Abstract TP268: Induction Profile of Mesencephalic Astrocyte-derived Neurotrophic Factor by Cerebral Ischemia and its Implication for Neuroprotection

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Ludmila Belayev ◽  
Sung-Ha Hong ◽  
Pranab K Mukherjee ◽  
Hemant Menghani ◽  
Larissa Khoutorova ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Dentate Gyrus ◽  
Mrna Expression ◽  
Neurotrophic Factor ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Ischemic Penumbra ◽  
Protein Levels

Introduction: Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been identified as a secretion protein, which biases immune cells toward an anti-inflammatory phenotype, thereby promoting tissue repair after various injuries to neurons in vivo or in vitro. However, the function of MANF during and after brain ischemia is still not known. The purpose of our study was to examine the characteristics and implication of MANF expression induced by focal cerebral ischemia. In addition we investigated if docosahexaenoic acid (DHA) potentiates MANF mRNA expression and provides additional neuroprotection. Methods: Male SD (280-320) rats were anesthetized with isoflurane and subjected to 2 h of middle cerebral artery occlusion (MCAo) by intraluminal suture. DHA (5 mg/kg; n=13) or vehicle (saline; n=8) was administered IV at 3 h after the onset of MCAo. Neurological function was evaluated during occlusion (60 min) and on days 1, 3 and 7 after MCAo. MANF mRNA expression, protein levels, and apoptosis were measured by immunohistochemistry and Western blotting. Results: Behavioral deficit was significantly improved by treatment with DHA compared to vehicle on days 1, 3 and 7. MANF was found to be extremely upregulated in the ischemic penumbra. The expression of MANF was neuronal in the cortex and dentate gyrus. DHA administration significantly increased the number of MANF + /NeuN + cells in the cortex (by 76.6 %) and dentate gyrus (by 20.5 %) compared to saline-treated animals. The number of MANF/NeuN-positive cells was not different in the subcortex, CA1 and CA3 regions between DHA- and saline-treated groups. Treatment with DHA increased MANF + /GFAP + cells in the subcortex (by 27.7 %) and dentate gyrus (by 38.0 %) compared to the vehicle-treated brains. Total and cortical infarct volumes were attenuated by DHA treatment by 48 % and by 73 % compared to vehicle treatment at 24 h after MCAo. Conclusion: MANF mRNA expression and protein levels are increased after focal cerebral ischemia. It was found to be extremely upregulated in the ischemic penumbra and dentate gyrus. The expression of MANF was mostly neuronal and astrocytic. DHA potentiates MANF expression and provides additional neuroprotection.

scholarly journals The Rapid Decrease in Astrocyte-Associated Dystroglycan Expression by Focal Cerebral Ischemia is Protease-Dependent

2007 ◽  
Vol 28 (4) ◽  
pp. 812-823 ◽  
Author(s):  
Richard Milner ◽  
Stephanie Hung ◽  
Xiaoyun Wang ◽  
Maria Spatz ◽  
Gregory J del Zoppo
Keyword(s):  
Cerebral Ischemia ◽  
Basal Lamina ◽  
Focal Cerebral Ischemia ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Receptor Expression ◽  
Cerebral Microvessels ◽  
The Impact

During focal cerebral ischemia, the detachment of astrocytes from the microvascular basal lamina is not completely explained by known integrin receptor expression changes. Here, the impact of experimental ischemia (oxygen—glucose deprivation (OGD)) on dystroglycan expression by murine endothelial cells and astrocytes grown on vascular matrix laminin, perlecan, or collagen and the impact of middle cerebral artery occlusion on αβ-dystroglycan within cerebral microvessels of the nonhuman primate were examined. Dystroglycan was expressed on all cerebral microvessels in cortical gray and white matter, and the striatum. Astrocyte adhesion to basal lamina proteins was managed in part by α-dystroglycan, while ischemia significantly reduced expression of dystroglycan both in vivo and in vitro. Furthermore, dystroglycan and integrin α6β4 expressions on astrocyte end-feet decreased in parallel both in vivo and in vitro. The rapid loss of astrocyte dystroglycan during OGD appears protease-dependent, involving an matrix metalloproteinase-like activity. This may explain the rapid detachment of astrocytes from the microvascular basal lamina during ischemic injury, which could contribute to significant changes in microvascular integrity.

Antioxidant Activities of Dracocephalum tanguticum Maxim Extract and Its Up-Regulation on the Expression of Neurotrophic Factors in a Rat Model of Permanent Focal Cerebral Ischemia

2011 ◽  
Vol 39 (01) ◽  
pp. 65-81 ◽  
Author(s):  
Jin-Xiu Xu ◽  
Mu Yang ◽  
Ke-Jun Deng ◽  
Hong Zhou
Keyword(s):  
Protein Synthesis ◽  
Cerebral Ischemia ◽  
Mrna Expression ◽  
Neurotrophic Factors ◽  
Neurotrophic Factor ◽  
Antioxidant Activities ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Intragastric Administration ◽  
Bdnf Mrna

The aim of this study was to investigate the effect of a BuOH-soluble fraction from Dracocephalum tanguticum Maxim (DME), which contained 52% of total flavonoid, on the cerebral ischemia injury induced by permanent middle cerebral artery occlusion (pMCAO) in rats. RT-PCR and Western blot analysis showed that DME (30 mg/kg/day for seven days) by intragastric administration modulated the mRNA expression and protein synthesis of two neurotrophic factors: brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3). DME was effective in stimulating BDNF mRNA expression and protein synthesis in the ipsilateral frontal cortex (IFC) of both the sham-operated and pMCAO rats and this effect was also observed in the hippocampus of the pMCAO rats. DME significantly increased NT-3 mRNA expression and protein synthesis in the IFC and hippocampus of the pMCAO rats, although it had no effect on NT-3 expression in the sham-operated groups. Meanwhile, DME also decreased the malondialdehyde contents in the hippocampus of the sham-operated and pMCAO groups, and significantly attenuated the decrease of endogenous antioxidant (superoxide dismutase, glutathione peroxidase and catalase) activities in both the IFC and hippocampus of the rats after ischemia insult injury. Moreover, DME facilitated the neurobehavioral recovery after the cerebral ischemia. These findings suggested that DME has potential for treatment of ischemia-induced brain damage through stimulation of antioxidant activity and neurotrophic factor synthesis.

scholarly journals LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3

Human Cell ◽  
2021 ◽  
Author(s):  
Jiaying Zhu ◽  
Zhu Zhu ◽  
Yipin Ren ◽  
Yukang Dong ◽  
Yaqi Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Mice Model ◽  
Down Regulation

AbstractLINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen–glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.

scholarly journals Neuroprotection by Brazilian Green Propolis againstIn vitroandIn vivoIschemic Neuronal Damage

2005 ◽  
Vol 2 (2) ◽  
pp. 201-207 ◽  
Author(s):  
Masamitsu Shimazawa ◽  
Satomi Chikamatsu ◽  
Nobutaka Morimoto ◽  
Satoshi Mishima ◽  
Hiroichi Nagai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Folk Medicine ◽  
Neuroprotective Function ◽  
Brazilian Green Propolis

We examined whether Brazilian green propolis, a widely used folk medicine, has a neuroprotective functionin vitroand/orin vivo.In vitro, propolis significantly inhibited neurotoxicity induced in neuronally differentiated PC12 cell cultures by either 24 h hydrogen peroxide (H2O2) exposure or 48 h serum deprivation. Regarding the possible underlying mechanism, propolis protected against oxidative stress (lipid peroxidation) in mouse forebrain homogenates and scavenged free radicals [induced by diphenyl-p-picrylhydrazyl (DPPH). In micein vivo, propolis [30 or 100 mg/kg; intraperitoneally administered four times (at 2 days, 1 day and 60 min before, and at 4 h after induction of focal cerebral ischemia by permanent middle cerebral artery occlusion)] reduced brain infarction at 24 h after the occlusion. Thus, a propolis-induced inhibition of oxidative stress may be partly responsible for its neuroprotective function againstin vitrocell death andin vivofocal cerebral ischemia.

scholarly journals Leukocyte-Endothelium Interactions during Permanent Focal Cerebral Ischemia in Mice

2004 ◽  
Vol 24 (6) ◽  
pp. 668-676 ◽  
Author(s):  
Hiroharu Kataoka ◽  
Seong-Woong Kim ◽  
Nikolaus Plesnila
Keyword(s):  
Cerebral Ischemia ◽  
Brain Damage ◽  
Molecular Mechanisms ◽  
Focal Cerebral Ischemia ◽  
Fluorescent Microscopy ◽  
Capillary Density ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
Adherent Leukocytes

The contribution of leukocyte infiltration to brain damage after permanent focal cerebral ischemia and the underlying molecular mechanisms are still unclear. Therefore, the aim of this study was to establish a mouse model for the visualization of leukocytes in the cerebral microcirculation in vivo and to investigate leukocyte-endothelial interaction (LEI) after permanent middle cerebral artery occlusion (MCAO). Sham-operated 129/Sv mice showed physiologic LEI in pial venules as observed by intravital fluorescent microscopy. Permanent focal cerebral ischemia induced a significant increase of LEI predominantly in pial venules. The number of rolling and adherent leukocytes reached 36.5 ± 13.2/100 μm × min and 22.5 ± 7.9/100 μm × min, respectively at 120 minutes after MCAO ( P = 0.016 vs. control). Of note, rolling and adherent leukocytes were also observed in arterioles of ischemic animals (7.3 ± 3.0/100 μm × min rolling and 3.0 ± 3.6/100 μm × min adherent). Capillary density was not different between groups. These results demonstrate that leukocytes accumulate in the brain not only after transient but also after permanent focal cerebral ischemia and may therefore contribute to brain damage after stroke without reperfusion.

scholarly journals PET Imaging of Serotoninergic Neurotransmission with [11C]DASB and [18F]altanserin after Focal Cerebral Ischemia in Rats

2013 ◽  
Vol 33 (12) ◽  
pp. 1967-1975 ◽  
Author(s):  
Abraham Martín ◽  
Boguslaw Szczupak ◽  
Vanessa Gómez-Vallejo ◽  
Sandra Plaza ◽  
Daniel Padró ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Functional Recovery ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Focal Cerebral Ischemia ◽  
Recovery Process ◽  
Artery Occlusion ◽  
Functional Improvement ◽  
Binding Potential ◽  
Positron Emission

The use of selective serotonin reuptake inhibitors has shown functional improvement after stroke. Despite this, the role of serotoninergic neurotransmission after cerebral ischemia evolution and its involvement in functional recovery processes are still largely unknown. For this purpose, we performed in parallel in vivo magnetic resonance imaging and positron emission tomography (PET) with [11C]DASB and [18F]altanserin at 1, 3, 7, 14, 21, and 28 days after middle cerebral artery occlusion (MCAO) in rats. In the ischemic territory, PET with [11C]DASB and [18F]altanserin showed a dramatic decline in serotonin transporter (SERT) and 5-HT2A binding potential in the cortex and striatum after cerebral ischemia. Interestingly, a slight increase in [11C]DASB binding was observed from days 7 to 21 followed by the uppermost binding at day 28 in the ipsilateral midbrain. In contrast, no changes were observed in the contralateral hemisphere by using both radiotracers. Likewise, both functional and behavior testing showed major impaired outcome at day 1 after ischemia onset followed by a recovery of the sensorimotor function and dexterity from day 21 to day 28 after cerebral ischemia. Taken together, these results might evidence that SERT changes in the midbrain could have a key role in the functional recovery process after cerebral ischemia.

scholarly journals Assessment of the Therapeutic Potential of Metallothionein-II Application in Focal Cerebral Ischemia In Vitro and In Vivo

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0144035 ◽  
Author(s):  
Abass Eidizadeh ◽  
Manuel Khajehalichalehshtari ◽  
Dorette Freyer ◽  
George Trendelenburg
Keyword(s):  
Cerebral Ischemia ◽  
Therapeutic Potential ◽  
Focal Cerebral Ischemia

scholarly journals Evaluation of the PBR/TSPO Radioligand [18F]DPA-714 in a Rat Model of Focal Cerebral Ischemia

2009 ◽  
Vol 30 (1) ◽  
pp. 230-241 ◽  
Author(s):  
Abraham Martín ◽  
Raphaël Boisgard ◽  
Benoit Thézé ◽  
Nadja Van Camp ◽  
Bertrand Kuhnast ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Pet Imaging ◽  
Time Course ◽  
Focal Cerebral Ischemia ◽  
Quantitative Information ◽  
Translocator Protein ◽  
Experimental Stroke ◽  
Tspo Expression

Focal cerebral ischemia leads to an inflammatory reaction involving an overexpression of the peripheral benzodiazepine receptor (PBR)/18-kDa translocator protein (TSPO) in the cerebral monocytic lineage (microglia and monocyte) and in astrocytes. Imaging of PBR/TSPO by positron emission tomography (PET) using radiolabeled ligands can document inflammatory processes induced by cerebral ischemia. We performed in vivo PET imaging with [18F]DPA-714 to determine the time course of PBR/TSPO expression over several days after induction of cerebral ischemia in rats. In vivo PET imaging showed significant increase in DPA ( N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) uptake on the injured side compared with that in the contralateral area on days 7, 11, 15, and 21 after ischemia; the maximal binding value was reached 11 days after ischemia. In vitro autoradiography confirmed these in vivo results. In vivo and in vitro [18F]DPA-714 binding was displaced from the lesion by PK11195 and DPA-714. Immunohistochemistry showed increased PBR/TSPO expression, peaking at day 11 in cells expressing microglia/macrophage antigens in the ischemic area. At later times, a centripetal migration of astrocytes toward the lesion was observed, promoting the formation of an astrocytic scar. These results show that [18F]DPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke.

scholarly journals Intraventricular Brain-Derived Neurotrophic Factor Reduces Infarct Size after Focal Cerebral Ischemia in Rats

1997 ◽  
Vol 17 (5) ◽  
pp. 500-506 ◽  
Author(s):  
Wolf-R. Schäbitz ◽  
Stefan Schwab ◽  
Matthias Spranger ◽  
Werner Hacke
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Neurotrophic Factor ◽  
Cortical Neurons ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion

Brain-derived neurotrophic factor (BDNF), acting through the high-affinity receptor tyrosine kinase (TrkB), is widely distributed throughout the central nervous system and displays in vitro trophic effects on a wide range of neuronal cells, including hippocampal, cerebellar, and cortical neurons. In vivo, BDNF rescues motorneurons, hippocampal, and substantia nigral dopaminergic cells from traumatic and toxic brain injury. After transient middle cerebral artery occlusion (MCAO), upregulation of BDNF-mRNA in cortical neurons suggests that BDNF potentially plays a neuroprotective role in focal cerebral ischemia. In the current study, BDNF (2.1 μg/d) in vehicle or vehicle alone (controls) was delivered intraventricularly for 8 days, beginning 24 hours before permanent middle cerebral artery occlusion by intraluminal suture in Wistar rats (n = 13 per group). There were no differences in physiological variables recorded during surgery for the two groups. Neurological deficit (0 to 4 scale), which was assessed on a daily basis, improved in BDNF-treated animals compared with controls ( P < 0.05; analysis of variance and Scheffe's test). There were no significant differences in weight in BDNF-treated animals and controls during the experiment. After elective killing on day 7 after MCAO, brains underwent 2,3,5-triphenyltetrazolium chloride staining for calculation of the infarct volume and for histology (hematoxylin and eosin and glial fibrillary acid protein). The mean total infarct volume was 83.1 ± 27.1 mm3 in BDNF-treated animals and 139.2 ± 56.4 mm3 in controls (mean ± SD; P < 0.01, unpaired, two-tailed t-test). The cortical infarct volume was 10.8 ± 7.1 mm3 in BDNF-treated animals and 37.9 ± 19.8 mm3 in controls (mean ± SD; P < 0.05; unpaired, two-tailed t-test), whereas ischemic lesion volume in caudoputaminal infarction was not significantly different. These results show that pretreatment with intraventricular BDNF reduces infarct size after focal cerebral ischemia in rats and support the hypothesis of a neuroprotective role for BDNF in stoke.

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