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1.
In recent experimental studies, a selective antagonist of endothelin ET(A) receptors, SB 234551, improved neurological and histological outcome in both head trauma and transient focal cerebral ischemia. The present study was conducted to ascertain the degree to which hemodynamic alterations are responsible for this therapeutic effect in a model of permanent middle cerebral artery occlusion (MCAo) in rats. Anesthetized Sprague-Dawley rats were subjected to permanent MCAo by insertion of an intraluminal nylon suture coated with poly-L-lysine. The agent (SB 234551, 30 microg/kg/min = 1.8 mg/kg/h) or vehicle (PBS; 0.6 ml/h) was administered by i.v. infusion beginning 15 min after onset of MCAo and lasting for 23.75 h. Autoradiographic measurement of local cerebral blood flow (lCBF) was performed at 24 h. Physiological data were similar among groups. SB 234551 augmented perfusion by 1.7- to 1.8-fold in both the ischemic hemisphere and in the contralateral (non-ischemic) hemisphere when compared to vehicle-treated ischemic animals. In the ischemic hemisphere, the brain regions significantly benefited were those lying outside the zone of most dense ischemia (i.e., paramedian cortex and thalamus), while in the non-ischemic hemisphere all regions measured showed significant lCBF augmentation. This study demonstrates that SB 234551 therapy results in significant improvement of local cerebral perfusion in the ischemic as well as in the non-ischemic hemispheres after permanent MCAo.  相似文献   

2.
Ischemic preconditioning (IP) protects the brain from subsequent, prolonged, and lethal ischemia in experimental studies. Erythropoietin (EPO) participates in the brain's intrinsic response to injury and may play a role in preconditioning. By using a middle cerebral artery occlusion (MCAo) model of transient ischemic attack (TIA), we sought to determine whether EPO is required for IP in the protective response against focal ischemic stroke. Rats underwent three 10-min MCA occlusions or sham surgery. Three days later, animals underwent 2 hr of MCAo and 22 hr of reperfusion. Experimental TIAs reduced infarct volumes by 55% (P < 0.05), inhibited DNA fragmentation, and improved neurological outcome by 50% (P < 0.05) after ischemic stroke. EPO and its receptor were up-regulated by IP in the ipsilateral hemisphere by 24 hr after IP, before ischemic stroke and soluble EPO receptor attenuated neuroprotection by IP (88% reduction, P < 0.05). Pretreatment with the PI-3 kinase inhibitor wortmannin abolished the protective effect of IP against ischemic injury (P < 0.05). IP may be mediated in part by EPO through a PI-3 kinase pathway.  相似文献   

3.
We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elucidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we tested the hypothesis that estradiol decreases cell death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ERalpha and ERbeta in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2, as expression of other members of the bcl-2 family (bax, bcl-x(L), bcl-x(S), and bad) was unaffected by estradiol treatment. We also found that estrogen receptors were differentially modulated in injury, with ERbeta expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ERbeta protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.  相似文献   

4.
Leukemia inhibitory factor(LIF) contributes to the neuroprotection by neural stem cells(NSCs) after ischemic stroke. Our aim was to explore whether LIFtransfected NSCs(LIF-NSCs) can ameliorate brain injury and promote neuroprotection in a rat model of cerebral ischemia. To accomplish this goal, we transfected NSCs with a lentivirus carrying the LIF gene to stably overexpress LIF. The LIF-NSCs reduced caspase 3 activation under conditions of oxygen-glucose deprivation in vitro.Transient cerebral ischemia was induced in rats by 2 h of middle cerebral artery occlusion(MCAo), and LIF-NSCs were intravenously injected at 6 h post-ischemia. LIF-NSC treatment reduced the infarction volume and improved neurological recovery. Moreover, LIF-NSCs improved glial cell regeneration and ameliorated white matter injuryin the MCAo rats. The NSCs acted as carriers and increased the expression of LIF in the lesions to protect against cerebral infarction, suggesting that LIF-NSCs could be a potential treatment for cerebral infarction.  相似文献   

5.
Postischemic hypothermia provides long-lasting neuroprotection against global cerebral ischemia in adult rats and gerbils. Studies indicate that hypothermia must be prolonged (e.g., 24 h) to indefatigably salvage hippocampal CA1 neurons. Delayed hypothermia also reduces focal ischemic injury. However, no study has examined long-term outcome following postischemic hypothermia in adult animals. Furthermore, most studies examined only brief hypothermia (e.g., 3 h). Since previous studies may have overestimated long-term benefit and have likely used suboptimal durations of hypothermia, we examined whether prolonged cooling would attenuate infarction at a 2-month survival time following middle cerebral artery occlusion (MCAo) in rats. Adult male Wistar rats were implanted with telemetry brain temperature probes and later subjected to 30 min of normothermic MCAo (contralateral to side of probe placement) or sham operation. Ischemia was produced by the insertion of an intraluminal suture combined with systemic hypotension (60 mm Hg). Sham rats and one ischemic group controlled their own postischemic temperature while another ischemic group was cooled to 34 degrees C for 48 h starting at 30 min following the onset of reperfusion. The infarct area was quantified after a 2-month survival time. Normothermic MCAo resulted in almost complete striatal destruction (91% loss +/- 12 SD) with extensive cortical damage (36% +/- 16 SD). Delayed hypothermia treatment significantly reduced cortical injury to 10% +/- 10 SD (P < 0.001) while striatal injury was marginally reduced to 79% loss +/- 17 SD (P < 0.05). Delayed hypothermia of only 34 degrees C provided long-lasting cortical and striatal protection in adult rats subjected to a severe MCAo insult. These results strongly support the clinical assessment of hypothermia in acute stroke.  相似文献   

6.
The effect of postmenopausal estrogen replacement therapy (ERT) on the risk or severity of cerebrovascular disorders is as yet unclear, and the evidence for flow preservation being a mechanism of estrogen neuroprotection remains elusive. The authors examined whether estrogen-mediated flow-preserving neuroprotective mechanisms, if any, may involve its angiogenic action. This study was conducted using middle-aged (44 weeks) female rats because of the importance of aging in cerebrovascular disease in women. Middle-aged female rats were subjected to sham operation, ovariectomy, or ovariectomy with ERT. The anatomic cerebral capillary morphology showed a significant reduction in the total capillary density in the frontal cortex after ovariectomy. This was associated with marked decreases in protein and gene expression of vascular endothelial growth factor and its angiogenic receptors in cerebral vessels, as demonstrated by immunohistochemistry and hybridization. The expression levels of both estrogen receptor (ER) subtypes, ERalpha and ERbeta, in cerebral vessels were significantly reduced after ovariectomy, but ERbeta was more dramatically downregulated as assessed by the ERbeta/ERalpha ratio. These ovariectomy-induced changes were completely prevented by ERT. Vascular endothelial growth factor appears to be a critical regulatory molecule for physiologic cerebral angiogenesis in middle-aged female rats and may play an important role in the flow-preserving neuroprotective action of estrogen through its angiogenic and antiapoptotic properties.  相似文献   

7.
Nestin is an intermediate filament protein, transiently and abundantly expressed early in embryogenesis, e.g., in neuroepithelial cells, radial glia, germinal matrix cells and vascular cells. In the adult rat brain, nestin is only present in endothelial and select subventricular cells. We tested the hypothesis that after an experimental stroke, nestin expression is induced in glial cells and neurons. We measured the temporal profile of nestin expression after induction of focal cerebral ischemia in adult rats. Brain from rats (n=24) subjected to 2 h of transient middle cerebral artery occlusion (MCAo) and 3 h, 6 h, 12 h, 1 day, 2 days, 3 days, 7 days and 28 days (n=3, per time point) of reperfusion, and control sham operated (n=3) rats were processed for Western blotting to quantify nestin. Another set of brains from rats (n=28), subjected to 2 h of MCAo and 6 h, 12 h, 2 days, 7 days, 14 days, 21 days, and 28 days (n=4, per time point, except n=8 at 2 days) of reperfusion, and control sham operated (n=3) and normal (n=2) rats were processed by single and double labeled immunohistochemistry for cellular identification of nestin expression. By Western blotting, nestin within ischemic tissue increased slightly as early as 6 h, peaked at 7 days, and expression persisted for at least 4 weeks after 2 h of MCAo. By immunohistochemistry, nestin was expressed in astrocytes in the ischemic core from 6 to 12 h after MCAo. Nestin immunoreactivity was present in large numbers of astrocytes, and in scattered oligodendroglia and monocytes/macrophages in both the inner and outer boundary zones to the ischemic core at 1–7 days after MCAo. Nestin expression in glial cells declined at longer durations of survival, although for least 4 weeks after MCAo the nestin immunoreactivity delineated the boundary zone adjacent to the ischemic core. Nestin expression was present in some neurons localized to the outer boundary zone of the ischemic lesion in the cortex and striatum, and in most ependymal cells in the ventricular and subventricular zone (VZ/SVZ) from day 2 after MCAo and onward. The expression of nestin increased throughout the microvasculature in both the ischemic core and the boundary zone in all ischemic rats after 12 h of reperfusion. After stroke, nestin immunoreactivity in glial, neuronal and ependymal cells is suggestive of a protein expression pattern found in developing brain.  相似文献   

8.
BACKGROUND: Both prolonged brain ischemia and preconditioning (PC) induce expression of neurotrophic factors. However, the influence of PC on their expression after a long-term ischemia remains vague. Previously, we have found various effects of PC on mRNA levels of different cytokines after focal brain ischemia. Thus, we investigated mRNA expression of nerve growth factor, brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor after 90-min middle cerebral artery occlusion (MCAo) preceded by ischemic or chemical PC. METHODS: MCAo was induced in rats using the suture method. PC had been carried out 3 days earlier. There were 4 experimental groups: MCAo alone; ischemic PC and MCAo; chemical PC and MCAo, and sham-operated rats. Expression of mRNAs in the ipsi- and contralateral cortex was studied by semiquantitative RT-PCR at 12 and 24 h after MCAo. RESULTS: Despite clearly neuroprotective effects of both PC strategies, mRNA levels of neurotrophic factors were similar in tolerant and nontolerant rats. Only BDNF mRNA expression, 12 h after reperfusion, was lower when ischemic PC was applied prior to long-term ischemia. CONCLUSIONS: These results suggest that PC generally does not change the expression of neurotrophic factor expression after a long-term focal brain ischemia compared to the nontolerant state.  相似文献   

9.
The NMDA antagonist CGX-1007 (Conantokin-G) has previously been shown to possess potent neuroprotective properties when administered intracranially following experimental ischemic brain injury. Using the same model of middle cerebral artery occlusion (MCAo) in rats we now report the neuroprotective effects of CGX-1007 when delivered intrathecally (i.t.). When given 4 h post-occlusion, a reduction in brain infarction was measured along with significant neurological recovery. Furthermore, we describe an i.t. neuroprotective therapeutic window lasting > or = 8 h from the start of the injury. Critically, this is the first comprehensive report of a neuroprotective agent that can be administered i.t. to ameliorate experimental brain injury and potentially provide an excellent therapeutic window as a neuroprotection treatment.  相似文献   

10.
Reactive oxygen species play a role in neuronal damage following cerebral ischemia-reperfusion. We tested whether activity of the superoxide-generating enzyme, NADPH-oxidase, is enhanced in cerebral arteries within, adjacent and distant from the ischemic core. The right middle cerebral artery (MCA) of conscious rats was temporarily occluded by perivascular injection of endothelin-1 to induce stroke (ET-1; n=19). Control rats were injected with saline (n=9). At 24 h or 72 h post-administration of ET-1, the MCA and its branches within the ipsilateral penumbra and infarcted core, corresponding arteries in the contralateral hemisphere, and basilar artery were excised. Anatomically similar arteries were excised from saline-injected rats. At 24 h after stroke, NADPH-stimulated superoxide production by arteries from the infarcted core did not differ from levels generated by arteries from control rats, whereas levels were significantly lower 72 h after stroke. However, at both time points after stroke, superoxide production by arteries from the ischemic penumbra was 8-fold greater than levels generated by arteries from control rats. Surprisingly, even in the non-ischemic arteries from the contralateral hemisphere and in the basilar artery, superoxide production was increased approximately 4- to 6-fold at 24 h, but had returned to normal 72 h after stroke. The NADPH-oxidase inhibitor, diphenyleneiodonium, virtually abolished superoxide production by all arteries. Thus, the activity of NADPH-oxidase is enhanced in cerebral arteries from the ischemic penumbra at 24 h and 72 h following cerebral ischemia. Additionally, NADPH-oxidase activity is temporarily enhanced after cerebral ischemia within arteries from non-ischemic parts of the brain.  相似文献   

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