Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, not only improves insulin resistance in patients with type II diabetes but also exerts a broad spectrum protective effects in variable animal models of neurologic or cardiovascular diseases. We studied the effect of rosiglitazone on angiogenesis and neurological recovery after focal cerebral ischemia. Rosiglitazone (3 mg/kg or 0.3 mg/kg, p.o.) was administered for 7 days prior to and 3 days after the induction of focal ischemia (total 10 days) in adult rats. The rosiglitazone-treated group showed the enhanced neurologic improvement, the reduced infarction volume compared to the ischemia-vehicle group with dose dependency, and the reduced hemispheric atrophy. Rosiglitazone treatment reduced TUNEL(+)/activated caspase-3(+) cells, MPO(+)/Ox-42(+) inflammatory cell infiltrations, caspase-3 activity, and Bax(+) cells, as compared to the ischemia-vehicle group. The vascular surface area, the vascular branch points, the vascular length, and the number of BrdU(+) endothelial cells were significantly increased in the rosiglitazone group compared with the ischemia-vehicle group. Rosiglitazone increased eNOS expression around the ischemic margin with downregulation of FasL. Here, we show that rosiglitazone treatment enhances angiogenesis and functional recovery with dose-dependent induction of ischemic tolerance.
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PMID:Peroxisome proliferator-activated receptor-gamma-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia. 1669 56

Carbamylerythropoietin (CEPO) does not bind to the classical erythropoietin (EPO) receptor. Nevertheless, similarly to EPO, CEPO promotes neuroprotection on the histologic level in short-term stroke models. In the present study, we investigated whether CEPO and other nonerythropoietic EPO analogs could enhance functional recovery and promote long-term histologic protection after experimental focal cerebral ischemia. Rats were treated with the compounds after focal cerebral ischemia. Animals survived 1, 7, or 60 days and underwent behavioral testing (sensorimotor and foot-fault tests). Brain sections were stained and analyzed for Iba-1, myeloperoxidase, Tau-1, CD68 (ED1), glial fibrillary acidic protein (GFAP), Fluoro-Jade B staining, and overall infarct volumes. Treatment with CEPO reduced perifocal microglial activation (P<0.05), polymorphomonuclear cell infiltration (P<0.05), and white matter damage (P<0.01) at 1 day after occlusion. Carbamylerythropoietin-treated rats showed better functional recovery relative to vehicle-treated animals as assessed 1, 7, 14, 28, and 50 days after stroke. Both GFAP and CD68 were decreased within the ipsilateral thalamus of CEPO-treated animals 60 days postoperatively (P<0.01 and P<0.05, respectively). Furthermore, behavioral analysis showed efficacy of CEPO treatment even if administered 24 h after the stroke. Other nonerythropoietic derivatives such as carbamylated darbepoetin alfa and the mutant EPO-S100E were also found to protect against ischemic damage and to improve postischemic neurologic function. In conclusion, these results show that postischemic intravenous treatment with nonerythropoietic EPO derivatives leads to improved functional recovery, which may be linked to their long-term effects against neuroinflammation and secondary tissue damage.
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PMID:Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. 1683 29

Phospholipase A2s (PLA2s) seem to be involved in the pathophysiology of ischemic brain injury, but their specific role is far from being completely understood. The present study was carried out to ascertain how and to what extent secretory PLA2s (sPLA2s) activity influences outcome after cerebral ischemia-reperfusion, and to correlate this with the inflammatory response. To do this we used the potent and selective sPLA2 inhibitor, 12-epi-scalaradial. Male Wistar rats were separated into three groups: a control group receiving intracerebroventricular vehicle, and two groups receiving intracerebroventricular 0.005 or 0.5 microg/h 12-epi-scalaradial. Every animal was subjected to middle cerebral artery (MCA) occlusion (90 min, intraluminal thread technique) under continuous moni-torization of cerebrocortical perfusion (CP, laser-Doppler flowmetry), followed by reperfusion (3 days). Neurological status, infarct volume, and myeloperoxidase (MPO) activity were the main end points. Three days after the 90-min ischemia period, neurological examination did not reveal significant differences between the three groups of rats. Control rats showed a mean infarct volume of 145.9 +/- 24.7 mm3 (21 +/- 4.1% of the ipsilateral hemisphere volume), while mean infarct volume in rats treated with 0.005 or 0.5 microg/h 12-epi-scalaradial increased to 164.8 +/- 86.8 mm3 (22.0 +/- 10.9%) and 211.5 +/- 12.2 mm3 (28 +/- 3%, P < 0.05), respectively. Treatment with the highest dose of 12-epi-scalaradial (0.5 microg/h) increased MPO activity in the ipsilateral hemisphere by about 140% (from 0.59 +/- 0.59 to 1.42 +/- 1.03 units of activity/g of tissue in comparison with the control ischemic hemisphere, P < 0.05). Overall, our results point to a positive rather than a negative influence of sPLA2 activity during ischemia. This, along with its inability to decrease the inflammatory response, does not allow to propose the use of 12-epi-scalardial as a potential drug for stroke therapy.
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PMID:Chronic intracerebroventricular delivery of the secretory phospholipase A2 inhibitor, 12-epi-scalaradial, does not improve outcome after focal cerebral ischemia-reperfusion in rats. 1687 15

The rewarming phase after therapeutic hypothermia in cerebral ischemia appears crucial as rapid rewarming may lead to rebound phenomena and enhance deleterious ischemic effects. We hypothesized that slow and controlled rewarming after moderate hypothermia is superior to fast rewarming in rats subjected to 90 min temporary middle cerebral artery occlusion (tMCAO). Two experiments were designed: (i) 34 rats were randomly assigned to either normothermic treatment, to hypothermia (33 degrees C) with rapid rewarming within 20 min, or to hypothermia with slow rewarming within 2 h after 4 h of hypothermia starting 2 h after tMCAO. Infarct size, neuroscore, myeloperoxidase and aquaporin 4 (AQP4) positive cells were assessed on day 5 after tMCAO. (ii) In 15 rats, striatal cerebral microdialysis was performed from 1.5 h before until 8 h after tMCAO. Total infarct volume was largest in the normothermic group (89.9+/-16.8 mm(3)) followed by the fast rewarming group (69.2+/-12.6 mm(3)), and a significantly smaller infarct volume in the slow rewarming group (41.1+/-6.6 mm(3), p<0.05). Neurological functions improved in both hypothermia groups at day 5 after tMCAO (Neuroscore median 2.5 in normothermia vs. 1.5 in both hypothermia groups) though without any difference between slowly and fast rewarmed animals. Periinfarct expression of AQP4 was less prominent in slowly rewarmed animals as was the count of MPO-positive cells in subcortical regions. Glutamate release was significantly higher at 4 distinct time points in the control group. Slow rewarming after a period of hypothermia is superior to fast rewarming. It may blunt deleterious rebound effects such as overexpression of AQP4, sustain anti-inflammatory mechanisms and thereby preserve the neuroprotection delivered by hypothermia.
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PMID:Hypothermia in acute stroke--slow versus fast rewarming an experimental study in rats. 1711 13

To investigate the protective effect of ginsenoside Re (Re) against cerebral ischemia-reperfusion injury, adult male Wistar rats weighing 250-300 g were subjected to either sham surgery or middle cerebral artery occlusion (MCAO) for 2 h of brain ischemia and 2 h reperfusion. A fluorescence polarization assay was carried out for membrane fluidity of brain mitochondria. Lipid peroxidation [malondiadehyde (MDA) formation], superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) of rat brain were estimated by fluorometric methods. It was observed that Re (5, 10, 20 mg kg-1 p.o. pretreatment for 7 d, once a day) significantly improved the fluidity of mitochondrial membranes as demonstrated by a reduction of average microviscosity, ameliorated lipid peroxidation by raising the activities of SOD and GSH-Px, and reduced the content of MDA in rat brain. This study demonstrated a direct protective effect of Re against cerebral ischemia-reperfusion injury.
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PMID:Protective effect of ginsenoside-Re against cerebral ischemia/reperfusion damage in rats. 1714 90

Several studies suggest that cyclooxygenase (COX)-2 plays a pivotal role in the progression of ischaemic brain damage. In the present study, we investigated the effects of selective inhibition of COX-2 with nimesulide (12 mg/kg) and selective inhibition of COX-1 with valeryl salicylate (VAS, 12-120 mg/kg) on prostaglandin E(2) (PGE(2)) levels, myeloperoxidase (MPO) activity, Evans blue (EB) extravasation and infarct volume in a standardized model of transient focal cerebral ischaemia in the rat. Post-ischaemic treatment with nimesulide markedly reduced the increase in PGE(2) levels in the ischaemic cerebral cortex 24 h after stroke and diminished infarct size by 48% with respect to vehicle-treated animals after 3 days of reperfusion. Furthermore, nimesulide significantly attenuated the blood-brain barrier (BBB) damage and leukocyte infiltration (as measured by EB leakage and MPO activity, respectively) seen at 48 h after the initial ischaemic episode. These studies provide the first experimental evidence that COX-2 inhibition with nimesulide is able to limit BBB disruption and leukocyte infiltration following transient focal cerebral ischaemia. Neuroprotection afforded by nimesulide is observed even when the treatment is delayed until 6 h after the onset of ischaemia, confirming a wide therapeutic window of COX-2 inhibitors in experimental stroke. On the contrary, selective inhibition of COX-1 with VAS had no significant effect on the evaluated parameters. These data suggest that COX-2 activity, but not COX-1 activity, contributes to the progression of focal ischaemic brain injury, and that the beneficial effects observed with non-selective COX inhibitors are probably associated to COX-2 rather than to COX-1 inhibition.
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PMID:Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats. 1717 64

In order to evaluate the neuroprotective effect of Rosiglitazone Maleate (RSG) against brain ischemic injury, the effects of Rosiglitazone Maleate on the inflammation following cerebral ischemia/reperfusion were investigated. Focal cerebral ischemia was induced by the intraluminal thread for cerebral middle artery (MCA) occlusion. Rosiglitazone Maleate at concentrations of 0.5, 2 and 5 mg/kg was infused by intragastric gavage twice immediately and 2 h after MCA occlusion, respectively. The effects of Rosiglitazone Maleate on brain swelling, myeloperoxidase and interleukin-6 mRNA level in brain tissue after MCA occlusion and reperfusion were evaluated. The results showed that as compared with the model control group, RSG (0.5 mg/kg) had no significant influence on brain swelling (P>0.05), but 2 mg/kg and 5 mg/kg RSG could significantly alleviate brain swelling (P<0.05). All different doses of RSG could obviously reduce MPO activity in brain tissue after MCA occlusion and reperfusion in a dose-dependent manner. RSG (0.5 and 2 mg/kg) could decrease the expression levels of IL-6 mRNA in brain tissue after MCA occlusion and reperfusion to varying degrees (P<0.05) with the difference being significant between them. It was concluded that RSG could effectively ameliorate brain ischemic injury after 24 h MCA occlusion and inhibit the inflammatory response after ischemia-reperfusion in this model.
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PMID:Effect of Rosiglitazone Maleate on inflammation following cerebral ischemia/reperfusion in rats. 1764 46

Aberrant oxidation of norepinephrine (1) via the transient o-quinone has been implicated as a critical pathogenetic mechanism underlying the degeneration of noradrenergic cell bodies in the locus coeruleus in Parkinson's disease, the degeneration of noradrenergic nerve terminals in Alzheimer's disease and following transient cerebral ischemia, and the onset and progression of idiopathic vitiligo. An oxidative pathway of 1 is also believed to account for the slow deposition of neuromelanin in pigmented neurons of the locus coeruleus. Remarkably, after extensive investigations spanning over several decades, there is still a lack of knowledge of the oxidation chemistry of 1 beyond the classic cyclization route leading to aminochrome and lutin intermediates. We report herein that oxidation of 1 in the 50-500 microM concentration range with H2O2-dependent oxidizing agents, such as the Fenton reagent (Fe2+-EDTA/H2O2) and the horseradish peroxidase (HRP)/H2O2 system, leads not only to the known cyclization products, such as noradrenochrome and 5,6-dihydroxyindole (3), but also to a significant proportion of chain breakdown products, including 3,4-dihydroxybenzaldehyde, 3,4-dihydroxybenzoic acid, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylglyoxylic acid, which has never been described among the oxidation products or metabolites of 1. Analysis of the brown melanin-like pigment obtained by oxidation of 1 with HRP/H2O2 gave pyrrole-2,3-dicarboxylic acid and pyrrole-2,3,5-tricarboxylic acid, diagnostic markers of 3-derived units in eumelanins. Comparison with reference pigments prepared by similar oxidation of dopamine and 3 indicated that in the case of 1 oxidative polymerization of indole units through the 2-position contributes only to a minor extent to melanin formation. Overall, the results of this study provide a complete characterization of the oxidative chain fission pathways of 1, highlight 3,4-dihydroxyphenylglyoxylic acid as a novel possible metabolic product of this catecholamine, and yield an insight into norepinephrine-melanin, a putative component of locus coeruleus neuromelanin.
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PMID:Oxidation chemistry of norepinephrine: partitioning of the O-quinone between competing cyclization and chain breakdown pathways and their roles in melanin formation. 1789 64

Elevated activities of matrix metalloproteinases (MMPs) following ischemic stroke have been shown to mediate ischemic injury as well as neurovascular remodeling. The extracellular MMP inducer (EMMPRIN) is a 58-kDa cell surface glycoprotein, which has been known to play a key regulatory role for MMP activities. The roles of EMMPRIN in stroke injury are not clearly understood. In this study, we investigated changes of EMMPRIN in a mouse model of permanent focal cerebral ischemia, and examined potential association between EMMPRIN and MMP-9 expression. Adult male CD-1 mice were subjected to permanent focal ischemia by intraluminal occlusion of the left middle cerebral artery (MCAO) under anesthesia. EMMPRIN expression was markedly upregulated in the peri-infarct area at 2-7 days after ischemia compared to the contralateral non-ischemic hemisphere by Western blot analysis. Immunofluorescent double staining demonstrated that EMMPRIN signals co-localized with vwF-positive endothelial cells and GFAP-positive peri-vascular astrocytes. In contrast, EMMPRIN signal did not co-localize with NeuN-positive neurons, or MPO-positive neutrophils. Dual fluorescent staining revealed that EMMPRIN co-localized with MMP-9. Our data also demonstrated that increased EMMPRIN expression correlated with increased MMP-9 levels in a temporal manner. In summary, we report for the first time that EMMPRIN expression was significantly increased in a mouse model of permanent focal cerebral ischemia. The spatial and temporal association between increased EMMPRIN expression and elevated MMP-9 levels suggest that EMMPRIN may modulate MMP-9 activity, and participate in neurovascular remodeling after ischemic stroke.
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PMID:Upregulation of EMMPRIN after permanent focal cerebral ischemia. 1816 15

1. The present study was designed to investigate the neuroprotective effect of trimetazidine (TMZ) following focal cerebral ischaemia-reperfusion (I/R) injury in rat forebrain. 2. Cerebral I/R injury was induced in rats by middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion for 22 h. Trimetazidine (5 and 25 mg/kg, i.p.) was administered 1 h after induction of MCAO. The effects of TMZ were investigated by measuring neurological deficit, volume of infarct and brain swelling after 22 h reperfusion. Oxidative stress and inflammatory reactivity were assessed by estimating anti-oxidant markers and myeloperoxidase (MPO) activity in brain homogenates. Rectal temperature was measured during the study. The effects of TMZ on blood-brain barrier (BBB) permeability and apoptosis were also investigated in rat brain. Apoptosis was observed by DNA fragmentation studies using agarose gel electrophoresis. 3. Treatment with TMZ significantly (P < 0.01) reduced infarct volume and brain swelling. Superoxide dismutase (SOD) activity was reduced in ipsilateral hemispheres of vehicle (saline)-treated reperfused (RI) animals. Treatment with TMZ significantly restored SOD activity (P < 0.01) and glutathione levels (P < 0.05) after reperfusion compared with RI animals. Lipid peroxidation, MPO activity, BBB permeability and rectal temperature were all significantly (P < 0.01, P < 0.05 and P < 0.001, respectively) reduced in TMZ-treated animals compared with RI animals. 4. These results suggest that TMZ protects the brain against cerebral I/R injury and that this neuroprotective activity could be mediated by its anti-oxidant properties. The reduction in rectal temperature by TMZ treatment may be responsible for maintaining the delicate energy balance during I/R injury in rat brain and could have contributed to the neuroprotective activity of TMZ.
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PMID:Anti-oxidant activity mediated neuroprotective potential of trimetazidine on focal cerebral ischaemia-reperfusion injury in rats. 1831 45


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