Comparison of two rat models of cerebral ischemia under hyperglycemic conditions

Hyperglycemia worsens outcome of stroke either in the clinical setting or in animal models. In the present study, two focal cerebral ischemia models, permanent middle cerebral artery occlusion (MCAO, 3-4 h) and reversible MCAO (1 h ischemia + 3 h reperfusion), under hyperglycemic conditions were compared. Using 2,3,5-triphenyltetrazolium chloride staining to define viable tissue, this resulted in the infarction area being confined primarily to the cerebral cortex in the permanent MCAO group, while it extended to the subcortical area in the reversible MCAO group, and the lesion areas were respectively 27.7 +/- 5.3% and 46.8 +/- 12.0% of the ipsilateral hemisphere (P = 0.012). Hyperglycemia accelerated the cerebral damage compared to normoglycemia and ascorbic acid pre-treatment maintained tissue viability during the acute phase of hyperglycemic MCAO. In conclusion, hyperglycemia combined with either of the two MCAO models resulted in rapid infarction associated with increased oxidative stress. The hyperglycemic models are suitable for pharmaceutical therapeutic studies of antioxidant efficacy.     

阿片肽与缺血性脑损伤

阿片肽及其受体系统在缺血性脑损伤的病理生理发展过程中具有非常重要的作用。其在缺血性脑损伤中的作用尚存争议，本文综述了阿片肽及其受体系统在缺血性脑损伤中的作用及其可能机制，有助于探索阿片肽在围术期的合理应用，为缺血性脑损伤防治研究提供新方向。     

Arachidonic acid metabolite production following focal cerebral ischemia: time course and effect of meclofenamate

Arachidonic acid metabolites have been implicated in the development of cerebral edema following ischemia. To define the time course of metabolite production, subtemporal craniectomies were performed on 60 male Sprague-Dawley rats (350-400 g). Thirty rats underwent middle cerebral artery occlusion while 30 rats underwent craniectomy alone. Five rats in each of two groups (middle cerebral artery occlusion and sham) were sacrificed at 15 minutes, 1 hour, 4 hours, 1 day, 3 days, and 6 days. The cerebral hemispheres were removed and divided in the midsagittal plane. Each hemisphere was immediately frozen in isopentane cooled in dry ice and stored at -70 degrees C. Tissue prostaglandins E2 and 6-keto F1 alpha, and leukotrienes (LT) B4 and C4 were measured by radioimmunoassay. Prostaglandin E2 and 6-keto prostaglandin F1 alpha were significantly elevated at 15 minutes in the middle cerebral artery occlusion hemispheres (p less than 0.05). Prostaglandins were not significantly elevated after 15 minutes. LT B4 and C4 were never significantly elevated. Meclofenamate, a nonsteroidal anti-inflammatory agent, was administered to 21 additional rats. Seven controls underwent middle cerebral artery occlusion alone, 7 were given intraperitoneal meclofenamate (20 mg/kg) 30 minutes prior to middle cerebral artery occlusion, and 7 underwent middle cerebral artery occlusion followed immediately by intraperitoneal meclofenamate (20 mg/kg). The animals were sacrificed at 15 minutes and similarly studied. There was a significant reduction of prostaglandin E2 and 6-keto prostaglandin F1 alpha following pretreatment with meclofenamate (p less than 0.01 and p less than 0.05). In pretreated rats, leukotrienes were not affected by meclofenamate. Similarly, prostaglandins and leukotrienes did not change when meclofenamate was administered after middle cerebral artery occlusion. We conclude that cyclo-oxygenase metabolite production begins within 15 minutes of middle cerebral artery occlusion. Treatment with meclofenamate prior to middle cerebral artery occlusion significantly reduced cyclooxygenase metabolite production, suggesting a protective effect of meclofenamate against ischemia-induced elevations of vasoactive prostaglandins implicated in the development of cerebral edema. Lipoxygenase metabolite production was not affected by middle cerebral artery occlusion or pharmacological intervention.     

Histopathologic consequences of hyperglycemic cerebral ischemia during hypothermic cardiopulmonary bypass in pigs

BACKGROUND: This study examined whether 34 degrees C or 31 degrees C hypothermia during global cerebral ischemia with hyperglycemic cardiopulmonary bypass (CPB) in surviving pigs improves electroencephalographic (EEG) recovery and histopathologic scores when compared with normothermic animals. METHODS: Anesthetized pigs were placed on CPB and randomly assigned to 37 degrees C (n = 9), 34 degrees C (n = 10), or 31 degrees C (n = 8) management. After increasing serum glucose to 300 mg/dL, animals underwent 15 minutes of global cerebral ischemia by temporarily occluding the innominate and left subclavian arteries. Following reperfusion, rewarming, and termination of CPB, animals were recovered for 24 (37 degrees C animals) or 72 hours (34 degrees C and 31 degrees C animals). Daily EEG signals were recorded, and brain histopathology from cortical, hippocampal, and cerebellar regions was graded by an independent observer. RESULTS: Before ischemia, serum glucose concentrations were similar in the 37 degrees C (307+/-9 mg/dL), 34 degrees C (311+/-14 mg/dL), and 31 degrees C (310+/-15) groups. By the first postoperative day, EEG scores in 31 degrees C animals (4.2+/-0.6) had returned to baseline and were greater than those in the 34 degrees C (3.4+/-0.5) and 37 degrees C (2.5+/-0.4) groups (p < 0.05, respectively, between groups). Cooling to 34 degrees C showed selective improvement over 37 degrees C in hippocampal, temporal cortical, and cerebellar regions, but the greatest improvement in all regions occurred with 31 degrees C. Cumulative neuropathology scores in 31 degrees C animals (13.5+/-2.2) exceeded 34 degrees C (6.8+/-2.2) and 37 degrees C (1.9+/-2.1) animals (p < 0.05, respectively, between groups). CONCLUSIONS: Hypothermia during CPB significantly reduced the morphologic consequences of severe, temporary cerebral ischemia under hyperglycemic conditions, with the greatest protection at 31 degrees C.     

Pulsed ultrasound attenuates the hyperglycemic exacerbation of myocardial ischemia–reperfusion injury

ObjectiveAcute hyperglycemia during myocardial infarction worsens outcomes in part by inflammatory mechanisms. Pulsed ultrasound has anti-inflammatory potential in bone healing and neuromodulation. We hypothesized that pulsed ultrasound would attenuate the hyperglycemic exacerbation of myocardial ischemia–reperfusion injury via the cholinergic anti-inflammatory pathway.MethodsAcute hyperglycemia was induced in wild-type C57BL6 or acetylcholine-receptor knockout (α7nAChR^-/-) mice by intraperitoneal injection of glucose. Pulsed ultrasound (frequency 7 MHz, bursting mechanical index 1.2, duration 1 second, repeated every 6 seconds for 2 minutes, 20-second total exposure) was performed at the spleen or neck after glucose injection. Separate mice underwent vagotomy before treatment. The left coronary artery was occluded for 20 minutes, followed by 60 minutes of reperfusion. The primary end point was infarct size in explanted hearts.ResultsSplenic pulsed ultrasound significantly decreased infarct size in wild-type C57BL6 mice exposed to acute hyperglycemia and myocardial ischemia–reperfusion injury (5.2% ± 4.4% vs 16.9% ± 12.5% of risk region, P = .013). Knockout of α7nAChR abrogated the beneficial effect of splenic pulsed ultrasound (22.2% ± 12.1%, P = .79 vs control). Neck pulsed ultrasound attenuated the hyperglycemic exacerbation of myocardial infarct size (3.5% ± 4.8%, P = .004 vs control); however, the cardioprotective effect disappeared in mice that underwent vagotomy. Plasma acetylcholine, β2 adrenergic receptor, and phosphorylated Akt levels were increased after splenic pulsed ultrasound treatment.ConclusionsPulsed ultrasound treatment of the spleen or neck attenuated the hyperglycemic exacerbation of myocardial ischemia–reperfusion injury leading to a 3-fold decrease in infarct size. Pulsed ultrasound may provide cardioprotection via the cholinergic anti-inflammatory pathway and could be a promising new nonpharmacologic, noninvasive therapy to reduce infarct size during acute myocardial infarction and improve patient outcomes.     

七氟醚后处理对局灶性脑缺血-再灌注损伤的保护作用

目的评价在缺血后期及再灌注早期吸入不同浓度的七氟醚行后处理对大鼠局灶性脑缺血-再灌注损伤的保护作用及其剂量依赖性。方法雄性SD大鼠50只,随机分为空白对照组、吸氧组和0.5、1.0、1.5MAC七氟醚后处理组,每组10只。采用大脑中动脉线栓法阻闭(middle cerebral artery occlusion,MCAO)120min后再灌注72h制备局灶性脑缺血模型。各七氟醚后处理组于再灌注即刻的前20min和后10min给予不同浓度七氟醚吸入。再灌注后的24、48和72h行神经功能评分(NDS),并于最后一次评分后测定脑梗死容积比。结果0.5、1.0和1.5MAC组的脑梗死容积比分别为0.39±0.03,0.31±0.03和0.24±0.03(P<0.05),明显小于对照组0.53±0.05(P<0.05)。吸氧组为0.51±0.05,与对照组比差异无统计学意义。各个时间点七氟醚后处理组NDS明显优于对照组和吸氧组。结论在局灶性脑缺血-再灌注的缺血后期和再灌注早期吸入0.5、1.0和1.5MAC七氟醚行后处理均具有脑保护作用,并呈现剂量依赖性。     

小鼠局灶性脑缺血的脑血流动力学和脑损害的评价

目的　建立一种可靠的小鼠脑缺血模型,了解永久性和暂时性阻断血管后的脑病理生理变化。方法　 Ｃ Ｄ１ 小鼠,单侧大脑中动脉线栓阻断,监测脑血流,测量梗塞体积和血脑屏障破坏程度。结果　小鼠均出现成熟缺血核心区和半暗区。不同缺血／ 再灌注时间产生不同缺血损害和血脑屏障破坏,但有时限。结论　建立了一种可靠、复制性强的小鼠局灶性缺血模型。血脑屏障破坏在缺血损害中起重要作用。短时间缺血后的再灌注能减轻缺血性脑损害。     

热休克蛋白与脑缺血再灌注损伤

HSP作为一类结构保守、功能复杂的蛋白质家族,除了正常情况下维持细胞生理功能和内环境的稳定之外,在脑缺血/再灌注损伤和细胞凋亡方面有着重要的意义。     

Leukocyte involvement in cerebral ischemia and reperfusion injury

Leukocytes have been postulated to contribute to cerebral ischemia and reperfusion injury. The present study implies that leukocytes have a deleterious effect in the brain following ischemia. We compared the alteration of cortical electrical activity following transient, incomplete cerebral ischemia in control and leukopenic rats by monitoring somatosensory evoked potentials and electroencephalographic activity. There was complete cessation of electroencephalographic activity, and the cortical peak of the evoked potential was abolished during ischemia in the control animals. However, when the animals were rendered leukopenic, there was maintenance of electroencephalographic activity with reduced amplitude and preservation of the cortical peak of the evoked response during the ischemic period. This indicates that when the animals are made leukopenic, even under ischemic conditions, the neurophysiologic functioning is still maintained to a certain extent.     

Reduced incidence of cerebral ischemia following rupture of intracranial aneurysms.

A randomized study was carried out to determine if the administration of reserpine and kanamycin to lower the concentration of vasoactive biogenic monoamines would reduce the incidence of cerebral vascular ischemic complications and death following the rupture of intracranial aneurysms. Twenty-six treated and twenty-eight control (untreated) patients were studied. In the preoperative period, eight control (untreated) patients developed symptomatic cerebral ischemia as opposed to one treated patient. There was no correlation between the preoperative clinical findings of ischemia and angiographic evidence of vasospasm. In the post-operative period four control and one treated patient developed symptomatic cerebral ischemia; vasospasm, as demonstrated by cerebral angiography, paralleled these findings.     

Cognitive deficits following traumatic brain injury produced by controlled cortical impact.

Traumatic brain injury produces significant cognitive deficits in humans. This experiment used a controlled cortical impact model of experimental brain injury to examine the effects of brain injury on spatial learning and memory using the Morris water maze task. Rats (n = 8) were injured at a moderate level of cortical impact injury (6 m/sec, 1.5-2.0 mm deformation). Eight additional rats served as a sham-injured control group. Morris water maze performance was assessed on days 11-15 and 30-34 following injury. Results revealed that brain-injured rats exhibited significant deficits (p less than 0.05) in maze performance at both testing intervals. Since the Morris water maze task is particularly sensitive to hippocampal dysfunction, the results of the present experiment support the hypothesis that the hippocampus is preferentially vulnerable to damage following traumatic brain injury. These results demonstrate that controlled cortical impact brain injury produces enduring cognitive deficits analogous to those observed after human brain injury.     

Relations between decision-making deficits and discriminating contingencies following brain injury

Deficits in decision-making characterized by failures to respond adaptively to consequences that follow responding are common following brain injury. To examine decision-making about consequences, individuals with and without acquired brain injury responded under different response-reinforcer contingencies. In two control conditions, reinforcement was contingent on responding and response repetition. Results showed responding (pressing four computer keys) by both groups produced similar amounts of reinforcement (money) and highlight equal sensitivity to money as a reinforcer. In subsequent experimental conditions, reinforcement was contingent upon varying responses. Results showed both groups produced variable response patterns, but injured subjects earned less reinforcement than controls. With instructions to vary responding across trials, injured subjects earned similar amounts of reinforcement as controls. Collectively, the results suggest reductions in sensitivity to contingencies may be present following injury and function as one behavioural mechanism of maladaptive decision-making.     

丙泊酚对全脑缺血/再灌注损伤大鼠保护作用研究

目的探讨丙白酚对大鼠全脑缺血/再灌注损伤（ischemia/reperfusion injury,I/RI）的保护作用。方法65只Wistar雄性大鼠采用完全随机法分为5组：假手术组（S组）、缺血/再灌注(ischemia/reperfusion,I/R)组(I/R)组、丙泊酚组1(P1)、丙泊酚组2(P2)、丙泊酚组...     

Focal brain injury results in severe cerebral ischemia despite maintenance of cerebral perfusion pressure.

Severe head injury often causes an increase in intracranial pressure (ICP) and decreases in cerebral blood flow (CBF) and cerebral oxygen delivery (CO2del). To determine if this reduction in CBF and CO2del would produce cerebral ischemia and if this reduction would be abrogated by maintaining global cerebral perfusion pressure (CPP), we studied CPP, ICP, CBF, CO2del, cerebral oxygen extraction ratio (CO2ER), and cortical water content (CWC) in a porcine model of focal cryogenic brain injury. Fifteen mature swine were randomized to two groups. The experimental group (n = 7) had a brain lesion and was studied for 24 hours. The control group (n = 8) was instrumented only. Cryogenic injury significantly increased ICP and decreased CBF and CO2del compared with controls. There were no significant differences in CPP between the groups for the entire experiment, and the CPP was well above the ischemic threshold. The CO2ER significantly increased in the first three hours after brain injury. However, CO2ER in experimental animals tended to decrease 12 hours after brain injury and was not significantly different from that in controls. Cryogenic injury significantly increased the CWC in the lesioned hemisphere. These data indicate that focal brain injury results in persistent ischemia despite the normalization of CPP, suggesting that a significant increase in cerebral vascular resistance (CVR) occurs after brain injury. We conclude that in addition to maintenance of CPP, intervention to reduce CVR may be important in the management of brain injury.     

Temporary cerebral ischemia. Effects of pentastarch or albumin on reperfusion injury.

Recent investigations have proposed that, after temporary ischemia, pentastarch may reduce microvascular permeability and reperfusion injury. However, this hypothesis has not been tested in the brain. Accordingly, after 180 min of temporary middle cerebral artery occlusion, the effect of pentastarch or albumin on blood-brain barrier permeability and cerebral injury was investigated in isoflurane-anesthetized rats. One of the following was maintained for the final 60 min of occlusion and throughout reperfusion: control-hematocrit was not manipulated; pentastarch-hematocrit was decreased to approximately 30% with pentastarch; or albumin-hematocrit was decreased (approximately 30%) with albumin. Part A (n = 21): 30 min of reperfusion was allowed, and blood-brain barrier permeability was determined with the indicator dye Evans Blue. Part B (n = 14): in different animals, 120 min of reperfusion was allowed, and cerebral injury (2,3,5-triphenyltetrazolium chloride stain) and edema (specific gravity) were assessed. Part C (n = 4): in different animals, the blood-brain barrier was evaluated by electron microscopy. Evans Blue (micrograms per gram brain tissue, mean +/- SD) was greater in the control (20.8 +/- 9.0) and albumin (15.5 +/- 7.3) groups versus the pentastarch (4.7 +/- 2.7) group (P less than 0.05). Brain injury (percent of hemisphere ipsilateral to occlusion) was less and specific gravity greater in the pentastarch (33 +/- 8 and 1.040 +/- 0.003 respectively) versus the albumin group (45 +/- 6 and 1.035 +/- 0.003). This study supports the hypothesis that during temporary cerebral ischemia, pentastarch decreases brain injury and edema.(ABSTRACT TRUNCATED AT 250 WORDS)     

血小板活化因子与脑缺血/再灌注损伤

血小板活化因子(plateht-activating factor,PAF)是由体内多种细胞在特定条件下所释放的一种活性强大的内源性介质.PAF在脑缺血,再灌注损伤中含量明显增高,对脑缺血,再灌注损伤的发生和发展可能起着主导作用.PAF的作用是由其特异性受体(一种G蛋白耦联受体)所介导的.PAF受体拮抗剂能通过降低PAF的浓度以及抑制PAF受体活性来减轻其脑损伤效应,从而起到脑保护作用.