Hawthorn extract reduces infarct volume and improves neurological score by reducing oxidative stress in rat brain following middle cerebral artery occlusion

In our present investigation the neuroprotective effect of alcoholic extract of Hawthorn (Crataegus oxycantha) was evaluated against middle cerebral artery occlusion induced ischemia/reperfusion injury in rats. Male Sprague–Dawley rats were pretreated with 100 mg/kg body weight of the extract by oral gavage for 15 days. The middle cerebral artery was then occluded for 75 min followed by 24 h of reperfusion. The pretreated rats showed significantly improved neurological behavior with reduced brain infarct when compared to vehicle control rats. The glutathione level in brain was found to be significantly (p < 0.05) low in vehicle control rats after 24 h of reperfusion when compared to sham operated animals. However, in Hawthorn extract pretreated rats the levels were found to be close to that of sham. Malondialdehyde levels in brain of sham and pretreated group were found to be significantly lower than the non-treated vehicle group (p < 0.05). The nitric oxide levels in brain were measured and found to be significantly (p < 0.05) higher in vehicle than in sham or extract treated rats.     

Rat middle cerebral artery occlusion by an intraluminal thread compromises collateral blood flow

We compared in Wistar rats collateral blood flow through leptomeningeal anastomoses after middle cerebral artery occlusion using craniotomy (‘extravasal occlusion'), which results in a small volume of cerebral infarction, and after intraluminal thread occlusion (‘intravasal occlusion'), which produces a large volume of cerebral infarction. Simultaneous laser–Doppler flowmetry with two probes placed on the cerebral cortex was used to measure and compare collateral blood flow. Extravasal occlusion caused a cortical blood flow reduction along a gradient in lateral direction, whereas blood flow reduction after intravasal occlusion was more uniformly distributed. It is concluded that permanent intravasal occlusion compromises collateral blood flow and therefore may not be a suitable model for measuring the ability of pharmacotherapeutic agents, if any, to improve collateral blood flow acutely after middle cerebral artery occlusion. The two models can be useful for testing drugs on parenchymal neuroprotective properties. Thereby, the intraluminal technique is preferred because of the possibility to study reperfusion damage when transient occlusion is applied.     

大鼠大脑中动脉阻断可逆性局灶脑缺血模型的研究

采用普通外科手术，以一顶端贫成光滑圆球的4—0单丝尼龙线，可逆性阻断大鼠一侧大脑中动脉（MCA）的血流，制备局灶性脑缺血及再灌注模型。通过观察动物的神经行为学、脑电生理学及病理形态学变化情况，对该模型的可靠性进行客观评价。结果表明这种改良栓线法制备的模型操作简单，与临床缺血性脑卒中的发病情况相近似，适用于局灶性脑缺血及再灌注损伤机制的研究以及治疗手段的评价。     

Cortical infarct volume is dependent on the ischemic reduction of perifocal cerebral blood flow in a three-vessel intraluminal MCA occlusion/reperfusion model in the rat

Occlusion of the middle cerebral artery (MCA) causes a reduction of cerebral blood flow (CBF), which shows a progressive decrease from the periphery to the core of the MCA territory. The severity of ischemia is dependent on the duration of the ischemic episode and degree of CBF reduction. Fixing the ischemic episode to 1 h, we have examined whether or not cortical infarct size was related to the degree of CBF reduction in a perifocal cortical area in rats. One-hour intraluminal MCA occlusion accompanied with bilateral common carotid artery (CCA) occlusion (three-vessel occlusion/reperfusion model) was carried out in Sprague-Dawley rats and CBF was monitored with laser-Doppler flowmetry in the fronto-parietal cortex, an area which is perifocal to the core of the MCA territory. Finally, infarct size was measured 7 days later and was related to the corresponding CBF decrease. Sequential ipsilateral CCA, MCA and contralateral CCA occlusions produced reductions of CBF to 96%, 52% and 33% of baseline, respectively. Cortical infarct volume was found to be dependent on the corresponding reduction of perifocal cortical CBF during the ischemic episode. These results show that the reduction of CBF in the periphery of the MCA territory during 1-h focal ischemia determines infarct size in a three-vessel occlusion/reperfusion model.     

Qualitative and quantitative analysis of the progressive cerebral damage after middle cerebral artery occlusion in mice

The middle cerebral artery occlusion (MCAO) in mice induces a focal cerebral ischaemia at the level of the tempo-parietal cortex. Histological staining and immunohistochemical markers were used to characterize the temporal progression of the cerebral infarct: both qualitative and quantitative analyses were performed at different days after the MCAO. At 3 days after MCAO, an extensive necrosis of the cerebral parenchyma was accompanied by extravasation and by massive oedema. After 7 days, GFAP marker showed a gliotic reaction with alteration of the astrocytes membrane permeability (S100 marker). Positivity for acid phosphatase staining indicated the presence of macrophages. At Day 14 and 21 following MCAO, the histological profile was essentially similar. Interestingly, at Day 7, 14 and 21, a previously unreported gliosis was observed in the subthalamic area. Quantitative analysis showed a significantly larger infarct volume at Day 3 (7.88 ± 1.95 mm³ ± S.E.M.) compared to Day 7 (4.28 ± 0.47 mm³ ± S.E.M.). At Day 14 and Day 21 the infarct volumes were further decreased to 2.00 ± 0.52 and 1.43 ± 0.39 mm³ ± S.E.M., respectively. These results suggest that it is important to consider the time of evaluation of cerebral ischaemia-induced cerebral infarct, especially in studies which aim to evaluate the neuroprotective effect of putative therapeutic agents.     

大鼠自体血栓大脑中动脉闭塞模型的改良

目的 进一步改良大鼠自体血栓大脑中动脉闭塞（MCAO）模型。方法 通过神经功能缺损评分，MRI，TTC染色，墨汁染色和病理观察。对改良血栓和普通血栓的栓塞效果进行比较。同时对不同体重大鼠对血栓直径的要求进行了观察。结果 6个改良血栓可形成与12个普通血栓相同的MCAO，两组之间神经功能缺损评分，梗死面积无显著性差异。结论 改良后保证了Willis环后半部的完整；动物不需两次手术，使操作时间明显缩短，使模型推广成为可能。     

Local hemodynamic changes during transient middle cerebral artery occlusion and recirculation in the rat: a [C]iodoantipyrine autoradiographic study

We evaluated acute alterations of local cerebral perfusion following 30 min of transient right proximal middle cerebral artery (MCA) clip-occlusion in the rat and following two intervals of postischemic reperfusion. Local cerebral blood flow (1CBF) was assessed by [¹⁴C]iodoantipyrine autoradiography. Brain temperature was controlled at 35.5–36.5°C throughout the experiment. We measured ICBF in four groups of rats: (a) sham-operated controls (n = 5), (b), following 30 min MCA occlusion (n = 5), (c) following 30 min of MCA occlusion with 15-min reperfusion (n = 6) and (d) following 30 min of MCA with 120-min reperfusion (n = 6). 1CBF was measured in seven regions of the ischemic and non-ischemic hemispheres. MCA occlusion induced an ipsilateral reduction of 1CBF, which was most severe in the parietal cortex (8.4 ± 4.0% of control, mean ± S.D.), and dorsolateral caudoputamen (20.0 ± 13.4% of control). 1CBF in the non-ischemic hemisphere and in ipsilateral regions lying outside the MCA territory also decreased significantly. 1CBF recovery was incomplete when assessed following only 15 min of reperfusion. Reperfusion of 120 min led to return of cortical CBF to control levels, but 1CBF in the caudoputamen remained depressed (50–55% of control values). Caudoputaminal CBF and cortical CBF values were highly correlated with one another under normal and ischemic conditions, but this correlation was disrupted following reperfusion. On the basis of these results, we speculate that, if a means were found to enhance the early recovery of 1CBF following transient ischemia, this might expand the therapeutic window of opportunity for the institution of other neuroprotective strategies.     

Histopathological effects of delayed reperfusion after middle cerebral artery occlusion in the anesthetized baboon

In patients with middle cerebral artery (MCA) territory stroke, attempts to recanalize the brain are currently being extended beyond the classic 3-h time window. Mechanical thrombectomy is particularly attractive as it may carry lesser risks of severe hemorrhagic transformation than thrombolysis. However, whether late reperfusion per se promotes hemorrhagic transformation and increases infarct volume as compared to permanent occlusion is unclear. There is no study of the histopathologic sequelae of late reperfusion following MCA occlusion (MCAo) in the non-human primate. Five young adult baboons completed a specially designed protocol of 20-h MCAo (under etomidate anaesthesia), followed by 4-week survival and finally perfusion-fixation. Infarct volume was measured histologically using validated stereological methods. The results were compared to our previously published series of 6 h and permanent MCAo performed with identical experimental and post mortem procedures. An infarct was present in each baboon, consistently involving the caudate head, internal capsule and putamen; the adjacent inferior frontal cortex was involved in one subject. Infarct volume was significantly larger than with 6 h MCAo, as expected, but did not differ from permanent MCAo. There was no evidence of hemorrhage around the infarcted area in any animal. We found that following a 20 h ischemic episode, the infarct volume was similar to that found with permanent occlusion, with no evidence of hemorrhagic transformation. Cautiously extrapolating to the human situation, our findings suggest that even late mechanical recanalization may not promote brain damage and could be considered in selected cases.     

l-Arginine ameliorates cerebral blood flow and metabolism and decreases infarct volume in rats with cerebral ischemia

Effects ofl-arginine, 300 mg/kg, i.p., on the regional cerebral blood flow (rCBF), brain metabolism, and infarct volume were examined in spontaneously hypertensive rats subjected to occlusion of both left middle cerebral artery and left common carotid artery. Rats treated withl-arginine had higher rCBF, determined by hydrogen clearance method, in the ischemic core (7 ± 1 ml/100 g/min, mean ± S.E.M.) and penumbral regions (16 ± 2) than did rats treated with saline (5 ± 0 and 7 ± 1, respectively). Simultaneously,l-arginine attenuated metabolic derangement in the ischemic tissue at 60 min, i.e. well maintained adenosine triphosphate (ATP) in ischemic region (1.29 ± 0.07 mmol/kg inl-arginine group vs. 1.05 ± 0.06 in saline group), and also close to normal levels in ATP (2.61 ± 0.02 mmol/kg vs. 2.45 ± 0.05), glucose (2.29 ± 0.12 mmol/kg vs. 1.80 ± 0.17) and lactate (1.63 ± 0.10 mmol/kg vs. 2.24 ± 0.21) in periischemic region. In another experiment, the effects ofl-arginine on rCBF in the subcortical regions and on infarct volume were evaluated.l-arginine, compared with saline, increased rCBF by 8 ml/100 g/min in the ischemic side and reduced infarct volume by 29% at 24 h of ischemia. These findings support thatl-arginine may be potentially useful for the treatment of acute cerebral ischemia.     

The transient intraluminal filament middle cerebral artery occlusion model as a model of endovascular thrombectomy in stroke

The clinical relevance of the transient intraluminal filament model of middle cerebral artery occlusion (tMCAO) has been questioned due to distinct cerebral blood flow profiles upon reperfusion between tMCAO (abrupt reperfusion) and alteplase treatment (gradual reperfusion), resulting in differing pathophysiologies. Positive results from recent endovascular thrombectomy trials, where the occluding clot is mechanically removed, could revolutionize stroke treatment. The rapid cerebral blood flow restoration in both tMCAO and endovascular thrombectomy provides clinical relevance for this pre-clinical model. Any future clinical trials of neuroprotective agents as adjuncts to endovascular thrombectomy should consider tMCAO as the model of choice to determine pre-clinical efficacy.     

A change of P-selectin immunoreactivity in rat brain after transient and permanent middle cerebral artery occlusion

Abstract

Although the role of an adhesion molecule such as P-selectin may be important in the pathogenesis of stroke, temporal, spacial, and cellular profiles of the expression ofsuch a protein has not been fully studied in the case ofthe middle cerebral artery (MCA) occlusion and reperfusion in rat brain. Change in expression of immunoreactive P-selectin was examined in rat brain after transient MCA occlusion (MCAO) in comparison to that of permanent occlusion with an anti-P-selectin monoclonal antibody. Western blot analyses were performed to ensure the selective detection of immunoreactive P-selectin protein with the monoclonal antibody using brain homogenates before and after MCAO. Temporal, spacial, and cellular changes of P-selectin expressions were evaluated with rat brain sections at 2, 8 h, 1 and 3 days of permanent MCAO, and at 2, 8 h, 1, 3 and 7 days of reperfusion after 1 h of transient MCAO. Western blot showed a single band with a molecular weight of 140 kOa for both cases with permanent occlusion and reperfusion. P-selectin immunoreactivity was not normally present in rat brain sections. However, it was expressed mainly in the post-capillary venules of the cerebral cortex and caudate in the MCA territory with a peak at 2-8 h after permanent occlusion and at 8 h to 1 day after the reperfusion. The expression was diminished by 1 day ofpermanent occlusion and 3 days of reperfusion. The maximum staining in the case of permanent MCAO was stronger than the case with reperfusion. However, spacial distribution of the staining was similar in the cerebral cortex and caudate between the cases with permanent or transient MCAO. These results suggest a different temporal but similar spacial and cellular expression of P-selectin immunoreactivity between permanent occlusion and reperfusion of MCA in rat brain. [Neural Res 1998; 20: 463–469]     

Regional cerebral blood flow after occlusion of the middle cerebral artery

Occlusions of the middle cerebral artery (MCA) are mostly of embolic origin (appr. 80%) and give rise to about one third of all ischemic strokes, most of these being major strokes. MCA occlusions lasting for less than 1/2 h are tolerated without occurrence of permanent tissue damage. Occlusions lasting between 1/2 h to 4-8 h lead to permanent tissue damage and neurological deficits that are proportional to the duration of occlusion. Maximal tissue damage is obtained after 4-8 h occlusion. A cerebral blood flow of 8-23 ml/100 gr/min is sufficient for cellular viability but insufficient for normal tissue function ("ischemic penumbra"). Cellular function is completely abolished in the interval 8-16 ml/100 gr/min and flow at that level is tolerated only for 1-3 h before neuronal death ensues. In the interval 18-23 ml/100 gr/min there is some functional activity although it is reduced. Experimental and clinical evidence suggests that flow in this interval may be tolerated for several days, months or even longer ("chronic ischemic penumbra"). After MCA occlusion the blood flow falls below 8 ml/100 gr/min in most cases and permanent MCA occlusion always leads to relatively large areas of frank infarction. The ischemic infarcts may be surrounded by collaterally perfused areas where the blood flow is pressure-dependent (impaired autoregulation) and quite commonly insufficient for normal neuronal function (below 23 ml/100 gr/min). Such collaterally perfused areas may include a "chronic ischemic penumbra". Emboli causing MCA occlusions commonly disintegrate and/or migrate more peripherally within the first few weeks post stroke. This leads to reperfusion and changes of ischemic infarcts into hyperemic infarcts where flow is severely increased. The vascular reactivity is completely abolished in hyperemic infarcts and the hyperemic state lasts for about two weeks. Probably, anemic infarcts are equivalent to ischemic infarcts while the hemorrhagic variety is equivalent to hyperemic infarcts. The "partial infarct" with selective neuronal necrosis occurs in experimental animals after MCA occlusions of less than four h but not after permanent MCA occlusion. The significance of partial infarction in human stroke is not clarified. The extent of irreversible tissue damage can be reduced only if therapy sets in within 4-8 h after the occlusion. If a "chronic penumbra" exists the extension of reversible tissue damage can be reduced if therapy aimed at increasing the blood flow in the penumbra sets in within weeks or even months after the stroke.(ABSTRACT TRUNCATED AT 400 WORDS)     

Iron intake increases infarct volume after permanent middle cerebral artery occlusion in rats

Experimental and clinical data suggest an important role of iron in cerebral ischaemia. We measured infarct volume and analysed the oxidative stress, and also the excitatory and inflammatory responses to brain injury in a rat stroke model after an increased oral iron intake. Permanent middle cerebral artery occlusion (MCAO) was performed in ten male Wistar rats fed with a diet containing 2.5% carbonyl iron for 9 weeks, and in ten control animals. Glutamate, interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were determined in blood samples before and at 2, 4, 6, 8, 24 and 48 h after MCAO, and thiobarbituric acid reaction substances (TBARS) were analysed at 48 h. Infarct volume was measured at 48 h by image analysis on brain slices stained with 1% TTC. Tissue iron was measured by atomic absorption spectrophotometry. Infarct volume was 66% greater in the iron fed rats than in the control group (178±49 mm³ versus 107±53 mm³, P<0.01). Significant higher levels of glutamate, IL-6 and TNF-α were observed in the group with iron intake (peak values were obtained at 6, 8 and 4 h, respectively). Iron-fed animals also showed significantly higher levels of TBARS than those receiving a normal diet (6.52±0.59 vs. 5.62±0.86 μmol/l, P=0.033) Liver iron stores (3500±199 vs. 352±28 μg Fe/g, P<0.0001), but not brain iron stores (131 vs. 139 μg Fe/g, P=0.617), were significantly higher in the iron fed rats group. These results suggest that iron intake is associated with larger infarct volumes after MCAO in the rat. This effect seems to be associated with higher oxidative stress, excitotoxicity and inflammatory responses.     

Testosterone increases and estradiol decreases middle cerebral artery occlusion lesion size in male rats

This study was undertaken to determine the effects of estrogen and testosterone on cerebral ischemic lesion size induced by middle cerebral artery (MCA) occlusion in male rats. Rats were gonadectomized and treated with testosterone, estrogen, or testosterone plus estrogen filled Silastic® pellets. The animals were divided into 6 groups: intact, intact+estrogen (E2), castrate, castrate+testosterone (T), castrate+E2, and castrate+T+E2. One week after treatment, cerebral ischemia was induced by MCA occlusion for 40 min, followed by reperfusion. After 24 h, rats were sacrificed and slices were then stained to assess lesion size. The presence of testosterone increased and the removal of testosterone decreased lesion size. A strong positive correlation (r²=0.922) between plasma testosterone concentrations and ischemic lesion size was observed. Estradiol treatment reduced ischemic area. In summary, the present study provides evidence that testosterone exacerbates and estrogens ameliorate ischemic brain damage in an animal model of cerebral ischemia.     

两种局灶性脑缺血再灌注模型的比较

目的比较两种大鼠大脑中动脉闭塞(middle cerebral artery occlusion,MCAO)局灶性脑缺血再灌注模型,寻找一种更加理想、稳定和可靠的模型。方法将22只SD大鼠随机分为颈外动脉插线组和颈总动脉插线组,采用线栓法建立大鼠脑缺血再灌注模型,MCAO2h再灌注24h,采用TTC染色和NF-κB免疫组化染色,并分别测定脑梗死体积和NF-κB表达量。结果两种插线方法都能造成大鼠局灶性脑梗死,颈外动脉插线组再灌注状态优于颈总动脉插线组,且脑梗死体积和NF-κB表达量均高于颈总动脉插线组。结论颈外动脉插线闭塞大脑中动脉是一种较为理想和可靠的大鼠MCAO局灶性脑缺血再灌注模型制作方法。     

D1和D2受体拮抗剂对乙灶性脑缺血梗塞体积及脑血流的影响

目的 研究多巴胺（ＤＡ）Ｄ１受体拮抗剂ＳＣＨ－２３３９０和Ｄ２受体拮抗剂Ｅｔｉｃｌｏｐｒｉｄｅ对可逆性乙灶性脑缺血梗塞体积及皮层半暗带脑血流的影响。方法 采用激光多普勒脑血流计测量大鼠可逆性乙灶性脑缺血各时相皮层半暗带脑血流,并于缺血后２４小时断头取脑切片,ＴＴＣ染色,计算机图样分析系统测量脑梗塞体积。结果 Ｄ１受体拮抗剂ＳＣＨ－２３３９０可明显缩小局灶性脑缺血梗塞体积,改善缺血期各时相皮层半暗带     

Effect of suture size and carotid clip application upon blood flow and infarct volume after permanent and temporary middle cerebral artery occlusion in mice

Problems with the intraluminal suture method for induction of focal cerebral ischemia in genetically altered mice include occurrence of subarachnoid hemorrhage (SAH) and variability of infarct volume. We hypothesized that use of 5-0 curved or 6-0 straight suture for carotid cannulation might decrease SAH and that the application of a microvascular clip to the common carotid artery (CCA) might decrease variability of infarct volume. The purpose of this study is to evaluate and explain the results of these technical modifications. Strain related differences in vascular anatomy were evaluated. Male C57BL/6 mice were divided into two groups for permanent and temporary middle cerebral artery occlusion (MCAO). Results of 5-0 curved suture and 6-0 straight suture insertion with and without CCA clip application were examined. Cerebral perfusion was monitored by laser-Doppler flowmetry and infarct volume was measured. After permanent MCAO, larger and more consistent infarct volumes resulted using CCA clip application with a 6-0 but not with a 5-0 suture. After temporary MCAO, the SAH rate was 12.5% with a 5-0 curved suture and 11.1% with a 6-0 straight suture. A 40% rate was observed in a pilot study with 5-0 straight suture. Infarct volume after temporary MCAO with a CCA clip was significantly larger and variability of infarct volume was smaller than without the CCA clip using 5-0 curved and 6-0 straight suture. In summary, SAH is less frequent using a 5-0 curved or 6-0 straight suture. Infarct volume is enlarged by application of a CCA clip (249).     

急性脑梗死患者脑动脉狭窄或闭塞后梗死灶体积的影响因素

目的：探讨急性脑梗死患者脑动脉狭窄或者闭塞后梗死灶体积的影响因素。方法选取2015年1～12月收入我院神经内科的急性脑梗死患者80例为研究对象,采用 mRS 评分判断患者的临床转归情况,采用 ROC 曲线预测患者临床转归梗死灶体积的最佳切点,采用 Logistic 多因素回归模型分析影响梗死灶体积的因素。结果梗死灶体积≤29．23 ml 时,其临床转归的效果较好,且灵敏度及特异度较高,ROC 曲线下面积为0．997。梗死灶体积≤29．23 ml 组和梗死灶体积＞29．23 ml 组患者,在年龄、NIHSS 评分、白细胞数、血清白蛋白、hs － CRP 、GHbA1c 水平及脑白质疏松程度方面比较,差异有统计学意义（P ＜0．05）。 Logistic 多因素分析显示,血清白蛋白是脑动脉狭窄或者闭塞后梗死灶体积＞29．23 ml 的保护因素（P ＜0．05）,GHbA1c 和脑白质疏松程度是危险因素（P ＜0．05）。结论血清白蛋白、GHbA1c 水平和脑白质疏松程度是急性脑梗死患者脑动脉狭窄或者闭塞后梗死灶体积的影响因素。     

Postischemic spontaneous hyperthermia and its effects in middle cerebral artery occlusion in the rat

This study examined the time course and effects of postischemic spontaneous hyperthermia after transient and permanent focal ischemia. Rats underwent a 90-min, 120-min, or permanent middle cerebral artery occlusion (MCAO). Body temperatures started rising 15-20 min after MCAO and reached 39-40.5 degrees C during the first hour. Sustained hyperthermia was observed during the rest of the first 24 h. In another experiment, rats were subjected to the same interventions, but a normothermic body temperature was maintained. Spontaneous hyperthermia significantly increased the infarct volumes measured 48 h after MCAO in all groups. Reperfusion 2 h after the onset of ischemia was not beneficial in the hyperthermic animals in contrast to the normothermic group. We also examined the effect of spontaneous hyperthermia on the temporal progression of infarcted and penumbral areas 4, 12, or 48 h after MCAO. During spontaneous hyperthermia, penumbral areas became infarcted areas more rapidly, which was most expressed at 4 h. These findings demonstrate that severe spontaneous hyperthermia can occur in rats after MCAO and that it not only increases the infarct volumes in both transient and permanent ischemia, but also accelerates the incorporation of penumbral areas into necrotic areas, which significantly decreases the window of opportunity for therapeutic interventions.     

Effect of the kappa-1 opioid agonist CI-977 on ischemic brain damage and cerebral blood flow after middle cerebral artery occlusion in the rat

The effects of the kappa-1 opioid agonist CI-977 upon the volume of ischemic brain damage (defined using quantitative neuropathology) and local cerebral blood flow (CBF) (defined using quantitative [¹⁴C]iodoantipyrine autoradiography) have been examined at 4 h and 30 min, respectively, after permanent middle cerebral artery (MCA) occlusion in halothane-anesthetised rats. Treatment with CI-977 (0.3 mg/kg, s.c.) 30 min before and 30 min after occlusion of the MCA reduced the volume of infarction in the cerebral hemisphere (reduced by 27% when compared to vehicle;P<0.05) and cerebral cortex (reduced by 32%;P<0.05), despite a marked and sustained hypotension, with only minimal effect on damage in the caudate nucleus. In the hemisphere contralateral to the occluded MCA, treatment with CI-977 (0.3 mg/kg, s.c.) 30 min prior to the induction of ischemia failed to demonstrate any significant effect on either the level of local CBF in any of the 25 regions examined or on the volume of low CBF determined by frequency distribution analysis. In the hemisphere ipsilateral to MCA occlusion, CI-977 failed to produce statistically significant alterations in either the level of local CBF in 23 of the 25 regions or on the volume of low CBF, but areas of hyperemia were observed in both the medial caudate nucleus and lateral thalamus (local CBF increased by 65% and 86%, respectively, when compared to vehicle). The results of the present study indicate that the kappa-1 opioid agonist CI-977 is neuroprotective in a rat model of focal cerebral ischemia where key physiological variables have been assessed throughout the entire post-ischemic period, and fail to demonstrate that the neuroprotective effects of CI-977 in this model are due to improved blood flow to ischemic tissue.