Rapid tolerance to focal cerebral ischemia in rats is attenuated by adenosine A1 receptor antagonist.

Two types of ischemic tolerance in the brain, rapid and delayed, have been reported in terms of the interval between the conditioning and test insults. Although many reports showed that delayed-phase neuroprotection evoked by preconditioning is evident after 1 week or longer, there have been a few investigations about rapidly induced tolerance, and the reported neuroprotective effects become ambiguous 7 days after the insults. The authors examined whether this rapid ischemic tolerance exists after 7 days of reperfusion in a rat focal ischemic model, and investigated modulating effects of the adenosine A 1 receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine). Preconditioning with 30 minutes of middle cerebral artery occlusion reduced infarct volume 7 days after 180 minutes of subsequent focal ischemia given after 1-hour reperfusion. The rapid preconditioning also improved neurologic outcome. These beneficial effects were attenuated by pretreatment of 0.1 mg/kg DPCPX, which did not influence the infarct volume after conditioning (30 minutes) or test (180 minutes) ischemia when given alone. The results show that preconditioning with a brief focal ischemia induces rapid tolerance to a subsequent severe ischemic insult, the effect of which is still present after 7 days of reperfusion, and that the rapid ischemic tolerance is possibly mediated through an adenosine A 1 receptor-related mechanism.     

Administration of transforming growth factor-alpha reduces infarct volume after transient focal cerebral ischemia in the rat.

Growth factors promote cell growth and survival and protect the brain from developing injury after ischemia. In this article, the authors examined whether transforming growth factor-alpha (TGF-alpha) was protective in transient focal ischemia and whether alteration of cerebral circulation was involved. Rats received intraventricular TGF-alpha (50 ng, either split into 2 doses given 30 minutes before and 30 minutes after middle cerebral artery occlusion (MCAO), or 1 dose given 30 minutes after MCAO) or vehicle. Rats were subjected to 1-hour intraluminal MCAO and cerebral blood flow was recorded continuously by laser-Doppler flowmetry. Infarct volume was measured 1 and 4 days later. The effects of TGF-alpha on arterial tone were assessed in isolated rabbit basilar and common carotid arteries. Transforming growth factor-alpha before and after ischemia reduced infarct volume by 70% at 1 day and 50% at 4 days. Transforming growth factor-alpha given only after ischemia also did reduce infarct volume by 70% at 1 day and 80% at 4 days. The protective effect was more marked in cortex than in striatum. Transforming growth factor-alpha did not change cortical microvascular perfusion and did not modify arterial passive tone nor agonist-induced active tone. It can be concluded that TGF-alpha reduces infarct volume, even when the factor is exclusively administered at reperfusion, and that this effect is not mediated by changes in microvascular perfusion or cerebral arteries. It is therefore suggested that TGF-alpha has a protective effect against neuronal cell death after transient focal ischemia.     

Moderate cerebral venous congestion induces rapid cerebral protection via adenosine A1 receptor activation

Stroke is a devastating complication in cardiovascular surgery, and neuronal damage is worsened by intracranial pressure elevation caused by cerebral venous circulatory disturbances (CVCD). However, we have previously reported that CVCD before cerebral ischemia decreases the infarct area. In the present study, focal cerebral ischemia was induced in spontaneously hypertensive rats by filament insertion through the carotid artery. Rats were divided into the following four groups: sham-operated, mild or severe venous congestion (VC), and DPCPX. The DPCPX group received the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) prior to mild VC. Behavior, infarct volume, edema and S-100 protein were evaluated among the four groups. The infarct volume rates in mild VC and severe VC groups were significantly less than that in sham-operated and DPCPX groups. However, the mortality of the severe VC group worsened in a time-dependent manner. We observed a significant decrease in edema in the mild VC group compared to the DPCPX group. Behavioral scores also indicated that the mild VC group had fewer neurological deficits than the other three groups, including the DPCPX group. We were able to induce rapid cerebral protection via adenosine A1 receptor activation by administering an appropriate degree of VC prior to cerebral ischemia produced by middle cerebral artery occlusion. Our work suggests possible mechanisms by which such effective VC may lead to cerebral protection and adenosine A1 receptor activation.     

Isoflurane induced prolonged protection against cerebral ischemia in mice: a redox sensitive mechanism?

We here demonstrate that general anesthesia with isoflurane can have profound effects on the brain of mice long after the anesthetic has been discontinued. Three hours of exposure to 1% isoflurane induced rapid and longlasting protection against 60 min transient focal cerebral ischemia induced by filament occlusion of the middle cerebral artery (MCAO). Mean infarct volumes were significantly smaller in animals pretreated with isoflurane 0, 12, and 24 h before MCAO (-38%, -31%, -24%, respectively). Mild hypoxia (17% O(2)) during or 5 mg/kg desferrioxiamine administered at the onset of isoflurane pretreatment completely abrogated the development of delayed tolerance (12 h) against focal cerebral ischemia, suggesting that the signaling of delayed protection induced by isoflurane is sensitive to the intracellular oxygenation state.     

Cell permeable exogenous ceramide reduces infarct size in spontaneously hypertensive rats supporting in vitro studies that have implicated ceramide in induction of tolerance to ischemia.

Previous work in primary cell culture has shown that TNF-alpha and ceramide are involved in the signaling that induces tolerance to brain ischemia (Ginis et al., 1999; Liu et al., 2000). To validate the in vitro studies, the authors administered cell permeable analogs of ceramides intracisternally or intravenously to examine their effect on neuroprotection after focal cerebral ischemia. Permanent middle cerebral artery occlusion (MCAO) was performed in spontaneously hypertensive rats. Infarct volumes were assessed at 24 hours after surgery. D-erythro-N-acetylsphingosine (C2-ceramide) or its vehicle was infused intracisternally for 1 hour before MCAO. In a second set of studies, D-erythro-N-octanoylsphingosine (C8-ceramide) or its vehicle was injected intravenously 48 or 24 hours before MCAO to mimic preconditioning (PC) and was also injected 5 minutes after MCAO. C2-ceramide infusion significantly reduced infarct volumes by approximately 14% (P < 0.05). C8-ceramide injection reduced infarct volumes approximately 17% compared with controls. This effect was constant and significant compared with controls over the time periods examined (P < 0.01). This work supports findings in primary brain cell cultures that implicate ceramide as a downstream signal that is proximate to development of tolerance to brain ischemia. Because the degree of protection represents approximately 50% of the maximal infarct reduction observed in this model, there are probably additional signaling pathways that subserve tolerance.     

The low molecular weight heparin enoxaparin reduces infarct size in a rat model of temporary focal ischemia

Low molecular weight heparins (LMWHs) have significantly reduced infarct size in animal studies but they have not been effective in clinical trials, probably because they were administered after ischemic injury had become irreversible. The present study was designed to explore the temporal characteristics of the LMWH enoxaparin with the objective of determining the duration of the treatment window in a rat model of temporary focal ischemia. Focal cerebral ischemia was induced by the intraluminal suture, middle cerebral artery occlusion (MCAO) method. Enoxaparin (10 mg/kg) was administered subcutaneously twice; the first dose was administered to different groups of animals either 1 h before or 1.5, 3, or 5 h after MCAO, and the second 4, 6, 9, or 25 h after the first dose. At 48 h animals were tested for motor coordination and brains were removed for determination of infarct size. Results showed that infarct size and degree of motor impairment were a function of time of the first and the second treatments. If the first treatment was given 1 h prior to MCAO, significant reductions in infarct size were obtained when the second treatment was given up to 6 h after the first (5 h after MCAO), but not when the second dose was given at longer intervals. If the first treatment was given 1.5 h after stroke onset, reduced infarct size was observed only in the group treated for the second time 4 h after the first injection. If the first treatment was given 3 h after MCAO, infarct size was not reduced in any group. However, if enoxaparin was administered intravenously rather than subcutaneously, significant reductions in infarct size were obtained when the first dose was given as long as 5 h after MCAO. These findings indicate that enoxaparin can reduce infarct size in rats when administered prior to stroke onset and suggest that the drug might be considered for prophylactic treatment in a phase 3 clinical trial.     

Cannabinoid CB(2) receptor activation decreases cerebral infarction in a mouse focal ischemia/reperfusion model.

Cannabinoid CB(2) Receptor (CB(2)) activation has been shown to have immunomodulatory properties without psychotropic effects. The hypothesis of this study is that selective CB(2) agonist treatment can attenuate cerebral ischemia/reperfusion injury. Selective CB(2) agonists (O-3853, O-1966) were administered intravenously 1 h before transient middle cerebral artery occlusion (MCAO) or 10 mins after reperfusion in male mice. Leukocyte/endothelial interactions were evaluated before MCAO, 1 h after MCAO, and 24 h after MCAO via a closed cranial window. Cerebral infarct volume and motor function were determined 24 h after MCAO. Administration of the selective CB(2) agonists significantly decreased cerebral infarction (30%) and improved motor function (P<0.05) after 1 h MCAO followed by 23 h reperfusion in mice. Transient ischemia in untreated animals was associated with a significant increase in leukocyte rolling and adhesion on both venules and arterioles (P<0.05), whereas the enhanced rolling and adhesion were attenuated by both selective CB(2) agonists administered either at 1 h before or after MCAO (P<0.05). CB(2) activation is associated with a reduction in white blood cell rolling and adhesion along cerebral vascular endothelial cells, a reduction in infarct size, and improved motor function after transient focal ischemia.     

Upregulation of mitochondrial base-excision repair capability within rat brain after brief ischemia.

The mechanism by which brief episodes of cerebral ischemia confer protection (tolerance) against subsequent prolonged ischemic challenges remains unclear, but may involve upregulation of cell injury repair capability. The mitochondrion is a key site for the regulation of cell death pathways, and damage to mitochondrial genes has been linked to a number of neurologic diseases and aging. Therefore, the authors examined the response of the DNA base excision repair (BER) pathway in rat brain mitochondria after either brief (tolerance-inducing) or prolonged (injury-producing) focal cerebral ischemia. Brief (30-minute) middle cerebral artery occlusion (MCAO) induced mild oxidative mitochondrial DNA damage and initiated a prolonged (up to 72-hour) activation above control levels of the principal enzymes of the mitochondrial BER pathway, including uracil DNA glycosylase, apurinic/apyrimidinic (AP) endonuclease, DNA polymerase-gamma, and DNA ligase. In contrast, prolonged (100-minute MCAO) ischemia induced more substantial mitochondrial oxidative DNA damage whereas elevation of BER activity was transient (approximately 1 hour), declining to less than control levels over the course of 4 to 72 hours. These data reveal the differences in BER capacity after brief or prolonged ischemia, which may contribute to the neuron's ability to resist subsequent ischemic insults.     

The mitochondrial K(ATP) channel opener BMS-191095 reduces neuronal damage after transient focal cerebral ischemia in rats.

Activation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels protects the brain against ischemic or chemical challenge. Unfortunately, the prototype mitoK(ATP) channel opener, diazoxide, has mitoK(ATP) channel-independent actions. We examined the effects of BMS-191095, a novel selective mitoK(ATP) channel opener, on transient ischemia induced by middle cerebral artery occlusion (MCAO) in rats. Male Wister rats were subjected to 90 mins of MCAO. BMS-191095 (25 microg; estimated brain concentration of 40 micromol/L) or vehicle was infused intraventricularly before the onset of ischemia. In addition, the effects of BMS-191095 on plasma and mitochondrial membrane potentials and reactive oxygen species (ROS) production in cultured neurons were examined. Finally, we determined the effects of BMS-191095 on cerebral blood flow (CBF) and potassium currents in cerebrovascular myocytes. Treatment with BMS-191095 24 h before the onset of ischemia reduced total infarct volume by 32% and cortical infarct volume by 38%. However, BMS-191095 administered 30 or 60 mins before MCAO had no effect. The protective effects of BMS-191095 were prevented by co-treatment with 5-hydroxydecanoate (5-HD), a mitoK(ATP) channel antagonist. In cultured neurons, BMS-191095 (40 micromol/L) depolarized the mitochondria without affecting ROS levels, and this effect was inhibited by 5-HD. BMS-191095, similar to the vehicle, caused an unexplained but modest reduction in the CBF. Importantly, BMS-191095 did not affect either the potassium currents in cerebrovascular myocytes or the plasma membrane potential of neurons. Thus, BMS-191095 afforded protection against cerebral ischemia by delayed preconditioning via selective opening of mitoK(ATP) channels and without ROS generation.     

局灶预缺血诱导脑缺血耐受的动物模型

目的　建立一种简便可靠的 SD大鼠局灶性脑缺血预处理模型。方法　将大鼠随机分为 3组 ,分别给予 10 m in大脑中动脉缺血 ( MCAO)预处理 ( PC) ;10 min PC后 2 h MCAO( PC MCAO)及假手术 ( SS)后 2 hMCAO( SS MCAO) ,再灌注 2 2 h后处死 ,观察各组神经功能缺损、梗死体积及脑含水量变化。结果　 PC MCAO组神经功能评分、梗死体积及含水量均明显低于 SS MCAO组 ,PC组无神经功能缺损及梗死灶形成。结论　 2次线栓法建立的大鼠局灶脑缺血预处理模型 ,能有效减轻 MCAO所致的神经损伤 ,操作简便 ,稳定性好 ,是一种研究局灶脑缺血耐受的有用工具。     

Broad-spectrum cation channel inhibition by LOE 908 MS reduces infarct volume in vivo and postmortem in focal cerebral ischemia in the rat

Cation channels conduct calcium, sodium and potassium, cations that are likely deleterious in the evolution of focal ischemic injury. We studied the effects of a novel, broad-spectrum inhibitor of several cation channels, LOE 908 MS, on acute ischemic lesion development with diffusion-weighted magnetic resonance imaging (DWI) and on cerebral perfusion with perfusion imaging (PI) in vivo and on cerebral infarct size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem. A total of 18 male Sprague-Dawley rats underwent 90 min of middle cerebral artery occlusion (MCAO) and were randomly and blindly assigned to either LOE 908 MS or vehicle starting 30 min after inducing focal ischemia and continuing for 4 h. Whole-brain DWI and multislice PI were done before initiation of treatment and repeated frequently for the next 3.5 h. DWI-derived lesion volume at 4 h showed a significant difference in favor of the drug treated group (P=0.03), whereas PI-derived perfusion deficit volumes did not significantly differ between the groups. The postmortem infarct volume at 24 h was significantly attenuated in the treated group in comparison to controls (P=0.0001) and neurological score was significantly better in the treated group (P<0.02). Blocking several distinct cation channels with LOE 908 MS significantly reduced infarct size and improved neurological outcome without observable adverse effects in this focal ischemia model.     

Peripheral and central administration of neuropeptide Y in a rat middle cerebral artery occlusion stroke model reduces cerebral blood flow and increases infarct volume

Recent studies have shown increased immunoreactivity for neuropeptide Y (NPY) within the perilesional cortex following experimental middle cerebral artery occlusion (MCAO) or focal excitotoxic damage. Downregulation of the NPY Y1 receptor gene using an antisense oligodeoxynucleotide produced a doubling of the infarct volume, implying that NPY may mediate neuroprotection against focal ischemia. The effects of treatment with NPY on infarct volume and hemodynamic parameters were investigated in the present study. Adult male Sprague-Dawley rats were anesthetized with sodium pentobarbital to undergo right-sided endovascular MCAO for 2 h. A single dose of NPY was given via intracarotid injection (10 microg/kg) at the beginning of reperfusion, intracisternal injection (10 or 30 microg/kg) at 30 min of ischemia, or intracerebroventricular (i.c.v.) injection (10 or 70 microg/kg) at 30 min of ischemia. Control groups received the vehicle only via the same route. Body temperature was maintained constant, and hemodynamic parameters were monitored during anesthesia. Laser Doppler flowmetry was used to monitor the regional cerebral blood flow (rCBF) during ischemia and reperfusion in some rats. The rats were decapitated on day 3, and their brains were cut into 2-mm thick coronal slices before reaction with a 2% solution of 2,3,5-triphenyltetrazolium chloride to reveal the infarct. Compared to the respective control groups, NPY treatment via any method of administration increased the relative infarct volume. Suppression of rCBF was observed during reperfusion. These results indicate that peripheral or central administration of NPY impairs reperfusion following experimental MCAO and worsens the outcome of focal cerebral ischemia.     

<Emphasis Type="Italic">N</Emphasis>-Acetylcysteine and Ceftriaxone as Preconditioning Strategies in Focal Brain Ischemia: Influence on Glutamate Transporters Expression

Glutamate (Glu) plays a key role in excitotoxicity-related injury in cerebral ischemia. In the brain, Glu homeostasis depends on Glu transporters, including the excitatory amino acid transporters and the cysteine/Glu antiporter (xc-). We hypothesized that drugs acting on Glu transporters, such as ceftriaxone (CEF, 200 mg/kg, i.p.) and N-acetylcysteine (NAC, 150 mg/kg, i.p.), administered repeatedly for 5 days before focal cerebral ischemia in rats and induced by a 90-min middle cerebral artery occlusion (MCAO), may induce brain tolerance to ischemia. We compared the effects of these drugs on brain infarct volume, neurological deficits and the mRNA and protein expression of the Glu transporter-1 (GLT-1) and xc- with the effects of ischemic preconditioning and chemical preconditioning using 3-nitropropionic acid. Administration of CEF and NAC significantly reduced infarct size and neurological deficits caused by a 90-min MCAO. These beneficial effects were accompanied by changes in GLT-1 expression caused by a 90-min MCAO at both the mRNA and protein levels in the frontal cortex, hippocampus, and dorsal striatum. Thus, the results of this study suggest that the regulation of GLT-1 and xc- plays a role in the development of cerebral tolerance to ischemia and that this regulation may be a novel approach in the therapy of brain ischemia.     

Protective role for type 4 metabotropic glutamate receptors against ischemic brain damage

We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10 mg/kg, subcutaneous, administered once 30 minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20 minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson''s disease and other central nervous system disorders.     

Pharmacological manipulations of ATP-dependent potassium channels and adenosine A1 receptors do not impact hippocampal ischemic preconditioning in vivo: evidence in a highly quantitative gerbil model.

Ischemic preconditioning models have been characterized in brain, heart, and other tissues, and previous pharmacologic studies have suggested an involvement of adenosine and ATP dependent potassium (KATP) channels in such tolerance phenomena. This question was reexamined in a reproducible gerbil model in which the duration of ischemic depolarization defined the severity of preconditioning and test insults. Agents studied were glibenclamide, a blocker of KATP channels; 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an adenosine A1 receptor antagonist; and N6-cyclopentyladenosine (CPA), an A1 agonist. Intraventricular glibenclamide injections aggravated neuron damage after brief priming insults, in parallel with a dose-dependent prolongation of ischemic depolarization. However, the depolarization thresholds for ischemic neuronal injury were identical in vehicle- and glibenclamide-treated animals, and glibenclamide did not affect preconditioning when equivalent insult severity was maintained during priming insults. Neither DPCPX nor CPA had any effect on the onset or duration of depolarization after intraperitoneal injection in this model, and neither drug affected neuron damage. In the case of CPA, it was necessary to maintain temperature for 4 to 6 hours of recirculation to avoid significant confounding hypothermia. These results fail to support a direct involvement of A1 receptors or KATP channels during early stages in the development of ischemic tolerance in vivo, and emphasize the need for robust, well-controlled, and quantitative models in such studies.     

Preconditioning with thrombin can be protective or worsen damage after endothelin-1-induced focal ischemia in rats

The serine protease thrombin has shown direct neuroprotective and neurotoxic effects on brain tissue in cerebral ischemia. Previous data suggested that thrombin-induced protection in vivo can be achieved by preconditioning rather than by acute treatment. In the current work, we used a model of mild ischemia to investigate the effects of preischemic intracerebral thrombin injection on neural damage. By intracerebral injection of endothelin-1 in freely moving animals, we achieved middle cerebral artery occlusion (MCAO), and 7 days postischemia we performed histological quantification of the infarct areas. Thrombin was injected as a preconditioning stimulus intracerebrally 7 days or 2 and 3 days before ischemia. For acute treatment, thrombin was injected 20 min before MCAO. Thrombin induced significant neuroprotection when given 7 days before endothelin-1-induced MCAO but was deleterious when given 2 and 3 days before the insult. The deleterious effect was not seen when thrombin was given acutely before ischemia. Our data demonstrate that preconditioning with thrombin can protect against damage or worsen ischemic damage. Its effect depended on the time interval between thrombin injection and insult. A low dose of thrombin did not induce a major deleterious effect in the acute phase of the infarct development after mild transient ischemia.     

NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat

Free radicals have gained wide acceptance as mediators of cerebral ischemic injury. It has previously been reported that a spin trap nitrone, alpha-phenyl-N-tert-butyl nitrone (PBN), can reduce infarct volumes in rats subjected to either permanent or transient focal cerebral ischemia. A recent study has demonstrated that NXY-059, a novel free radical trapping nitrone compound, has a neuroprotective effect against transient focal cerebral ischemia. This study was designed to determine the effect of NXY-059 in a rodent model of permanent focal cerebral ischemia. Male spontaneously hypertensive rats were subjected to permanent middle cerebral artery occlusion (MCAO) by placement of a microaneurysm clip on the middle cerebral artery (MCA). Animals were divided into three groups: (1) physiological saline given as a 1 ml/kg i.v. bolus administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 0.5 ml/h of physiological saline for 24 h (n=10); (2) 30 mg/kg, 1 ml/kg, i.v. bolus of NXY-059 dissolved in physiological saline administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 30 mg/kg/h, 0.5 ml/h, of NXY-059 for 24 h (n=9); (3) 60 mg/kg, 1 ml/kg, i.v. bolus of NXY-059 dissolved in physiological saline administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 60 mg/kg/h, 0.5 ml/h, of NXY-059 for 24 h (n=12). Infarction was quantified after a survival period of 24 h. Differences in infarct volume were examined with one-way ANOVA following Dunnet's multiple comparison test. The percentage of cortical infarction in the saline control group was 22.6 +/- 6.8% (mean+/-S.D.) of contra-lateral hemisphere, and in the 30 mg/kg/h NXY-059-treated group was 17.4% +/- 6.8% (NS). Plasma concentration (microM/l) of NXY-059 in the 30 mg/kg/h group was 80.2 +/- 52.2 (n=9), while in the 60 mg/kg/h group plasma concentration (microM/l) of NXY-059 was 391.0 +/- 207.0 (n=10). Infarction in the 60 mg/kg/h NXY-059-treated group was significantly reduced (P=0.009) to 14.5 +/- 5%. Our preliminary data demonstrate that administration of NXY-059 (60 mg/kg/h for 24 h) ameliorates cortical infarction in rats subjected to permanent focal cerebral ischemia with 24 h survival.     

3-硝基丙酸预处理对大鼠局灶性脑缺血再灌注损伤的保护作用

目的:研究3-硝基丙酸预处理对大鼠局灶性脑缺血再灌注损伤的作用。方法:采用线栓法建立大鼠局灶性脑缺血再灌注损伤模型,将38只大鼠随机分成4组,假手术组、缺血组、3-硝基丙酸预处理组、3-硝基丙酸预处理+5-羟癸酸盐组。观察各组脑梗死体积和线粒体标志酶活性变化。结果:与缺血组比较,3-硝基丙酸预处理组脑梗死体积明显减少(自23.57±7.83％减至10。50±2.37％),线粒体标志酶活性明显增高,差异具有显著性(P0.01)结论:3-硝基丙酸预处理对大鼠局灶性脑缺血再灌注损伤具有保护作用,其机理与开放线粒体ATP敏感性钾通道,维护线粒体功能和提高其耐受性有关。     

Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice.

In a process called ischemic preconditioning, a brief, sublethal ischemic insult protects tissue from subsequent, more severe injury. There have been no reports of rapidly induced ischemic preconditioning. The authors sought to develop a model of cerebral ischemic preconditioning in the mouse that can be applied to transgenic and knockout animals. They found that brief middle cerebral artery (MCA) occlusion only minutes before a severe ischemic insult can induce protection from that insult. Here the investigators describe a mouse model of preconditioning using intraluminal MCA occlusion as both the conditioning and the test stimulus. One or three 5-minute episodes of ischemia given 30 minutes before MCA occlusion for 1 or 24 hours (permanent occlusion) confer significant protection as assessed by infarct volume measurements 24 hours later.