Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apolipoprotein (apo) E isoforms are key determinants of susceptibility to Alzheimer's disease. The apoE4 isoform is the major known genetic risk factor for this disease and is also associated with poor outcome after acute head trauma or stroke. To test the hypothesis that apoE3, but not apoE4, protects against age-related and excitotoxin-induced neurodegeneration, we analyzed apoE knockout (Apoe-/-) mice expressing similar levels of human apoE3 or apoE4 in the brain under control of the neuron-specific enolase promoter. Neuronal apoE expression was widespread in the brains of these mice. Kainic acid-challenged wild-type or Apoe-/- mice had a significant loss of synaptophysin-positive presynaptic terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus. Expression of apoE3, but not of apoE4, protected against this excitotoxin-induced neuronal damage. ApoE3, but not apoE4, also protected against the age-dependent neurodegeneration seen in Apoe-/- mice. These differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of Alzheimer's disease and to the poor outcome after head trauma and stroke associated with apoE4 in humans.
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PMID:Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration. 1036 21

The goal of this study was to determine if synaptic plasticity in the thalamus of rats subjected to stroke could be altered by motor training. Transient occlusion of right middle cerebral artery in adult female Sprague-Dawley rats (n = 35) was induced with an intraluminal filament followed by three training conditions, 1. motor skill training on Rota-rod requiring balance and coordination skills, 2. simple exercise on treadmill, and 3. nontrained controls. Synaptic plasticity in brain was evaluated by synapotophysin immunocytochemistry at 14 or 28 days after training procedures. Infarct volume was determined in Nissl stained sections. Both at 14 and 28 days after Rota-rod training, intense synaptophysin immunoreactivity was present in the right but not the left mediodorsal and ventromedial nuclei of thalamus of ischemic rats. In treadmill-trained animals, however, similarly intense synaptic plasticity in these two thalamic nuclei was seen only at 28 days. Immunostaining was found also in other brain regions adjacent to or remote from infarct site. The data suggest that motor training, particularly motor skill training involving balance and coordination, facilitates a uniquely lateralized synaptogenesis in the thalamus.
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PMID:Synaptic plasticity in thalamic nuclei enhanced by motor skill training in rat with transient middle cerebral artery occlusion. 1263 21

We demonstrate that the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors atorvastatin and simvastatin enhance functional outcome and induce brain plasticity when administered after stroke to rats. With atorvastatin treatment initiated 1 day after stroke, animals exhibited significant increases in vascular endothelial growth factor, cyclic guanosine monophosphate, angiogenesis, endogenous cell proliferation and neurogenesis, and an increase in the synaptic protein, synaptophysin. Atorvastatin-induced angiogenesis in a tube formation assay was reduced by an antibody against the vascular endothelial growth factor receptor 2 (FIK-1) and by the nitric oxide synthase inhibitor, N-mono-methyl-L-arginine (L-NAME). Atorvastatin also induced phosphorylation of Akt and Erk in cultured primary cortical neurons. These data indicate that atorvastatin induced brain plasticity and has neurorestorative activity after experimental stroke.
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PMID:Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. 1278 20

Physical activity can induce neuroplastic adaptations and improve outcomes after cerebral injury. To determine if these outcomes are dependent on the type and timing of physical rehabilitation and the particular outcome/endpoint being tested, we evaluated the effect of voluntary exercise exposure beginning 24 h after cerebral ischemic injury on behavioral, physiological, and histological outcomes. In an observer-blinded fashion, Sprague-Dawley (300 g) male rats were allocated to three groups [sham-exercise (SHAM), stroke-exercise (SE), stroke-no exercise (SNE)] before a 1-h right middle cerebral artery occlusion (MCAo). Running wheels were used for voluntary exercise. A significant difference was found at 1 week post-infarction between the SNE and SE, with SNE showing worst neurological scores and higher number of foot faults. In addition, nearly 20% more of the SE animals regained their pre-MCAo weight by 7 days. These differences were not as evident at 2 weeks. No differences were found between the three groups in the paw preference test, wheel activity, and body temperature, as well as between SNE and SE with regards to infarct or hemispheric volumes, body weight, synaptophysin staining, and electroencephalography (EEG) testing. Within-group comparisons showed no relationships between infarct volume and foot faults, neurological scores, or exercise level. We conclude that (1) unlike behavioral outcomes, physiological and histological outcomes may not be influenced by the introduction of voluntary exercise once lesion maturation has occurred at 24 h, and (2) repetitive outcomes testing can obscure findings in rat models of cerebral ischemic injury.
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PMID:The effect of voluntary exercise exposure on histological and neurobehavioral outcomes after ischemic brain injury in the rat. 1463 13

Molecular mechanisms underlying the role of statins in the induction of brain plasticity and subsequent improvement of neurologic outcome after treatment of stroke have not been adequately investigated. Here, we use both in vivo and in vitro studies to investigate the potential roles of two prominent factors, vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), in mediating brain plasticity after treatment of stroke with atorvastatin. Treatment of stroke in adult mice with atorvastatin daily for 14 days, starting at 24 hours after MCAO, shows significant improvement in functional recovery compared with control animals. Atorvastatin increases VEGF, VEGFR2 and BDNF expression in the ischemic border. Numbers of migrating neurons, developmental neurons and synaptophysin-positive cells as well as indices of angiogenesis were significantly increased in the atorvastatin treatment group, compared with controls. In addition, atorvastatin significantly increased brain subventricular zone (SVZ) explant cell migration in vitro. Anti-BDNF antibody significantly inhibited atorvastatin-induced SVZ explant cell migration, indicating a prominent role for BDNF in progenitor cell migration. Mouse brain endothelial cell culture expression of BDNF and VEGFR2 was significantly increased in atorvastatin-treated cells compared with control cells. Inhibition of VEGFR2 significantly decreased expression of BDNF in brain endothelial cells. These data indicate that atorvastatin promotes angiogenesis, brain plasticity and enhances functional recovery after stroke. In addition, VEGF, VEGFR2 and BDNF likely contribute to these restorative processes.
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PMID:Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. 1567 29

Both increased and decreased testosterone levels have been reported to correlate with poor outcome after acute ischemic stroke. The present study focused on the role of testosterone during recovery from neurological deficits in a rat focal ischemia model. Castrate male rats were subjected to behavioral tests after 90 min of middle cerebral artery occlusion (MCAO). On day 7 post-MCAO, neurological deficit-matched rats were assigned to a treatment group implanted with subcutaneous testosterone pellets or a control group implanted with sham cholesterol pellets. After 4 weeks post-MCAO, the average infarct volume was not significantly different between the two groups. Rats in the testosterone group demonstrated significantly earlier improvement in neurological deficits and shortened latency of adhesive tape removal compared with the control group as analyzed by Wilcoxon signed ranks test. Walking on parallel bars improved in both groups with a trend towards early recovery observed in the testosterone group. Biased left body swings persisted during the test period in both groups post-MCAO. Serum testosterone was within physiological levels in the treatment group but was not detectable in the control group by radioimmunoassay. GAP-43 and synaptophysin expression did not differ between groups. Less GFAP expression and reactive astrocyte hypertrophy were found around the infarct area in testosterone-treated rats compared with control rats. In conclusion, testosterone replacement post-MCAO accelerated functional recovery in castrate rats, suggesting a potential therapeutic role for testosterone replacement in stroke recovery.
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PMID:Effect of testosterone on functional recovery in a castrate male rat stroke model. 1586 33

The present study investigates the induction of axon and myelin remodeling as a possible mechanism by which treatment of stroke with bone marrow stromal cells improves neurological functional recovery. Adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion, followed by an injection of 2 x 10(6) rat bone marrow stromal cells or phosphate-buffered saline into the internal carotid artery 24 h later. Animals were killed at 28 days after stroke. Functional tests, histo- and immunohistochemical staining were performed. Significant functional recovery was found after bone marrow stromal cell administration in all the three tests performed (modified neurological severity score, adhesive-removal and corner tests). Bone marrow stromal cell treatment markedly increased vessel sprouting, synaptophysin expression and NG2 positive cell numbers and density in the cortical peri-infarct area. In bone marrow stromal cell-treated rats, the number of Ki-67 positive proliferating cells and oligodendrocyte precursor cells in the corpus callosum increased significantly in concert with the enhancement of the areas of the corpus callosum in both hemispheres. These results suggest that bone marrow stromal cells facilitate axonal sprouting and remyelination in the cortical ischemic boundary zone and corpus callosum, which may underlie neurological functional improvement caused by bone marrow stromal cell treatment.
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PMID:Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. 1629 76

There is no specific treatment to improve the functional recovery in the chronic stage of ischemic stroke. To provide the new therapeutic options, we examined the effect of overexpression of hepatocyte growth factor (HGF) in the chronic stage of cerebral infarction by transferring the HGF gene into the brain using hemagglutinating virus of Japan envelope vector. Sixty rats were exposed to permanent middle cerebral artery occlusion (day 1). Based on the sensorimotor deficits at day 7, the rats were divided equally into control vector or HGF-treated rats. At day 56, rats transfected with the HGF gene showed a significant recovery of learning and memory in Morris water maze tests (control vector 50+/-4 s; HGF 33+/-5 s; P<0.05) and passive avoidance task (control vector 132.4+/-37.5 s; HGF 214.8+/-26.5 s; P<0.05). Although the total volume of cerebral infarction was not related to the outcome, immunohistochemical analysis for Cdc42 and synaptophysin in the peri-infarct region revealed that HGF enhanced the neurite extension and increased synapses. Immunohistochemistry for glial fibriary acidic protein revealed that the formation of glial scar was also prevented by HGF gene treatment. Additionally, the number of the arteries was increased in the HGF group at day 56. These data demonstrated that HGF has a pivotal role for the functional recovery after cerebral infarction through neuritogenesis, improved microcirculation, and the prevention of gliosis. Our results also provide evidence for the feasibility of gene therapy in the chronic stage of cerebral infarction.
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PMID:Gene transfer of hepatocyte growth factor gene improves learning and memory in the chronic stage of cerebral infarction. 1650 98

Bone morphogenetic proteins play a key role in astrocytic differentiation. Astrocytes express the gap junctional protein connexin-43, which permits exchange of small molecules in brain and enhances synaptic efficacy. Bone marrow stromal cells produce soluble factors including bone morphogenetic protein 2 and bone morphogenetic protein 4 (bone morphogenetic protein 2/4) in ischemic brain. Here, we tested whether intra-carotid infusion of bone marrow stromal cells promotes synaptophysin expression and neurological functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 h of right middle cerebral artery occlusion. Rats were treated with or without bone marrow stromal cells at 24 h after middle cerebral artery occlusion via intra-arterial injection (n=8/group). A battery of functional tests was performed. Immunostaining of 5-bromo-2-deoxyuridine, Ki67, bone morphogenetic protein 2/4, connexin-43, synaptophysin, glial fibrillary acidic protein, neuronal nuclear antigen, and double staining of 5-bromo-2-deoxyuridine/glial fibrillary acidic protein, 5-bromo-2-deoxyuridine/neuronal nuclear antigen, glial fibrillary acidic protein/bone morphogenetic protein 2/4 and glial fibrillary acidic protein/connexin-43 were employed. Rats treated with bone marrow stromal cells significantly (P<0.05) improved functional recovery compared with the controls. 5-Bromo-2-deoxyuridine and Ki67 positive cells in the ipsilateral subventricular zone were significantly (P<0.05) increased in bone marrow stromal cell treatment group compared with the controls, respectively. Administration of bone marrow stromal cells significantly (P<0.05) promoted the proliferating cell astrocytic differentiation, and increased bone morphogenetic protein 2/4, connexin-43 and synaptophysin expression in the ischemic boundary zone compared with the controls, respectively. Bone morphogenetic protein 2/4 expression correlated with the expression of connexin-43 (r=0.84, P<0.05) and connexin-43 expression correlated with the expression of synaptophysin (r=0.73, P<0.05) in the ischemic boundary zone, respectively. Administration of bone marrow stromal cells via an intra-carotid route increases endogenous brain bone morphogenetic protein 2/4 and connexin-43 expression in astrocytes and promotes synaptophysin expression, which may benefit functional recovery after stroke in rats.
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PMID:Bone marrow stromal cells upregulate expression of bone morphogenetic proteins 2 and 4, gap junction protein connexin-43 and synaptophysin after stroke in rats. 1673 Sep 12

Capybara might be a useful model for studying changes in cerebral circulation as the natural atrophy of the internal carotid artery (ICA) occurs in this animal at maturation. In this study, confocal and electron microscopy combined with immunohistochemical techniques were applied in order to reveal the changes in morphology and innervation to the proximal part of ICA in young (6-month-old) and mature (12-month-old) capybaras. Some features of the basilar artery (BA) were also revealed. The ICA of young animals degenerated to a ligamentous cord in mature animals. Immunolabelling positive for pan-neuronal marker protein gene product 9.5 but negative for tyrosine hydroxylase was observed in the proximal part of ICA at both ages examined. Axon varicosities positive for synaptophysin were present in the adventitia of ICA of young animals but were absent in the ligamentous cord of mature animals. In the ICA of young animals, adventitial connective tissue invaded the media suggesting that the process of regression of this artery began within the first 6 months of life. An increase in size of the BA was found in mature animals indicating increased blood flow in the vertebro-basilar system, possibly making capybara susceptible to cerebrovascular pathology (e.g. stroke). Capybara may therefore provide a natural model for studying adaptive responses to ICA regression/occlusion.
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PMID:On the atrophy of the internal carotid artery in capybara. 1682 74


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