi-Yong; Dong, Hong; Qian, Hua

    2016-08-01

    Cerebral ischemia/reperfusion (I/R) injury could cause neural apoptosis that involved the signaling cascades. Cytochrome c release from the mitochondria and the followed activation of caspase 9 and caspase 3 are the important steps. Now, a new mitochondrial protein, apoptosis-inducing factor (AIF), has been shown to have relationship with the caspase-independent apoptotic pathway. In this study, we investigated the protective effects of propofol through inhibiting AIF-mediated apoptosis induced by whole cerebral I/R injury in rats. 120 Wistar rats that obtained the permission of the animal care committee of Harbin Medical University were randomly divided into three groups: sham group (S group), cerebral ischemia/reperfusion injury group (I/R group), and propofol treatment group (P group). Propofol (1.0mg/kg/min) was administered intravenously for 1h before the induction of ischemia in P group. The apoptotic rate in three groups was detected by flow cytometry after 24h of reperfusion. The mitochondrial membrane potential (MMP) changes were detected via microplate reader. The expressions of B-cell leukemia-2 (Bcl-2), Bcl-2 associated X protein (Bax) and AIF were evaluated using Western blot after 6h, 24h and 48h of reperfusion. The results of our study showed that apoptotic level was lower in P group compared with I/R group and propofol could protect MMP. The ratio of Bcl-2/Bax was significantly higher in P group compared with I/R group. The translocation of AIF from mitochondrial to nucleus was lower in P group than that in I/R group. Our findings suggested that the protective effects of propofol on cerebral I/R injury might be associated with inhibiting translocation of AIF from mitochondrial to the nucleus in hippocampal neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. 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.

  15. Toward a theory of the general-anesthetic-induced phase transition of the cerebral cortex. I. A thermodynamics analogy.

    PubMed

    Steyn-Ross, M L; Steyn-Ross, D A; Sleigh, J W; Wilcocks, L C

    2001-07-01

    In a recent paper the authors developed a stochastic model for the response of the cerebral cortex to a general anesthetic agent. The model predicted that there would be an anesthetic-induced phase change at the point of transition into unconsciousness, manifested as a divergence in the electroencephalogram spectral power, and a change in spectral energy distribution from being relatively broadband in the conscious state to being strongly biased towards much lower frequencies in the unconscious state. Both predictions have been verified in recent clinical measurements. In the present paper we extend the model by calculating the equilibrium distribution function for the cortex, allowing us to establish a correspondence between the cortical phase transition and the more familiar thermodynamic phase transitions. This correspondence is achieved by first identifying a cortical free energy function, then by postulating that there exists an inverse relationship between an anesthetic effect and a quantity we define as cortical excitability, which plays a role analogous to temperature in thermodynamic phase transitions. We follow standard thermodynamic theory to compute a cortical entropy and a cortical "heat capacity," and we investigate how these will vary with anesthetic concentration. The significant result is the prediction that the entropy will decrease discontinuously at the moment of induction into unconsciousness, concomitant with a release of "latent heat" which should manifest as a divergence in the analogous heat capacity. There is clear clinical evidence of heat capacity divergence in historical anesthetic-effect measurements performed in 1977 by Stullken et al. [Anesthesiology 46, 28 (1977)]. The discontinuous step change in cortical entropy suggests that the cortical phase transition is analogous to a first-order thermodynamic transition in which the comatose-quiescent state is strongly ordered, while the active cortical state is relatively disordered.

  16. Toward a theory of the general-anesthetic-induced phase transition of the cerebral cortex. I. A thermodynamics analogy

    NASA Astrophysics Data System (ADS)

    Steyn-Ross, Moira L.; Steyn-Ross, D. A.; Sleigh, J. W.; Wilcocks, Lara C.

    2001-07-01

    In a recent paper the authors developed a stochastic model for the response of the cerebral cortex to a general anesthetic agent. The model predicted that there would be an anesthetic-induced phase change at the point of transition into unconsciousness, manifested as a divergence in the electroencephalogram spectral power, and a change in spectral energy distribution from being relatively broadband in the conscious state to being strongly biased towards much lower frequencies in the unconscious state. Both predictions have been verified in recent clinical measurements. In the present paper we extend the model by calculating the equilibrium distribution function for the cortex, allowing us to establish a correspondence between the cortical phase transition and the more familiar thermodynamic phase transitions. This correspondence is achieved by first identifying a cortical free energy function, then by postulating that there exists an inverse relationship between an anesthetic effect and a quantity we define as cortical excitability, which plays a role analogous to temperature in thermodynamic phase transitions. We follow standard thermodynamic theory to compute a cortical entropy and a cortical ``heat capacity,'' and we investigate how these will vary with anesthetic concentration. The significant result is the prediction that the entropy will decrease discontinuously at the moment of induction into unconsciousness, concomitant with a release of ``latent heat'' which should manifest as a divergence in the analogous heat capacity. There is clear clinical evidence of heat capacity divergence in historical anesthetic-effect measurements performed in 1977 by Stullken et al. [Anesthesiology 46, 28 (1977)]. The discontinuous step change in cortical entropy suggests that the cortical phase transition is analogous to a first-order thermodynamic transition in which the comatose-quiescent state is strongly ordered, while the active cortical state is relatively disordered.

  17. [Viruses and the neuroendocrine system: model of murine obesity induced by cerebral infection by canine distemper virus].

    PubMed

    Bernard, A; Akaoka, H; Giraudon, P; Belin, M

    1999-05-01

    It is currently well established that the nervous, endocrine and immune systems inter-communicate using biologically active soluble factors, synthesised and produced by these three systems themselves (e.g. immunomodulator effect of hormones, effect of substances secreted by immune cells on endocrine function.). In addition, these systems jointly express receptors for hormones, peptides, growth factors and cytokines. Immuno-neuroendocrine interactions therefore underlie physiological processes and their deregulation can result in various pathological states. By entering into complex relationships with the specialized and differentiated cells of these three systems viruses can alter inter-cellular communication and result in the appearance of pathological processes directly linked to these disturbances. In order to understand the role of viruses in the genesis of neuroimmunoendocrine pathologies, we have developed a cerebral infection model using canine distemper virus (CDV). In infected mice, this paramyxovirus, closely related to the human measles virus, induces early neurological pathologies (encephalitis) which are associated with active viral replication. Mice surviving the acute phase of infection exhibit motor deficits (paralysis and turning behaviour) or obesity during the viral persistence phase, despite the fact that the virus is no longer detectable. The obesity is characterised by hyperinsulinaemia, hyperleptinaemia and hyperplasia of the adipocytes, associated with decreased expression of the OB-Rb hypothalamic leptin receptor and modulated expression of hypothalamic monoamines and neuropeptides. These results support the viral "hit and run" theory, since the initial viral impact in the hypothalamus may be the origin of the changes in later immunoneuroendocrine communication. Thus, certain human neurodegenerative or neuroendocrine diseases may have a previous viral infection aetiology without it being possible to clearly identify the agent responsible.

  18. Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans

    PubMed Central

    Farmer, Adam D; Ban, Vin F; Coen, Steven J; Sanger, Gareth J; Barker, Gareth J; Gresty, Michael A; Giampietro, Vincent P; Williams, Steven C; Webb, Dominic L; Hellström, Per M; Andrews, Paul L R; Aziz, Qasim

    2015-01-01

    Abstract An integrated understanding of the physiological mechanisms involved in the genesis of nausea remains lacking. We aimed to describe the psychophysiological changes accompanying visually induced motion sickness, using a motion video, hypothesizing that differences would be evident between subjects who developed nausea in comparison to those who did not. A motion, or a control, stimulus was presented to 98 healthy subjects in a randomized crossover design. Validated questionnaires and a visual analogue scale (VAS) were used for the assessment of anxiety and nausea. Autonomic and electrogastrographic activity were measured at baseline and continuously thereafter. Plasma vasopressin and ghrelin were measured in response to the motion video. Subjects were stratified into quartiles based on VAS nausea scores, with the upper and lower quartiles considered to be nausea sensitive and resistant, respectively. Twenty-eight subjects were exposed to the motion video during functional neuroimaging. During the motion video, nausea-sensitive subjects had lower normogastria/tachygastria ratio and cardiac vagal tone but higher cardiac sympathetic index in comparison to the control video. Furthermore, nausea-sensitive subjects had decreased plasma ghrelin and demonstrated increased activity of the left anterior cingulate cortex. Nausea VAS scores correlated positively with plasma vasopressin and left inferior frontal and middle occipital gyri activity and correlated negatively with plasma ghrelin and brain activity in the right cerebellar tonsil, declive, culmen, lingual gyrus and cuneus. This study demonstrates that the subjective sensation of nausea is associated with objective changes in autonomic, endocrine and brain networks, and thus identifies potential objective biomarkers and targets for therapeutic interventions. Key points Nausea is a highly individual and variable experience. The reasons for this variability are incompletely understood although

  19. Modeling modulation of intracranial pressure by variation of cerebral venous resistance induced by ventilation.

    PubMed

    Pasley, Richard L; Leffler, Charles W; Daley, Michael L

    2003-11-01

    To test, theoretically, the hypothesis that: (1) cyclic extravascular compressional modulation of the terminal venous bed occurs with positive pressure inhalation; and (2) the degree of modulation is diminished with increasing vascular dilation induced by increasing the level of the partial pressure of arterial blood carbon dioxide (PCO2), two modifications of Ursino's model of cerebrospinal fluid dynamics were made: (1) terminal venous bed resistance was synchronously modulated with the ventilation cycle; and (2) both the depth of modulation and cerebrovascular resistance were progressively reduced with increasing levels of PCO2. Recordings of intracranial pressure (ICP) and arterial blood pressure of piglets were obtained and correlated at different levels of hypercapnia. Simulated and experimental correlation values progressively increased monotonically as the level of PCO2 increased. Group (n = 4) mean values of correlation (+/- standard deviation) were 0.54 (+/- 0.17), 0.61 (+/- 0.08), 0.79 (+/- 0.06), 0.86 (+/- 0.04), 0.87 (+/- 0.05) for respective mean PCO2 levels (+/- standard deviation) of 32.9 (+/- 1.75), 41.4 (+/- 2.5), 55.9 (+/- 4.0), 72.5 (+/- 6.45), and 87.4 (+/- 7.25) mmHg. These results support the stated premise that dilation of the cerebrovasculature reduces the influence of positive pressure ventilation on the ICP recording by increasing the venous pressure and thus diminishing the likelihood of vascular compression.

  20. Flight-induced inhibition of the cerebral median peptidergic neurosecretory system in Locusta migratoria

    SciTech Connect

    Diederen, J.H.; van Etten, E.W.; Biegstraaten, A.I.; Terlou, M.; Vullings, H.G.; Jansen, W.F.

    1988-08-01

    This study discusses the effects of a 1-hr period of flight on the peptidergic pars intercerebralis (PI)-corpus cardiacum storage part (CCS) system in male Locusta migratoria, particularly the effect on material in this system stained by a histochemical method for peptidergic neurosecretory material (NSM) or labeled by in vivo incorporation of radioactive amino acid molecules. By use of an automatic image analysis system a number of parameters of the stained or radioactively labeled substances were measured to quantify the flight-induced effects and to get information on the manner in which the neurosecretory cell bodies in the PI and their axonal endings in the CCS accommodate changing amounts of NSM. The CCS of flown locusts contained distinctly more stained and radioactively labeled substances than the CCS of unflown locusts. A tendency to similar differences was observed in the cluster of neurosecretory cell bodies in the PI. The results indicate that 1 hr flight inhibited the release of NSM by the PI-CCS system. After the onset of reduced release activity by flight, some NSM continued to be synthesized and transported from the PI to the CCS, gradually filling up and expanding the entire PI-CCS system, the NSM at the same time becoming more and more densely packed. It is concluded that the peptidergic PI-CCS system is not actively involved in the control of flight metabolism or flight behavior.

  1. Muscle Recruitment and Coordination following Constraint-Induced Movement Therapy with Electrical Stimulation on Children with Hemiplegic Cerebral Palsy: A Randomized Controlled Trial

    PubMed Central

    Xu, Kaishou; He, Lu; Mai, Jianning; Yan, Xiaohua; Chen, Ying

    2015-01-01

    Objective To investigate changes of muscle recruitment and coordination following constraint-induced movement therapy, constraint-induced movement therapy plus electrical stimulation, and traditional occupational therapy in treating hand dysfunction. Methods In a randomized, single-blind, controlled trial, children with hemiplegic cerebral palsy were randomly assigned to receive constraint-induced movement therapy (n = 22), constraint-induced movement therapy plus electrical stimulation (n = 23), or traditional occupational therapy (n = 23). Three groups received a 2-week hospital-based intervention and a 6-month home-based exercise program following hospital-based intervention. Constraint-induced movement therapy involved intensive functional training of the involved hand during which the uninvolved hand was constrained. Electrical stimulation was applied on wrist extensors of the involved hand. Traditional occupational therapy involved functional unimanual and bimanual training. All children underwent clinical assessments and surface electromyography (EMG) at baseline, 2 weeks, 3 and 6 months after treatment. Surface myoelectric signals were integrated EMG, root mean square and cocontraction ratio. Clinical measures were grip strength and upper extremity functional test. Results Constraint-induced movement therapy plus electrical stimulation group showed both a greater rate of improvement in integrated EMG of the involved wrist extensors and cocontraction ratio compared to the other two groups at 3 and 6 months, as well as improving in root mean square of the involved wrist extensors than traditional occupational therapy group (p<0.05). Positive correlations were found between both upper extremity functional test scores and integrated EMG of the involved wrist as well as grip strength and integrated EMG of the involved wrist extensors (p<0.05). Conclusions Constraint-induced movement therapy plus electrical stimulation is likely to produce the best outcome in

  2. Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study.

    PubMed

    Shearman, E; Rossi, S; Szasz, B; Juranyi, Z; Fallon, S; Pomara, N; Sershen, H; Lajtha, A

    2006-03-31

    ventral tegmental area. Our results suggest both region and drug specific neurotransmitter effects of these agents as well as some similarities. We conclude that drugs influencing cognitive mechanisms induce changes in a number of neurotransmitters with the changes being both region and drug specific. Release and metabolism are altered and extracellular neurotransmitter levels can be increased or decreased by the drugs. Other studies are in progress to determine the pharmacological effects associated with chronic treatment with these compounds, which may be more pertinent to the clinical situation in which patients take these medications for months or years.

  3. Cerebral blood flow and metabolism during cardiopulmonary bypass with special reference to effects of hypotension induced by prostacyclin

    SciTech Connect

    Feddersen, K.; Aren, C.; Nilsson, N.J.; Radegran, K.

    1986-04-01

    Cerebral blood flow and metabolism of oxygen, glucose, and lactate were studied in 43 patients undergoing aortocoronary bypass. Twenty-five patients received prostacyclin infusion, 50 ng per kilogram of body weight per minute, during cardiopulmonary bypass (CPB), and 18 patients served as a control group. Regional cerebral blood flow (CBF) was studied by intraarterially injected xenon 133 and a single scintillation detector. Oxygen tension, carbon dioxide tension, oxygen saturation, glucose, and lactate were measured in arterial and cerebral venous blood. Mean arterial blood pressure decreased during hypothermia and prostacyclin infusion to less than 30 mm Hg. The regional CBF was, on average, 22 (standard deviation (SD) 4) ml/100 gm/min before CPB. It increased in the control group during hypothermia to 34 (SD 12) ml/100 gm/min, but decreased in the prostacyclin group to 15 (SD 5) ml/100 gm/min. It increased during rewarming in the prostacyclin group. After CPB, regional CBF was about 40 ml/100 gm/min in both groups. The cerebral arteriovenous oxygen pressure difference decreased more in the control group than in the prostacyclin group during hypothermia. The cerebral metabolic rate of oxygen decreased in both groups from approximately 2 ml/100 gm/min to about 1 ml/100 gm/min during hypothermia, increased again during rewarming, and after CPB was at the levels measured before bypass in both groups. There was no difference between the groups in regard to glucose and lactate metabolism.

  4. Brazilein inhibits neuronal inflammation induced by cerebral ischemia and oxygen-glucose deprivation through targeting NOD2 expression.

    PubMed

    Yan, Xiao-Jin; Chai, Yu-Shuang; Yuan, Zhi-Yi; Wang, Xin-Pei; Jiang, Jing-Fei; Lei, Fan; Xing, Dong-Ming; DU, Li-Jun

    2016-05-01

    Brazilein is reported to have immunosuppressive effect on cardiovascular and cerebral-vascular diseases. The essential roles of innate immunity in cerebral ischemia are increasingly identified, but no studies concerning the influence of brazilein on the innate immunity receptors have been reported. The present study was designed to investigate the regulation of NOD2 (Nucleotide-binding oligomerization domain-containing protein 2) by brazilein for its protection of neuron in cerebral ischemia in vivo and oxygen-glucose deprivation in vitro. The results showed that brazilein could reverse the elevated expression of NOD2 and TNFα (tumor necrosis factor alpha) elicited by cerebral ischemia and reperfusion. This reduction could also be detected in normal mice and C17.2 cells, indicating that this suppressive effect of brazilein was correlated with NOD2. The results from GFP reporter plasmid assay suggested brazilein inhibited NOD2 gene transcription. In conclusion, brazilein could attenuate NOD2 and TNFα expression in cerebral ischemia and NOD2 may be one possible target of brazilein for its immune suppressive effect in neuro-inflammation.

  5. 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.

  6. Cerebral malaria

    PubMed Central

    Rénia, Laurent; Wu Howland, Shanshan; Claser, Carla; Charlotte Gruner, Anne; Suwanarusk, Rossarin; Hui Teo, Teck; Russell, Bruce; Ng, Lisa

    2012-01-01

    Cerebral malaria is the most severe pathology caused by the malaria parasite, Plasmodium falciparum. The pathogenic mechanisms leading to cerebral malaria are still poorly defined as studies have been hampered by limited accessibility to human tissues. Nevertheless, histopathology of post-mortem human tissues and mouse models of cerebral malaria have indicated involvement of the blood-brain barrier in cerebral malaria. In contrast to viruses and bacteria, malaria parasites do not infiltrate and infect the brain parenchyma. Instead, rupture of the blood-brain barrier occurs and may lead to hemorrhages resulting in neurological alterations. Here, we review the most recent findings from human studies and mouse models on the interactions of malaria parasites and the blood-brain barrier, shedding light on the pathogenesis of cerebral malaria, which may provide directions for possible interventions. PMID:22460644

  7. Astrocyte-derived CO is a diffusible messenger that mediates glutamate-induced cerebral arteriolar dilation by activating smooth muscle cell KCa channels

    PubMed Central

    Li, Anlong; Xi, Qi; Umstot, Edward S.; Bellner, Lars; Schwartzman, Michal L.; Jaggar, Jonathan H.; Leffler, Charles W.

    2012-01-01

    Astrocyte signals can modulate arteriolar tone, contributing to regulation of cerebral blood flow, but specific intercellular communication mechanisms are unclear. Here we used isolated cerebral arteriole myocytes, astrocytes, and brain slices to investigate whether carbon monoxide (CO) generated by the enzyme heme oxygenase (HO) acts as an astrocyte-to-myocyte gasotransmitter in the brain. Glutamate stimulated CO production by astrocytes with intact HO-2, but not those genetically deficient in HO-2. Glutamate activated transient KCa currents and single KCa channels in myocytes that were in contact with astrocytes, but did not affect KCa channel activity in myocytes that were alone. Pre-treatment of astrocytes with chromium mesoporphyrin (CrMP), a HO inhibitor, or genetic ablation of HO-2 prevented glutamate-induced activation of myocyte transient KCa currents and KCa channels. Glutamate decreased arteriole myocyte intracellular Ca2+ concentration and dilated brain slice arterioles and this decrease and dilation were blocked by CrMP. Brain slice arteriole dilation to glutamate was also blocked by L-2-alpha aminoadipic acid, a selective astrocyte toxin, and paxilline, a KCa channel blocker. These data indicate that an astrocytic signal, notably HO-2 derived CO, is employed by glutamate to stimulate arteriole myocyte KCa channels and dilate cerebral arterioles. Our study explains the astrocyte and HO dependence of glutamatergic functional hyperemia observed in the newborn cerebrovascular circulation in vivo. PMID:17991880

  8. Electrical stimulation of cerebellar fastigial nucleus promotes the expression of growth arrest and DNA damage inducible gene β and motor function recovery in cerebral ischemia/reperfusion rats.

    PubMed

    Liu, Bin; Li, Jianrui; Li, Longling; Yu, Lehua; Li, Changqing

    2012-06-27

    This study focused on the effects of electrical stimulation of cerebellar fastigial nucleus on the expression of growth arrest and DNA damage inducible gene β (Gadd45β) and on motor function recovery after focal cerebral ischemia/reperfusion (I/R) in rats. Sprague-Dawley (SD) rats were randomly divided into 4 groups: sham I/R (control group), I/R (I/R group), I/R with sham stimulation and I/R with electrical stimulation at 6h, 12h, 24h, 2d and 3d after I/R. Cerebral ischemia and reperfusion was established by nylon monofilament occlusion method. Fastigial nucleus (FN) electrical stimulation was applied at 2h after ischemia for 1h. The changes in the expression of Gadd45β were analyzed by immunohistochemistry, real-time polymerase chain reaction (PCR) and Western-blot respectively. Another group of rats were divided into the same 4 groups. Montoya staircase test score was used to test the motor function of affected forelimb. The levels of Gadd45β were significantly elevated after I/R injury. FN electrical stimulation treatment elevated the expression of Gadd45β further and improved motor function recovery. These results suggest that FN electrical stimulation can promote the expression of Gadd45β and motor function recovery after focal cerebral ischemia.

  9. Possible involvement of NO/NOS signaling in hippocampal amyloid-beta production induced by transient focal cerebral ischemia in aged rats.

    PubMed

    Li, Song; Wang, Wei; Wang, Che; Tang, Yi-Yuan

    2010-02-12

    In the present study, to define the roles of nitric oxide (NO) signaling in amyloid-beta (A beta) production after transient cerebral ischemia, extracellular levels of NO and A beta were monitored by intracerebral microdialysis in the hippocampus of aged rats exposed to transient middle cerebral artery occlusion and reperfusion (MCAO/R). The results indicated that 1-h MCAO significantly upregulated hippocampal NO and A beta levels. In addition, the NO elevation preceded the A beta changes. The Western blotting suggested that acute hypoperfusion could increase the expression of beta-secretase 1 (BACE1) but not BACE2. The enhanced NO concentration in acute stage of MCAO/R was coincident with increased eNOS expression, while in subacute stage was coincident with increased iNOS and nNOS. Our results also indicated that pretreatment of L-NAME, one non-selective NOS inhibitor could decrease the BACE1 expression, reverse both NO and A beta changes and rescue the delayed neuronal death. These preliminary findings indicated that activation of NOS/NO signaling system could trigger A beta production through BACE1 pathway during acute ischemic episode. The present data may be important in understanding, at least in part, the pathological role of NO/NOS system involved in hippocampal A beta production and neuronal damage induced by transient cerebral ischemia.

  10. Rapid Induction of Cerebral Organoids From Human Induced Pluripotent Stem Cells Using a Chemically Defined Hydrogel and Defined Cell Culture Medium.

    PubMed

    Lindborg, Beth A; Brekke, John H; Vegoe, Amanda L; Ulrich, Connor B; Haider, Kerri T; Subramaniam, Sandhya; Venhuizen, Scott L; Eide, Cindy R; Orchard, Paul J; Chen, Weili; Wang, Qi; Pelaez, Francisco; Scott, Carolyn M; Kokkoli, Efrosini; Keirstead, Susan A; Dutton, James R; Tolar, Jakub; O'Brien, Timothy D

    2016-07-01

    Tissue organoids are a promising technology that may accelerate development of the societal and NIH mandate for precision medicine. Here we describe a robust and simple method for generating cerebral organoids (cOrgs) from human pluripotent stem cells by using a chemically defined hydrogel material and chemically defined culture medium. By using no additional neural induction components, cOrgs appeared on the hydrogel surface within 10-14 days, and under static culture conditions, they attained sizes up to 3 mm in greatest dimension by day 28. Histologically, the organoids showed neural rosette and neural tube-like structures and evidence of early corticogenesis. Immunostaining and quantitative reverse-transcription polymerase chain reaction demonstrated protein and gene expression representative of forebrain, midbrain, and hindbrain development. Physiologic studies showed responses to glutamate and depolarization in many cells, consistent with neural behavior. The method of cerebral organoid generation described here facilitates access to this technology, enables scalable applications, and provides a potential pathway to translational applications where defined components are desirable. Tissue organoids are a promising technology with many potential applications, such as pharmaceutical screens and development of in vitro disease models, particularly for human polygenic conditions where animal models are insufficient. This work describes a robust and simple method for generating cerebral organoids from human induced pluripotent stem cells by using a chemically defined hydrogel material and chemically defined culture medium. This method, by virtue of its simplicity and use of defined materials, greatly facilitates access to cerebral organoid technology, enables scalable applications, and provides a potential pathway to translational applications where defined components are desirable. ©AlphaMed Press.

  11. Diffusion Tensor Imaging Detects Early Cerebral Cortex Abnormalities in Neuronal Architecture Induced by Bilateral Neonatal Enucleation: An Experimental Model in the Ferret

    PubMed Central

    Bock, Andrew S.; Olavarria, Jaime F.; Leigland, Lindsey A.; Taber, Erin N.; Jespersen, Sune N.; Kroenke, Christopher D.

    2010-01-01

    Diffusion tensor imaging (DTI) is a technique that non-invasively provides quantitative measures of water translational diffusion, including fractional anisotropy (FA), that are sensitive to the shape and orientation of cellular elements, such as axons, dendrites and cell somas. For several neurodevelopmental disorders, histopathological investigations have identified abnormalities in the architecture of pyramidal neurons at early stages of cerebral cortex development. To assess the potential capability of DTI to detect neuromorphological abnormalities within the developing cerebral cortex, we compare changes in cortical FA with changes in neuronal architecture and connectivity induced by bilateral enucleation at postnatal day 7 (BEP7) in ferrets. We show here that the visual callosal pattern in BEP7 ferrets is more irregular and occupies a significantly greater cortical area compared to controls at adulthood. To determine whether development of the cerebral cortex is altered in BEP7 ferrets in a manner detectable by DTI, cortical FA was compared in control and BEP7 animals on postnatal day 31. Visual cortex, but not rostrally adjacent non-visual cortex, exhibits higher FA than control animals, consistent with BEP7 animals possessing axonal and dendritic arbors of reduced complexity than age-matched controls. Subsequent to DTI, Golgi-staining and analysis methods were used to identify regions, restricted to visual areas, in which the orientation distribution of neuronal processes is significantly more concentrated than in control ferrets. Together, these findings suggest that DTI can be of utility for detecting abnormalities associated with neurodevelopmental disorders at early stages of cerebral cortical development, and that the neonatally enucleated ferret is a useful animal model system for systematically assessing the potential of this new diagnostic strategy. PMID:21048904

  12. Rapid Induction of Cerebral Organoids From Human Induced Pluripotent Stem Cells Using a Chemically Defined Hydrogel and Defined Cell Culture Medium

    PubMed Central

    Lindborg, Beth A.; Brekke, John H.; Vegoe, Amanda L.; Ulrich, Connor B.; Haider, Kerri T.; Subramaniam, Sandhya; Venhuizen, Scott L.; Eide, Cindy R.; Orchard, Paul J.; Chen, Weili; Wang, Qi; Pelaez, Francisco; Scott, Carolyn M.; Kokkoli, Efrosini; Keirstead, Susan A.; Dutton, James R.; Tolar, Jakub

    2016-01-01

    Tissue organoids are a promising technology that may accelerate development of the societal and NIH mandate for precision medicine. Here we describe a robust and simple method for generating cerebral organoids (cOrgs) from human pluripotent stem cells by using a chemically defined hydrogel material and chemically defined culture medium. By using no additional neural induction components, cOrgs appeared on the hydrogel surface within 10–14 days, and under static culture conditions, they attained sizes up to 3 mm in greatest dimension by day 28. Histologically, the organoids showed neural rosette and neural tube-like structures and evidence of early corticogenesis. Immunostaining and quantitative reverse-transcription polymerase chain reaction demonstrated protein and gene expression representative of forebrain, midbrain, and hindbrain development. Physiologic studies showed responses to glutamate and depolarization in many cells, consistent with neural behavior. The method of cerebral organoid generation described here facilitates access to this technology, enables scalable applications, and provides a potential pathway to translational applications where defined components are desirable. Significance Tissue organoids are a promising technology with many potential applications, such as pharmaceutical screens and development of in vitro disease models, particularly for human polygenic conditions where animal models are insufficient. This work describes a robust and simple method for generating cerebral organoids from human induced pluripotent stem cells by using a chemically defined hydrogel material and chemically defined culture medium. This method, by virtue of its simplicity and use of defined materials, greatly facilitates access to cerebral organoid technology, enables scalable applications, and provides a potential pathway to translational applications where defined components are desirable. PMID:27177577

  13. The Third, Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial

    ClinicalTrials.gov

    2017-07-05

    Cerebral Hemorrhage; Stroke; Hypertension; Diabetes; Anticoagulant-induced Bleeding; Cerebral Vascular Disorder; Brain Disorder; Hemorrhage; Intracranial Hemorrhages; Cardiovascular Diseases; Central Nervous System Diseases

  14. The role of voltage-operated and non-voltage-operated calcium channels in endothelin-induced vasoconstriction of rat cerebral arteries.

    PubMed

    Mamo, Yohannes A; Angus, James A; Ziogas, James; Soeding, Paul F; Wright, Christine E

    2014-11-05

    Endothelin-1 has been identified as a potential mediator in the pathogenesis of ischaemic stroke and cerebral vasospasm. The aim of this study was to analyse the role of voltage-operated calcium channels (VOCC) and non-VOCC in endothelin-1 induced vasoconstriction of rat cerebral arteries. Arterial segments were dissected from different regions of the cerebral circulation and responses assessed using wire myography. Endothelin-1 concentration-contraction curves were constructed in calcium-free medium or in the presence of nifedipine, NNC 55-0396 ((1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride) or SK&F 96365 (1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole) to inhibit the l-type VOCC, T-type VOCC and non-VOCC, respectively. Inhibition of the calcium channels or removal of calcium from the medium variably decreased the maximum effects (Emax) of endothelin-1, however its potency (pEC50) was unaltered. Endothelin-1 caused a small contraction (<22%) in calcium-free solution. Pre-treatment with nifedipine (1µM) did not affect responses to low concentrations of endothelin-1 but decreased Emax, while NNC 55-0396 (1µM) and SK&F 96365 (30-100µM) generally attenuated the endothelin-1-induced contraction. Combination of nifedipine with SK&F 96365 further decreased the Emax. The relaxant effect of the calcium channel antagonists was also assessed in pre-contracted arteries. Only nifedipine and SK&F 96365 relaxed the arteries pre-contracted with endothelin-1. In conclusion, VOCC and non-VOCC calcium channels are involved in different phases of the endothelin-1 contraction in rat cerebral vessels. T-type VOCC may be involved in contraction induced by low concentrations of endothelin-1, while l-type VOCC mediate the maintenance phase of contraction. VOCC and non-VOCC may work in concert in mediating contraction induced by endothelin-1. Copyright

  15. Right ventricular pressure changes during induced ventricular tachycardias predict clinical symptoms of cerebral hypoperfusion: implications for a reduction of unnecessary, painful ICD shocks.

    PubMed

    Petrucci, Ettore; Sarzi Braga, Simona; Balian, Vruyr; Pedretti, Roberto F E

    2009-03-01

    ICD shocks occurring in conscious patients (as in the case of well-tolerated arrhythmias, electromagnetic interference, or oversensing) have a deleterious impact on the quality of life. We evaluated if a hemodynamic parameter, calculated from the right ventricular pressure (RVP) or systemic arterial pressure (AP) signals, could predict early clinical symptoms of cerebral hypoperfusion during induced ventricular tachycardias (VTs). We analyzed 42 tolerated (no symptoms) and 30 untolerated (syncope or severe symptoms within 30 seconds from the onset) VTs, induced during electrophysiological study. The cycle length (CL) and the hemodynamic data (mean AP and RVP, arterial pulse pressure and RV pulse pressure, and maximum AP and RVP dP/dT) were automatically sampled in two VT epochs: the "detection" window, from beat 24 to 32, and the "preintervention" window, immediately before the first therapeutic attempt. Although the CL and all the hemodynamic parameters (expressed as % change versus pre-VT values) were significantly lower in untolerated versus tolerated VTs both at detection and preintervention (with the exception of the mean RVP which progressively increased in both groups), ROC analysis demonstrated that only the preintervention RV pulse pressure showed no overlap between groups, providing 100% sensitivity and positive predictive value. The reduction of the RV pulse pressure is a better predictor of early cerebral symptoms than CL or other hemodynamic indexes during induced VTs. Since long-term RVP monitoring is feasible, this parameter could be incorporated into ICDs decisional path, in the perspective of reducing unnecessary, painful shocks.

  16. Chotosan, a kampo formula, ameliorates chronic cerebral hypoperfusion-induced deficits in object recognition behaviors and central cholinergic systems in mice.

    PubMed

    Zhao, Qi; Murakami, Yukihisa; Tohda, Michihisa; Obi, Ryosuke; Shimada, Yutaka; Matsumoto, Kinzo

    2007-04-01

    We previously demonstrated that the Kampo formula chotosan (CTS) ameliorated spatial cognitive impairment via central cholinergic systems in a chronic cerebral hypoperfusion (P2VO) mouse model. In this study, the object discrimination tasks were used to determine if the ameliorative effects of CTS on P2VO-induced cognitive deficits are a characteristic pharmacological profile of this formula, with the aim of clarifying the mechanisms by which CTS enhances central cholinergic function in P2VO mice. The cholinesterase inhibitor tacrine (THA) and Kampo formula saikokeishito (SKT) were used as controls. P2VO impaired object discrimination performance in the object recognition, location, and context tests. Daily administration of CTS (750 mg/kg, p.o.) and THA (2.5 mg/kg, i.p.) improved the object discrimination deficits, whereas SKT (750 mg/kg, p.o.) did not. In ex vivo assays, tacrine but not CTS or SKT inhibited cortical cholinesterase activity. P2VO reduced the mRNA expression of m(3) and m(5) muscarinic receptors and choline acetyltransferase but not that of other muscarinic receptor subtypes in the cerebral cortex. Daily administration of CTS and THA but not SKT reversed these expression changes. These results suggest that CTS and THA improve P2VO-induced cognitive impairment by normalizing the deficit of central cholinergic systems and that the beneficial effect on P2VO-induced cognitive deficits is a distinctive pharmacological characteristic of CTS.

  17. Activation of the Basolateral Amygdala Induces Long-Term Enhancement of Specific Memory Representations in the Cerebral Cortex

    PubMed Central

    Chavez, Candice M.; McGaugh, James L.; Weinberger, Norman M.

    2013-01-01

    The basolateral amygdala (BLA) modulates memory, particularly for arousing or emotional events, during post-training periods of consolidation. It strengthens memories whose substrates in part or whole are stored remotely, in structures such as the hippocampus, striatum and cerebral cortex. However, the mechanisms by which the BLA influences distant memory traces are unknown, largely because of the need for identifiable target mnemonic representations. Associative tuning plasticity in the primary auditory cortex (A1) constitutes a well-characterized candidate specific memory substrate that is ubiquitous across species, tasks and motivational states. When tone predicts reinforcement, the tuning of cells in A1 shifts toward or to the signal frequency within its tonotopic map, producing an over-representation of behaviorally important sounds. Tuning shifts have the cardinal attributes of forms of memory, including associativity, specificity, rapid induction, consolidation and long-term retention and are therefore likely memory representations. We hypothesized that the BLA strengthens memories by increasing their cortical representations. We recorded multiple unit activity from A1 of rats that received a single discrimination training session in which two tones (2.0 s) separated by 1.25 octaves were either paired with brief electrical stimulation (400 ms) of the BLA (CS+) or not (CS−). Frequency response areas generated by presenting a matrix of test tones (0.5–53.82 kHz, 0–70 dB) were obtained before training and daily for three weeks post-training. Tuning both at threshold and above threshold shifted predominantly toward the CS+ beginning on Day 1. Tuning shifts were maintained for the entire three weeks. Absolute threshold and bandwidth decreased, producing less enduring increases in sensitivity and selectivity. BLA-induced tuning shifts were associative, highly specific and long-lasting. We propose that the BLA strengthens memory for important experiences by

  18. Facilitating Mitochondrial Calcium Uptake Improves Activation-Induced Cerebral Blood Flow and Behavior after mTBI

    PubMed Central

    Murugan, Madhuvika; Santhakumar, Vijayalakshmi; Kannurpatti, Sridhar S.

    2016-01-01

    Mild to moderate traumatic brain injury (mTBI) leads to secondary neuronal loss via excitotoxic mechanisms, including mitochondrial Ca2+ overload. However, in the surviving cellular population, mitochondrial Ca2+ influx, and oxidative metabolism are diminished leading to suboptimal neuronal circuit activity and poor prognosis. Hence we tested the impact of boosting neuronal electrical activity and oxidative metabolism by facilitating mitochondrial Ca2+ uptake in a rat model of mTBI. In developing rats (P25-P26) sustaining an mTBI, we demonstrate post-traumatic changes in cerebral blood flow (CBF) in the sensorimotor cortex in response to whisker stimulation compared to sham using functional Laser Doppler Imaging (fLDI) at adulthood (P67-P73). Compared to sham, whisker stimulation-evoked positive CBF responses decreased while negative CBF responses increased in the mTBI animals. The spatiotemporal CBF changes representing underlying neuronal activity suggested profound changes to neurovascular activity after mTBI. Behavioral assessment of the same cohort of animals prior to fLDI showed that mTBI resulted in persistent contralateral sensorimotor behavioral deficit along with ipsilateral neuronal loss compared to sham. Treating mTBI rats with Kaempferol, a dietary flavonol compound that enhanced mitochondrial Ca2+ uptake, eliminated the inter-hemispheric asymmetry in the whisker stimulation-induced positive CBF responses and the ipsilateral negative CBF responses otherwise observed in the untreated and vehicle-treated mTBI animals in adulthood. Kaempferol also improved somatosensory behavioral measures compared to untreated and vehicle treated mTBI animals without augmenting post-injury neuronal loss. The results indicate that reduced mitochondrial Ca2+ uptake in the surviving populations affect post-traumatic neural activation leading to persistent behavioral deficits. Improvement in sensorimotor behavior and spatiotemporal neurovascular activity following kaempferol

  19. Activation of the basolateral amygdala induces long-term enhancement of specific memory representations in the cerebral cortex.

    PubMed

    Chavez, Candice M; McGaugh, James L; Weinberger, Norman M

    2013-03-01

    The basolateral amygdala (BLA) modulates memory, particularly for arousing or emotional events, during post-training periods of consolidation. It strengthens memories whose substrates in part or whole are stored remotely, in structures such as the hippocampus, striatum and cerebral cortex. However, the mechanisms by which the BLA influences distant memory traces are unknown, largely because of the need for identifiable target mnemonic representations. Associative tuning plasticity in the primary auditory cortex (A1) constitutes a well-characterized candidate specific memory substrate that is ubiquitous across species, tasks and motivational states. When tone predicts reinforcement, the tuning of cells in A1 shifts toward or to the signal frequency within its tonotopic map, producing an over-representation of behaviorally important sounds. Tuning shifts have the cardinal attributes of forms of memory, including associativity, specificity, rapid induction, consolidation and long-term retention and are therefore likely memory representations. We hypothesized that the BLA strengthens memories by increasing their cortical representations. We recorded multiple unit activity from A1 of rats that received a single discrimination training session in which two tones (2.0 s) separated by 1.25 octaves were either paired with brief electrical stimulation (400 ms) of the BLA (CS+) or not (CS-). Frequency response areas generated by presenting a matrix of test tones (0.5-53.82 kHz, 0-70 dB) were obtained before training and daily for 3 weeks post-training. Tuning both at threshold and above threshold shifted predominantly toward the CS+ beginning on day 1. Tuning shifts were maintained for the entire 3 weeks. Absolute threshold and bandwidth decreased, producing less enduring increases in sensitivity and selectivity. BLA-induced tuning shifts were associative, highly specific and long-lasting. We propose that the BLA strengthens memory for important experiences by increasing the

  20. [Cerebral ischemia and histamine].

    PubMed

    Adachi, Naoto

    2002-10-01

    Cerebral ischemia induces excess release of glutamate and an increase in the intracellular Ca2+ concentration, which provoke catastrophic enzymatic processes leading to irreversible neuronal injury. Histamine plays the role of neurotransmitter in the central nervous system, and histaminergic fibers are widely distributed in the brain. In cerebral ischemia, release of histamine from nerve endings has been shown to be enhanced by facilitation of its activity. An inhibition of the histaminergic activity in ischemia aggravates the histologic outcome. In contrast, intracerebroventricular administration of histamine improves the aggravation, whereas blockade of histamine H2 receptors aggravates ischemic injury. Furthermore, H2 blockade enhances ischemic release of glutamate and dopamine. These findings suggest that central histamine provides beneficial effects against ischemic neuronal damage by suppressing release of excitatory neurotransmitters. However, histaminergic H2 action facilitates the permeability of the blood-brain barrier and shows deleterious effects on cerebral edema.

  1. Characterization of Cerebral Damage in a Monkey Model of Alzheimer's Disease Induced by Intracerebroventricular Injection of Streptozotocin.

    PubMed

    Yeo, Hyeon-Gu; Lee, Youngjeon; Jeon, Chang-Yeop; Jeong, Kang-Jin; Jin, Yeung Bae; Kang, Philyong; Kim, Sun-Uk; Kim, Ji-Su; Huh, Jae-Won; Kim, Young-Hyun; Sim, Bo-Woong; Song, Bong-Seok; Park, Young-Ho; Hong, Yonggeun; Lee, Sang-Rae; Chang, Kyu-Tae

    2015-01-01

    In line with recent findings showing Alzheimer's disease (AD) as an insulin-resistant brain state, a non-transgenic animal model with intracerebroventricular streptozotocin (icv-STZ) administration has been proposed as a representative experimental model of AD. Although icv-STZ rodent models of AD have been increasingly researched, studies in non-human primate models are very limited. In this study, we aimed to characterize the cerebral damage caused by icv-STZ in non-human primates; to achieve this, three cynomolgus monkeys (Macaca fascicularis) were administered four dosages of STZ (2 mg/kg) dissolved in artificial cerebrospinal fluid and another three controls were injected with only artificial cerebrospinal fluid at the cerebellomedullary cistern. In vivo neuroimaging was performed with clinical 3.0 T MRI, followed by quantitative analysis with FSL for evaluation of structural changes of the brain. Immunohistochemistry was performed to evaluate cerebral histopathology. We showed that icv-STZ caused severe ventricular enlargement and parenchymal atrophy, accompanying amyloid-β deposition, hippocampal cell loss, tauopathy, ependymal cell loss, astrogliosis, and microglial activation, which are observed in human aged or AD brain. The findings suggest that the icv-STZ monkey model would be a valuable resource to study the mechanisms and consequences of a variety of cerebral pathologies including major pathological hallmarks of AD. Furthermore, the study of icv-STZ monkeys could contribute to the development of treatments for age- or AD-associated cerebral changes.

  2. Sympathetically-induced changes in microvascular cerebral blood flow and in the morphology of its low-frequency waves.

    PubMed

    Deriu, F; Roatta, S; Grassi, C; Urciuoli, R; Micieli, G; Passatore, M

    1996-06-10

    The effect of bilateral cervical sympathetic nerve stimulation on microvascular cerebral blood flow, recorded at various depths in the parietal lobe and in ponto-mesencephalic areas, was investigated by laser-Doppler flowmetry in normotensive rabbits. These areas were chosen as representative of the vascular beds supplied by the carotid and vertebro-basilar systems, which exhibit different degrees of sympathetic innervation, the former being richer than the latter. Sympathetic stimulation at 30 imp/s affects cerebral blood flow in 77% of the parietal lobe and in 43% of the ponto-mesencephalic tested areas. In both cases the predominant effect was a reduction in blood flow (14.7 +/- 5.1% and 4.1 +/- 2.4%, respectively). The extent of the reduction in both areas was less if the stimulation frequency was decreased. Sometimes mean cerebral blood flow showed a small and transient increase, mainly in response to low-frequency stimulation. The morphology was analysed of low-frequency spontaneous oscillations in cerebral blood flow, attributed to vasomotion. Present in 41% of the tested areas (frequency 4-12 cycles/min, peak-to-peak amplitude 10-40% of mean value), these waves decreased in amplitude and increased in frequency during sympathetic stimulation, irrespective of changes in mean flow. The possibility has been proposed that the sympathetic action on low-frequency spontaneous oscillations may contribute to the protective influence that this system is known to exert on the blood-brain barrier in hypertension.

  3. The Comparisons of Cerebral Hemodynamics Induced by Obstructive Sleep Apnea with Arousal and Periodic Limb Movement with Arousal: A Pilot NIRS Study

    PubMed Central

    Zhang, Zhongxing; Schneider, Maja; Laures, Marco; Qi, Ming; Khatami, Ramin

    2016-01-01

    Obstructive sleep apnea syndrome (OSA) and restless legs syndrome (RLS) with periodic limb movement during sleep (PLMS) are two sleep disorders characterized by repetitive respiratory or movement events associated with cortical arousals. We compared the cerebral hemodynamic changes linked to periodic apneas/hypopneas with arousals (AHA) in four OSA-patients with periodic limb movements (PLMA) with arousals in four patients with RLS-PLMS using near-infrared spectroscopy (NIRS). AHA induced homogenous pattern of periodic fluctuations in oxygenated (HbO2) and deoxygenated (HHb) hemoglobin, i.e., the decrease of HbO2 was accompanied by an increase of HHb during the respiratory event and resolved to reverse pattern when cortical arousal started. Blood volume (BV) showed the same pattern as HHb but with relative smaller amplitude in most of the AHA events.These changing patterns were significant as Wilcoxon signed-rank tests gave p < 0.001 when comparing the area under the curve of these hemodynamic parameters to zero. By contrast, in PLMA limb movements induced periodic increments in HbO2 and BV (Wilcoxon signed-rank tests, p < 0.001), but HHb changed more heterogeneously even during the events coming from the same patient. Heart rate (HR) also showed different patterns between AHA and PLMA. It significantly decreased during the respiratory event (Wilcoxon signed-rank test, p < 0.001) and then increased after the occurrence of cortical arousal (Wilcoxon signed-rank test, p < 0.001); while in PLMA HR first increased preceding the occurrence of cortical arousal (Wilcoxon signed-rank test, p < 0.001) and then decreased. The results of this preliminary study show that both AHA and PLMA induce changes in cerebral hemodynamics. The occurrence of cortical arousal is accompanied by increased HR in both events, but by different BV changes (i.e., decreased/increased BV in AHA/PLMA, respectively). HR changes may partially account for the increased cerebral hemodynamics during PLMA

  4. Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression.

    PubMed

    Zhai, Xiao; Chen, Xiao; Shi, Jiazi; Shi, Duo; Ye, Zhouheng; Liu, Wenwu; Li, Ming; Wang, Qijin; Kang, Zhimin; Bi, Hongda; Sun, Xuejun

    2013-12-01

    Molecular hydrogen has been proven effective in ameliorating cerebral ischemia/reperfusion (I/R) injury by selectively neutralizing reactive oxygen species. Lactulose can produce a considerable amount of hydrogen through fermentation by the bacteria in the gastrointestinal tract. To determine the neuroprotective effects of lactulose against cerebral I/R injury in rats and explore the probable mechanisms, we carried out this study. The stroke model was produced in Sprague-Dawley rats through middle cerebral artery occlusion. Intragastric administration of lactulose substantially increased breath hydrogen concentration. Behavioral and histopathological verifications matched biochemical findings. Behaviorally, rats in the lactulose administration group won higher neurological scores and showed shorter escape latency time in the Morris test. Morphologically, 2,3,5-triphenyltetrazolium chloride showed smaller infarction volume; Nissl staining manifested relatively clear and intact neurons and TUNEL staining showed fewer apoptotic neurons. Biochemically, lactulose decreased brain malondialdehyde content, caspase-3 activity, and 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine concentration and increased superoxide dismutase activity. The effects of lactulose were superior to those of edaravone. Lactulose orally administered activated the expression of NF-E2-related factor 2 (Nrf2) in the brain as verified by RT-PCR and Western blot. The antibiotics suppressed the neuroprotective effects of lactulose by reducing hydrogen production. Our study for the first time demonstrates a novel therapeutic effect of lactulose on cerebral ischemia/reperfusion injury and the probable underlying mechanisms. Lactulose intragastrically administered possessed neuroprotective effects on cerebral I/R injury in rats, which could be attributed to hydrogen production by the fermentation of lactulose through intestinal bacteria and Nrf2 activation.

  5. CoCl2-induced biochemical hypoxia down regulates activities and expression of super oxide dismutase and catalase in cerebral cortex of mice.

    PubMed

    Rani, Anupama; Prasad, S

    2014-09-01

    Hypoxia-induced oxidative stress is one of the major hallmark reasons underlying brain dysfunction. In the present manuscript, we have used CoCl2-induced hypoxic mice to investigate alterations in the activities of chief antioxidative stress enzymes- superoxide dismutase (SOD) and catalase (CAT) and expression of their genes Sod1 and Cat in the cerebral cortex as this model has not been routinely used for carrying out such study. Hypoxia mimetic mice model was accordingly developed by oral CoCl2 administration to mice and validated by analyzing alterations in the expression of the hypoxia inducible factor gene Hif-1α and its immediate responsive genes. Our Western blot data demonstrated that a dose of 40 mg/kg BW of CoCl2 was able to generate hypoxia like condition in mice in which Hif-1α and its immediate responsive genes-glutamate transporter-1 (Slc2a1) and erythropoietin (Epo) expression were up regulated. Our in-gel assay data indicated that SOD and CAT activities significantly declined and it was associated with significant down regulation of Sod1 and Epo expression as evident from our semi quantitative RT-PCR and Western blot data, which might be correlated with up regulation of Hif-1α expression in the cerebral cortex of the CoCl2-treated hypoxic mice. Our findings suggest that CoCl2-induced hypoxic mouse model is useful for studying alterations in the anti oxidative enzymes and biochemical/molecular/neurobiological analysis of hypoxia-induced alterations in brain function.

  6. MicroRNA-25 Negatively Regulates Cerebral Ischemia/Reperfusion Injury-Induced Cell Apoptosis Through Fas/FasL Pathway.

    PubMed

    Zhang, Jun-Feng; Shi, Li-Li; Zhang, Li; Zhao, Zhao-Hua; Liang, Fei; Xu, Xi; Zhao, Ling-Yu; Yang, Peng-Bo; Zhang, Jian-Shui; Tian, Ying-Fang

    2016-04-01

    MicroRNA-25 (miR-25) has been reported to be a major miRNA marker in neural cells and is strongly expressed in ischemic brain tissues. However, the precise mechanism and effect of miR-25 in cerebral ischemia/reperfusion (I/R) injury needs further investigations. In the present study, the oxygen-glucose deprivation (OGD) model was constructed in human SH-SY5Y and IMR-32 cells to mimic I/R injury and to evaluate the role of miR-25 in regulating OGD/reperfusion (OGDR)-induced cell apoptosis. We found that miR-25 was downregulated in the OGDR model. Overexpression of miR-25 via miRNA-mimics transfection remarkably inhibited OGDR-induced cell apoptosis. Moreover, Fas was predicted as a target gene of miR-25 through bioinformatic analysis. The interaction between miR-25 and 3'-untranslated region (UTR) of Fas mRNA was confirmed by dual-luciferase reporter assay. Fas protein expression was downregulated by miR-25 overexpression in OGDR model. Subsequently, the small interfering RNA (siRNA)-mediated knockdown of Fas expression also inhibited cell apoptosis induced by OGDR model; in contrast, Fas overexpression abrogated the protective effects of miR-25 on OGDR-induced cells. Taken together, our results indicate that the upregulation of miR-25 inhibits cerebral I/R injury-induced apoptosis through downregulating Fas/FasL, which will provide a promising therapeutic target.

  7. Cerebral Paragonimiasis.

    PubMed

    Miyazaki, I

    1975-01-01

    The first case of cerebral paragonimiasis was reported by Otani in Japan in 1887. This was nine years after Kerbert's discovery of the fluke in the lungs of Bengal tigers and seven years after a human pulmonary infection by the fluke was demonstrated by Baelz and Manson. The first case was a 26-year-old man who had been suffering from cough and hemosputum for one year. The patient developed convulsive seizures with subsequent coma and died. The postmortem examination showed cystic lesions in the right frontal and occipital lobes. An adult fluke was found in the occipital lesion and another was seen in a gross specimen of normal brain tissue around the affected occipital lobe. Two years after Otani's discovery, at autopsy a 29-year-old man with a history of Jacksonian seizure was reported as having cerebral paragonimiasis. Some time later, however, it was confirmed that the case was actually cerebral schistosomiasis japonica. Subsequently, cases of cerebral paragonimiasis were reported. However, the majority of these cases were not confirmed histologically. It was pointed out that some of these early cases were probably not Paragonimus infection. After World War II, reviews as well as case reports were published. Recently, investigations have been reported from Korea, with a clinicla study on 62 cases of cerebral paragonimiasis seen at the Neurology Department of the National Medical Center, Seoul, between 1958 and 1964. In 1971 Higashi described a statistical study on 105 cases of cerebral paragonimiasis that had been treated surgically in Japan.

  8. The effect of long-term supplementation of vitamin C on leukocyte adhesion to the cerebral endothelium in STZ-induced diabetic rats.

    PubMed

    Jariyapongskul, Amporn; Patumraj, Suthiluk; Yamaguchi, Saburo; Niimi, Hideyuki

    2002-01-01

    The effect of long-term supplementation of vitamin C on leukocyte adhesion to the cerebral endothelium was investigated in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in male Wistar Furth rats by intravenous injection of STZ. The vitamin C, ascorbic acid, was supplemented with drinking water (1 g/l). The rats were divided into control and diabetic groups without or with supplementation of vitamin C. The cerebral microcirculation was directly observed through a cranial window after different periods (12, 24 and 36 weeks) of vitamin C supplementation, using fluorescence videomicroscopy. Leukocyte adhesion to the venular endothelium was examined by labeling leukocytes with rhodamin 6G. The number density of adherent leukocytes in STZ-diabetic rats was increased significantly, compared with control rats. This increase in leukocyte adhesion was prevented by the long-term supplemented vitamin C. It was suggested that the antioxidant effect of vitamin C might be responsible for the prevention of leukocyte adhesion in diabetes mellitus.

  9. In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells.

    PubMed

    Kokubu, Yasuhiro; Yamaguchi, Tomoko; Kawabata, Kenji

    2017-04-29

    Brain-derived microvascular endothelial cells (BMECs), which play a central role in blood brain barrier (BBB), can be used for the evaluation of drug transport into the brain. Although human BMEC cell lines have already been reported, they lack original properties such as barrier integrity. Pluripotent stem cells (PSCs) can be used for various applications such as regenerative therapy, drug screening, and pathological study. In the recent study, an induction method of BMECs from PSCs has been established, making it possible to more precisely study the in vitro human BBB function. Here, using induced pluripotent stem (iPS) cell-derived BMECs, we examined the effects of oxygen-glucose deprivation (OGD) and OGD/reoxygenation (OGD/R) on BBB permeability. OGD disrupted the barrier function, and the dysfunction was rapidly restored by re-supply of the oxygen and glucose. Interestingly, TNF-α, which is known to be secreted from astrocytes and microglia in the cerebral ischemia, prevented the restoration of OGD-induced barrier dysfunction in an apoptosis-independent manner. Thus, we could establish the in vitro BBB disease model that mimics the cerebral ischemia by using iPS cell-derived BMECs.

  10. Hyperthermia-induced seizures alter adenosine A1 and A2A receptors and 5'-nucleotidase activity in rat cerebral cortex.

    PubMed

    León-Navarro, David Agustín; Albasanz, José L; Martín, Mairena

    2015-08-01

    Febrile seizure is one of the most common convulsive disorders in children. The neuromodulator adenosine exerts anticonvulsant actions through binding adenosine receptors. Here, the impact of hyperthermia-induced seizures on adenosine A1 and A2A receptors and 5'-nucleotidase activity has been studied at different periods in the cerebral cortical area by using radioligand binding, real-time PCR, and 5'-nucleotidase activity assays. Hyperthermic seizures were induced in 13-day-old rats using a warmed air stream from a hair dryer. Neonates exhibited rearing and falling over associated with hindlimb clonus seizures (stage 5 on Racine scale criteria) after hyperthermic induction. A significant increase in A1 receptor density was observed using [(3) H]DPCPX as radioligand, and mRNA coding A1 was observed 48 h after hyperthermia-induced seizures. In contrast, a significant decrease in A2A receptor density was detected, using [(3) H]ZM241385 as radioligand, 48 h after hyperthermia-evoked convulsions. These short-term changes in A1 and A2A receptors were also accompanied by a loss of 5'-nucleotidase activity. No significant variations either in A1 or A2A receptor density or 5'-nucleotidase were observed 5 and 20 days after hyperthermic seizures. Taken together, both regulation of A1 and A2A receptors and loss of 5'-nucleotidase in the cerebral cortex suggest the existence of a neuroprotective mechanism against seizures. Febrile seizure is one of the most common convulsive disorders in children. The consequences of hyperthermia-induced seizures (animal model of febrile seizures) on adenosine A1 and A2A receptors and 5'-nucleotidase activity have been studied at different periods in cerebral cortical area. A significant increase in A1 receptor density and mRNA coding A1 was observed 48 h after hyperthermia-induced seizures. In contrast, a significant decrease in A2A receptor density and 5'-nucleotidase activity was detected 48 h after convulsions evoked by hyperthermia

  11. The ameliorative effects of exercise on cognitive impairment and white matter injury from blood-brain barrier disruption induced by chronic cerebral hypoperfusion in adolescent rats.

    PubMed

    Lee, Jae-Min; Park, Jong-Min; Song, Min Kyung; Oh, Yoo Joung; Kim, Chang-Ju; Kim, Youn-Jung

    2017-01-18

    Vascular dementia is the progressive change in blood vessels that leads to neuronal injuries in vulnerable areas induced by chronic cerebral hypoperfusion (CCH). CCH induces disruption of blood-brain barrier (BBB), and this BBB disruption can initiate the cognitive impairment and white matter injury. In the present study, we evaluated the effect of treadmill exercise on the cognitive impairment, white matter injury, and BBB disruption induced by CCH. Vascular dementia was induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats. The rats in the exercise group were made to run on a treadmill for 30min once a day for 14 weeks, starting 4 weeks after birth. Our results revealed that treadmill exercise group was alleviated the cognitive impairment and myelin degradation induced by CCH. The disruption of BBB after CCH indicates degradation of occludin, zonula occluden-1 (ZO-1), and up-regulation of matrix metalloproteinases (MMPs). Treadmill exercise may provide protective effects on BBB disruption from degradation of occludin, ZO-1, and overexpression of MMP-9 after CCH. These findings suggest that treadmill exercise ameliorates cognitive impairment and white matter injury from BBB disruption induced by CCH in rats. The present study will be valuable for means of prophylactic and therapeutic intervention for patients with CCH.

  12. Cerebral Palsy (For Parents)

    MedlinePlus

    ... Old Feeding Your 1- to 2-Year-Old Cerebral Palsy KidsHealth > For Parents > Cerebral Palsy A A A ... kids who are living with the condition. About Cerebral Palsy Cerebral palsy is one of the most common ...

  13. Cerebral palsy - resources

    MedlinePlus

    Resources - cerebral palsy ... The following organizations are good resources for information on cerebral palsy : National Institute of Neurological Disorders and Stroke -- www.ninds.nih.gov/disorders/cerebral_palsy/cerebral_palsy. ...

  14. Cerebral Palsy (For Teens)

    MedlinePlus

    ... Right Sport for You Healthy School Lunch Planner Cerebral Palsy KidsHealth > For Teens > Cerebral Palsy Print A A ... do just what everyone else does. What Is Cerebral Palsy? Cerebral palsy (CP) is a disorder of the ...

  15. Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling.

    PubMed

    Lee, Ki Mo; Bang, JiHye; Kim, Bu Yeo; Lee, In Sun; Han, Jung-Soo; Hwang, Bang Yeon; Jeon, Won Kyung

    2015-04-22

    Fructus mume (F. mume) has been used as a traditional medicine for many years in Asian countries. The present study was designed to determine the effect of a 70% ethanol extract of F. mume on white matter and hippocampal damage induced by chronic cerebral hypoperfusion. Permanent bilateral common carotid artery occlusion (BCCAo) was performed on male Wistar rats to induce chronic cerebral hypoperfusion. Daily oral administration of F. mume (200 mg/kg) was initiated 21 days after BCCAo and continued for 42 days. The experimental groups in this study were divided into three groups: a sham-operated group, a BCCAo group, and a BCCAo group that was administered with the F. mume extract. The activation of glial cells, including microglia and astrocytes, and the levels of myelin basic protein (MBP), inflammatory mediators, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p38 mitogen-activated protein kinase (MAPK) phosphorylation were measured in brains from rats subjected to chronic BCCAo. Our results revealed that F. mume alleviates the reduction in MBP expression caused by chronic BCCAo in the white matter and the hippocampus and significantly attenuates microglial and astrocytic activation induced by chronic BCCAo in the optic tract of white matter. In addition, F. mume treatment reduced the increased expression of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and interleukin-6 (IL-6), as well as the activation of TLR4/MyD88 and p38 MAPK signaling, in the hippocampus of rats subjected to chronic BCCAo. Taken together, our findings demonstrate that brain injury induced by chronic BCCAo is ameliorated by the anti-inflammatory effects of F. mume via inhibition of MBP degradation, microglial and astrocytic activation, increased inflammatory mediator expression, and activated intracellular signalings, including TLR4 and p38 MAPK, implying that F. mume is potentially an effective therapeutics for the treatment of vascular dementia.

  16. Ferulic acid exerts neuroprotective effects against cerebral ischemia/reperfusion-induced injury via antioxidant and anti-apoptotic mechanisms in vitro and in vivo.

    PubMed

    Ren, Zhongkun; Zhang, Rongping; Li, Yuanyuan; Li, Yu; Yang, Zhiyong; Yang, Hui

    2017-09-07

    Ferulic acid (FA) is a derivative of cinnamic acid. It is used in the treatment of heart head blood-vessel disease and exerts protective effects against hypoxia/ischemia-induced cell injury in the brain. This study investigated the potential neuroprotective effects of FA against ischemia/reperfusion (I/R)-induced brain injury in vivo and in vitro through hematoxylin and eosin (H&E) and Nissl staining assays, flow cytometry, Hoechst 33258 staining, quantitative PCR, western blot analysis and fluorescence microscopic analysis. In this study, models of cerebral I/R injury were established using rats and pheochromocytoma (PC-12) cells. The results revealed that treatment with FA significantly attenuated memory impairment, and reduced hippocampal neuronal apoptosis and oxidative stress in a dose-dependent manner. The results from in vitro experiments also indicated that FA protected the PC-12 cells against I/R-induced reactive oxygen species (ROS) generation and apoptosis by inhibiting apoptosis, Ca2+ influx, superoxide anion (O2-), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) production in a concentration-dependent manner. Moreover, FA inactivated the Toll-like receptor (TLR)/myeloid differentiation factor 88 (MyD88) pathway. MyD88 overexpression abolished the neuroprotective effects of FA. On the whole, we found that FA attenuated memory dysfunction and exerted protective effects against oxidative stress and apoptosis induced by I/R injury by inhibiting the TLR4/MyD88 signaling pathway. This study supports the view that FA may be a promising neuroprotective agent for use in the treatment of cerebral ischemia.

  17. Hypertension-Induced Vascular Remodeling Contributes to Reduced Cerebral Perfusion and the Development of Spontaneous Stroke in Aged SHRSP Rats

    DTIC Science & Technology

    2010-01-01

    hypertensive encephalopathy (Fredriksson et al, 1985; Smeda et al, 1999; Tamaki et al, 1984). With an acute spike in BP, there is loss of CBF...1984) Evidence that disruption of the blood-brain barrier precedes reduction in cere- bral blood flow in hypertensive encephalopathy . Hyper- tension...Journal of Cerebral Blood Flow & Metabolism (2010) 30, 827-836 Q 2010 ISCBFM All rights reserved 0271.07BX/10 $32.00 www.jcbfm.com Hypertension

  18. Adenosine receptor-dependent signaling is not obligatory for normobaric and hypobaric hypoxia-induced cerebral vasodilation in humans.

    PubMed

    Hoiland, Ryan L; Bain, Anthony R; Tymko, Michael M; Rieger, Mathew G; Howe, Connor A; Willie, Christopher K; Hansen, Alex B; Flück, Daniela; Wildfong, Kevin W; Stembridge, Mike; Subedi, Prajan; Anholm, James; Ainslie, Philip N

    2017-04-01

    Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and placebo-controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 ± 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline (P < 0.01), a finding explained by a lower [Formula: see text] (P < 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline (n = 6) had no effect on CBF compared with placebo (n = 6) when end-tidal gases were comparable (P > 0.05). We conclude that adenosine receptor-dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans.NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the

  19. [Mechanism of heart and lung injury induced by cerebral ischemia/reperfusion in both young and old mice].

    PubMed

    Lyu, Yanni; Fu, Longsheng; Qian, Yisong; Jiang, Mingjin; He, Libiao; Ouyang, Aijun; Zheng, Yu

    2017-06-01

    Objective To study the mechanism of heart and lung injury after cerebral ischemia/reperfusion in mice. Methods C57BL/6J mice were divided into young and old groups according to their ages, the former being 5-6 months old and the latter being 20-21 months old. Each group was divided into five subgroups subjected to sham operation, middle cerebral artery occlusion for 1-hour ischemia followed by 1-, 12-, 24-, 48-hour reperfusion. At different reperfusion time, HE and TUNEL staining were used to observe the morphological changes of heart and lung tissues; meanwhile, chemical colorimetry was performed to determine the changes of cardiac Na(+)-K(+)-ATPase and Ca(2+)-ATPase; the lung indexes were evaluated; the levels of nuclear factor (NF)-κBp65, p-NF-κBp65, IκBα, p-IκBα were detected by Western blotting; the levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) were determined by ELISA; and the release of NO was examined by colorimetry. Results We observed inflammatory responses in the lung tissues of young and old mice at 24-hour reperfusion and 1-hour reperfusion, respectively, and hemorrhage in the heart tissues of young and old mice at 24-hour reperfusion and 12-hour reperfusion, respectively.Lung tissues showed earlier response to the stimulation of cerebral ischemia/reperfusion than heart tissues did. Meanwhile, the results of Na(+)-K(+)-ATPase, Ca(2+)-ATPase, lung index, NF-κB signaling pathway and inflammatory cytokines in young and old mice were consistent with histological changes of heart and lung tissues. Conclusion Cerebral ischemia/reperfusion can cause heart and lung tissue injury in the old mice, and energy metabolism and inflammation cascade are the main mechanisms of the injury.

  20. Protective effect of olive leaf extract on hippocampal injury induced by transient global cerebral ischemia and reperfusion in Mongolian gerbils.

    PubMed

    Dekanski, Dragana; Selaković, Vesna; Piperski, Vesna; Radulović, Zeljka; Korenić, Andrej; Radenović, Lidija

    2011-10-15

    The beneficial effects of antioxidant nutrients, as well as complex plant extracts, in cerebral ischemia/reperfusion brain injury are well known. Mediterranean diet, rich in olive products, is associated with lower incidence of cardiovascular disease, cancer, inflammation and stroke. In this study, the possible neuroprotective effect of standardized dry olive leaf extract (OLE) is investigated for the first time. Transient global cerebral ischemia in Mongolian gerbils was used to investigate the OLE effects on different parameters of oxidative stress and neuronal damage in hippocampus. The biochemical measurements took place at different time points (80min, 2, 4 and 24h) after reperfusion. The effects of applied OLE were compared with effects of quercetin, a known neuroprotective plant flavonoid. Pretreatment with OLE (100mg/kg, per os) significantly inhibited production of superoxide and nitric oxide, decreased lipid peroxidation, and increased superoxide dismutase activity in all time points examined. Furthermore, OLE offered histological improvement as seen by decreasing neuronal damage in CA1 region of hippocampus. The effects of applied OLE were significantly higher than effects of quercetin (100mg/kg, per os). Our results indicate that OLE exerts a potent neuroprotective activity against neuronal damage in hippocampus after transient global cerebral ischemia, which could be attributed to its antioxidative properties.

  1. Time course of cerebral hypoperfusion-induced neurodegenerative changes in the cortex of male and female rats.

    PubMed

    Stanojlović, M; Horvat, A; Guševac, I; Grković, I; Mitrović, N; Buzadžić, I; Drakulić, D

    2014-01-01

    To study time-dependent and gender-specific intracellular and biochemical mechanisms that lead to neurodegeneration due to moderate but persistent reduction of cerebral blood flow, adult male and female Wistar rats were divided into two main groups - controls that underwent sham operation and animals subjected to permanent bilateral occlusion of common carotid arteries. Animals were sacrificed 3, 7 or 90 days following the insult. Expression of several apoptotic proteins in synaptic fractions along with Fluoro-Jade B staining and DNA fragmentation assay were used to estimate the apoptotic processes and potential neurodegeneration in cerebral cortex. Data suggest a time-specific increase of Bax as well as time- and gender-associated downregulation in protein expression of Bcl-2, up-regulation of procaspase 3, accompanied with increased cleavage of procaspase 3 and PARP in synaptic terminals. Furthermore, time- but not gender-specific neurodegeneration was observed. Our findings support the concept of time- and gender-associated response to permanent bilateral occlusion of common carotid arteries, which would enable better understanding of the mechanisms underlying cerebral hypoperfusion.

  2. QUANTITATIVE CHANGES IN REGIONAL CEREBRAL BLOOD FLOW INDUCED BY COLD, HEAT AND ISCHEMIC PAIN: A CONTINUOUS ARTERIAL SPIN LABELING STUDY

    PubMed Central

    Frölich, Michael A.; Deshpande, Hrishikesh; Ness, Timothy; Deutsch, Georg

    2012-01-01

    Background The development of arterial spin labeling methods, has allowed measuring regional cerebral blood flow (rCBF) quantitatively and to show the pattern of cerebral activity associated with any state such as a sustained pain state or changes due to a neurotropic drug. Methods We studied the differential effects of three pain conditions in ten healthy subjects on a 3T scanner during resting baseline, heat, cold and ischemic pain using continuous arterial spin labeling. Results Cold pain showed the greatest absolute rCBF increases in left anterior cingulate cortex, left amygdala, left angular gyrus, and Brodmann Area 6, and a significant rCBF decrease in the cerebellum. Changes in rCBF were characteristic of the type of pain condition: cold and heat pain showed increases, while the ischemic condition showed a reduction in mean absolute gray matter flow compared to rest. An association of subjects’ pain tolerance and cerebral blood flow was noted. Conclusions The observation that quantitative rCBF changes are characteristic of the pain task employed and that there is a consistent rCBF change in Brodman area 6, an area responsible for the integration of a motor response to pain, should provide extremely useful information in the quest to develop an imaging biomarker of pain. Conceivably, response in BA6 may serve as an objective measure of analgesic efficacy. PMID:22913924

  3. Measuring caffeine-induced changes in middle cerebral artery blood velocity using transcranial Doppler in patients recovering from ischaemic stroke.

    PubMed

    Lunt, Michael J; Hanrahan, Andrew; Kerr, David; Jenkinson, Damian F

    2002-05-01

    Acute ingestion of caffeine is known to reduce cerebral blood flow in normal volunteers and in certain patient groups. There is no evidence that this causes problems in the normal population. However, there may be implications if a similar reduction occurs in patients recovering from an ischaemic stroke, in whom local blood flow has already been reduced. Transcranial Doppler provides a non-invasive method for measuring changes in middle cerebral artery (mca) blood velocity. A method for obtaining consistent. reliable measurements was developed and used in a double blind, randomized, crossover study on 20 patients (18 M, 2 F; mean age 70) recovering from ischaemic stroke in the mca territory. Middle cerebral artery blood velocity was measured bilaterally using transcranial Doppler before and after 250 mg caffeine (equivalent to about two cups of filter coffee) or matched placebo. Caffeine caused an average 12% reduction in blood velocity compared to placebo in the hemisphere affected by the stroke (95%c CI 8%-16%, p < 0.00001), and a 12% reduction in the non-affected hemisphere (95% CI 6%-18%, p < 0.001). The clinical implications are unclear at present, and imaging techniques will be required to establish whether caffeine does reduce flow to hypo-perfused regions.

  4. Sesamin attenuates behavioral, biochemical and histological alterations induced by reversible middle cerebral artery occlusion in the rats.

    PubMed

    Khan, Mohd Moshahid; Ishrat, Tauheed; Ahmad, Ajmal; Hoda, Md Nasrul; Khan, M Badruzzaman; Khuwaja, Gulrana; Srivastava, Pallavi; Raza, Syed Shadab; Islam, Fakhrul; Ahmad, Saif

    2010-01-05

    Restoration of blood flow to an ischemic brain region is associated with generation of reactive oxygen species (ROS) with consequent reperfusion injury. ROS cause lipid peroxidation, protein oxidation, and DNA damage, all of which are deleterious to cells. So diminishing the production of free radicals and scavenging them may be a successful therapeutic strategy for the protection of brain tissue in cerebral stroke. The present study investigated the neuroprotective effect of sesamin (Sn) to reduce brain injury after middle cerebral artery occlusion (MCAO). The middle cerebral artery (MCA) of adult male Wistar rat was occluded for 2h and reperfused for 22h. Sesamin is the most abundant lignan in sesame seed oil is a potent antioxidant. Sesamin (30 mg/kg) was given orally twice, 30 min before the onset of ischemia and 12h after reperfusion. The initial investigations revealed that sesamin reduced the neurological deficits in terms of behavior and reduced the level of thiobarbituric acid reactive species (TBARS), and protein carbonyl (PC) in the different areas of the brain when compared with the MCAO group. A significantly depleted level of glutathione and its dependent enzymes (glutathione peroxidase [GPx] and glutathione reductase [GR]) in MCAO group were protected significantly in MCAO group treated with sesamin. The present study suggests that sesamin may be able to attenuate the ischemic cell death and plays a crucial role as a neuroprotectant in regulating levels of reactive oxygen species in the rat brain. Thus, sesamin may be a potential compound in stroke therapy.

  5. Effects and Mechanism of Action of Inducible Nitric Oxide Synthase on Apoptosis in a Rat Model of Cerebral Ischemia-Reperfusion Injury.

    PubMed

    Zheng, Li; Ding, Junli; Wang, Jianwei; Zhou, Changman; Zhang, Weiguang

    2016-02-01

    Inducible nitric oxide synthase (iNOS) is a key enzyme in regulating nitric oxide (NO) synthesis under stress, and NO has varying ability to regulate apoptosis. The aim of this study was to investigate the effects and possible mechanism of action of iNOS on neuronal apoptosis in a rat model of cerebral focal ischemia and reperfusion injury in rats treated with S-methylisothiourea sulfate (SMT), a high-selective inhibitor of iNOS. Seventy-two male Sprague-Dawley (SD) rats were randomly divided into three groups: the sham, middle cerebral artery occlusion (MCAO) + vehicle, and MCAO + SMT groups. Neurobehavioral deficits, infarct zone size, and cortical neuron morphology were evaluated through the modified Garcia scores, 2,3,5-triphenyltetrazolium chloride (TTC), and Nissl staining, respectively. Brain tissues and serum samples were collected at 72 hr post-reperfusion for immunohistochemical analysis, Western blotting, Terminal deoxynucleotidyl transferase-mediated dUTP-biotin Nick End Labeling assay (TUNEL) staining, and enzyme assays. The study found that inhibition of iNOS significantly attenuated the severity of the pathological changes observed as a result of ischemia-reperfusion injury: SMT reduced NO content as well as total nitric oxide synthase (tNOS) and iNOS ac