丹酚酸B对脑缺血再灌注大鼠神经细胞损伤和神经发生的影响

本文旨在观察丹酚酸B对脑缺血再灌注大鼠神经发生和神经细胞损伤的影响，探讨丹酚酸B促进机体功能恢复的作用环节。研究采用大鼠局灶性脑缺血再灌注模型，治疗给药，用BrdU法观察海马齿状回颗粒下层(sub-granular zone，SGZ)和侧脑室下层(sub-ventricular zone，SVZ)神经发生的变化；尼氏体染色观察神经细胞损伤；平衡杆法观察肢体功能恢复。结果显示，缺血后再灌注7 d，模型组SGZ和SVZ的BrdU细胞明显多于假手术组(P<0.05)，丹酚酸B(10 mg·kg^-1)显著增加SGZ和SVZ的BrdU细胞数目(P<0.01 vs模型组)；缺血再灌注14 d，模型动物缺血侧海马CA1区和皮层神经细胞明显减少，丹酚酸B(10 mg·kg^-1)明显改善神经细胞损伤(P<0.01 vs模型组)；同时，丹酚酸B(10 mg·kg^-1)明显促进缺血动物肢体功能恢复。以上结果表明，丹酚酸B能够增加脑缺血大鼠SVZ和SGZ的BrdU细胞数目，改善缺血区神经细胞损伤，促进肢体功能恢复，提示促进神经发生是丹酚酸B改善脑功能的重要环节。     

3H]ifenprodil binding to NMDA receptors in porcine hippocampal brain membranes

The present study characterized the behavioral effects of the selective alpha(2)-adrenoceptor antagonist, atipamezole, in a rat model of focal cerebral ischemia. Atipamezole (1 mg/kg, s.c.) or desipramine (5 mg/kg, i.p.), a noradrenaline reuptake blocker, was administered either as a single injection 2 days after ischemia induction or for 10 days thereafter (subacute administration). A subacute atipamezole treatment given 30 min before behavioral assessment improved performance in the limb-placing test (days 5, 7, 9, and 11) and in the foot-slip test (days 3 and 7), but not in the beam-walking test. There was no difference between experimental groups in behavioral performance following a single administration of atipamezole or following single or subacute administration of desipramine. The drug treatments did not attenuate the impairment of spatial cognitive performance of ischemic rats in the Morris water-maze test. These results suggest that repeated use-dependent release of noradrenaline by atipamezole facilitates the sensorimotor recovery following focal cerebral ischemia in rats.     

丹参多酚酸对脑梗死小鼠血管微循环的影响

目的 探究丹参多酚酸对脑梗死大鼠神经血管微循环及缺血侧血流的影响。方法 将大鼠随机分为假手术组、模型组、尼莫地平10 mg/kg组和丹参多酚酸低、高剂量组（10、25 mg/kg）。制备大鼠中动脉缺血模型,通过神经功能评分、2,3,5-三苯基氯化四氮唑染色以及采用激光散斑血流成像检测脑血流量,鉴定模型构建是否成功。各组大鼠按照分组进行给药,尼莫地平组ig尼莫地平10 mg/kg,丹参多酚酸组ip 10、25 mg/kg注射用丹参多酚酸,连续治疗7 d,1次/d。取脑组织分别进行2,3,5-三苯基氯化四氮唑染色染色评估脑梗死体积,伊文思蓝含量测定评估血、脑、脊液屏障结构完整性,免疫荧光染色测量血小板内皮细胞黏附分子（CD31）表达。采用Western blotting实验检测血管内皮生长因子（VEGF）、血管生成素-1(Ang-1)、磷酸甘油醛脱氢酶（GAPDH）蛋白表达。结果 与模型组相比,丹参多酚酸25 mg/kg组神经功能评分、脑梗死体积占比明显减低,脑血流量明显增加（P<0.05）;且缺血侧CD31相对表达明显减少;伊文思蓝含量以及VEGF与Ang1蛋白表达明显增加（P&l...     

Atropine and cerebral ischemic injury in the Mongolian gerbil

1. Cerebral ischemia of 5 min duration was induced in unanesthetized gerbils by bilateral occlusion of the carotid arteries.2. The extent of cerebral damage was assessed by the elevation of motor activity in comparison with control animals and by a histological assessment of the extent of neuronal degeneration in the CAl area of the hippocampus.3. Atropine, an antagonist of ACh, at either a low (1 mg/kg) or a high (10 mg/kg) dose administered 15 min prior to the ischemic episode, did not confer protection against cerebral ischemic damage.4. This finding suggests that ACh does not play a critical role in the generation of ischemia reperfusion injury.     

丹酚酸B对糖尿病肾病模型大鼠肾组织中Nrf-2和HO-1的影响

目的 观察不同剂量丹酚酸B对糖尿病肾病模型大鼠肾组织中转录因子NF-E2相关因子2（Nrf-2）和血红素加氧酶1（HO-1）的影响。方法 40只SPF级雄性SD大鼠随机分为对照组（不建模）、模型组、丹酚酸B低剂量组（10 mg/kg）、丹酚酸B高剂量组（20 mg/kg）。采用高糖高脂饮食联合腹腔注射链脲佐菌素（STZ,40 mg/kg）制备大鼠DN模型,建模后丹酚酸B处理组给予相应剂量药物灌胃,对照组及模型组给予等体积橄榄油灌胃,连续给药6周。处理结束后收集各组大鼠24 h尿液,检测24 h尿蛋白含量;取眼球血检测血糖、血肌酐、总胆固醇及三酰甘油水平。 采用免疫蛋白印迹（Western blot）和逆转录PCR（RT-PCR）检测肾组织中Nrf-2、HO-1蛋白及mRNA表达情况,PAS染色观察各组肾组织病变程度。结果 与对照组相比,模型组的24 h尿蛋白、血糖、血肌酐、总胆固醇及三酰甘油含量升高,肾组织中Nrf-2、HO-1蛋白及mRNA的表达量升高,差异均有统计学意义（P＜0.05）,肾组织的病变程度加重;与模型组相比,丹酚酸B低、高剂量组的24 h尿蛋白、血糖、血肌酐、总胆固醇及三酰甘油含量明显下降,肾组织中Nrf-2、HO-1蛋白及mRNA的表达量显著升高,差异均有统计学意义（P＜0.05）,肾组织的病变程度减轻,且丹酚酸B的效果呈剂量依赖性。结论 一定剂量的丹酚酸B可上调肾组织中Nrf-2及HO-1的表达,抵抗氧化应激。     

白三烯受体拮抗剂ONO-1078对大鼠短暂性全脑缺血的神经保护作用

AIM: To determine whether ONO-1078 {pranlukast, 4-oxo-8-[p-(4-phenylbutyloxy)benzoyl-amono]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate), a potent leukotriene receptor antagonist, possesses a neuroprotective effect on global cerebral ischemia in rats, and to explore its possible mechanism of action. METHODS: Transient global cerebral ischemia was induced by four-vessel occlusion for 10 min and followed by 72-h reperfusion. ONO-1078(0.03-0.3mg/kg) and edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one, a neuroprotective agent) 10 mg/kg were ip injected 30 rain before ischemia and 1 h after reperfusion, and once a day afterward. Neurological outcome was evaluated before ischemia and 24, 48, 72 h after reperfusion. Neuron density, the expressions of N-methyl-D-aspartate (NMDA) receptor subunit proteins (NR1, NR2A, NA2B) and vascular cell adhesion molecule 1 (VCAM-1) in the cerebral cortex and hippocampus were measured at 72h after reperfusion. RESULTS: ONO-1078 (0.1,0.3mg/kg) and edaravone (10 mg/kg) improved ischemia-induced neurological deficiency and reduced neuron death.ONO-1078 (0.1, 0.3mg/kg) significantly inhibited the enhanced expression of NMDA receptor subunit protein NR2A in the cortex and VCAM-1 in the hippocampus of ischemic rats. CONCLUSION: ONO-1078 possesses a neuroprotective effect on global cerebral ischemia in rats, and its mechanism may be partly related to the inhibition of the upregulation of NR2A and VCAM- 1 in different regions of the brain.     

Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist, on transient global cerebral ischemia in rats

AIM: To determine whether ONO-1078 {pranlukast, 4-oxo-8-[p-(4-phenylbutyloxy)benzoyl-amono]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate}, a potent leukotriene receptor antagonist, possesses a neuroprotective effect on global cerebral ischemia in rats, and to explore its possible mechanism of action. METHODS: Transient global cerebral ischemia was induced by four-vessel occlusion for 10 min and followed by 72-h reperfusion. ONO-1078 (0.03-0.3 mg/kg) and edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one, a neuroprotective agent) 10 mg/kg were ip injected 30 min before ischemia and 1 h after reperfusion, and once a day afterward. Neurological outcome was evaluated before ischemia and 24, 48, 72 h after reperfusion. Neuron density, the expressions of N-methyl-Daspartate (NMDA) receptor subunit proteins (NR1, NR2A, NA2B) and vascular cell adhesion molecule 1(VCAM-1) in the cerebral cortex and hippocampus were measured at 72 h after reperfusion. RESULTS: ONO-1078 (0.1, 0.3 mg/kg) and edaravone (10 mg/     

Effects of emopamil on postischemic blood flow and neuronal damage in rat brain

Summary The effects of the calcium entry blocker emopamil on physiological variables, local cerebral blood flow (LCBF) and on hippocampal cell damage were evaluated after 10 min of forebrain ischemia in the rat. LCBF was determined with the ¹⁴C-iodoantipyrine technique after 2, 10, and 60 min of postischemic recirculation. Histological evaluation was performed 7 days after ischemia in cortical and hippocampal tissue by determination of the percentage of necrotic neurons. Preischemic application of emopamil [4 mg/kg racemate or 2 mg/kg (S)-emopamil; i.v.] caused increases in LCBF in cortical areas but did not alter blood flow in the hippocampus at 2 min of recirculation. After 10 and 30 min of flow resumption no differences in LCBF between drug-treated and control animals were observed. In the histological series (S)-emopamil was applied at doses of 2, 4 or 6 mg/kg before the induction of ischemia. After 7 days of postischemic recovery, neuronal damage was significantly reduced by the calcium antagonist in hippocampal CA 1 sector at all doses tested, the most prominent effects being observed with the lowest dose. At this dose cell loss in the Ca3 sector was also reduced. In cortical tissue the number of necrotic cells remained unchanged by emopamil treatment. It is concluded that the calcium antagonist emopamil can reduce ischemia-induced neuronal cell damage. The compound improves circulation in cortical tissue only during early recovery but not at later phases of reflow, i.e. the period of delayed hypoperfusion. These increases in blood flow are not of crucial importance for ultimate neuronal death in this area. The ameliorative action of emopamil on the survival of hippocampal neurons is not associated with blood flow changes and therefore seems to reflect a direct effect on cerebral parenchyma. Send offprint requests to G. W. Bielenberg at the above address     

丹参酮ⅡA和丹酚酸B抗心脑缺血的比较研究

目的：比较研究等剂量的丹参酮ⅡA、丹酚酸B及其等质量混合物对4种常用心脑缺血整体动物模型的影响,为临床用药选择提供依据。方法：复制垂体后叶素和结扎冠脉所致大鼠实验性心肌缺血模型,双侧颈总动脉结扎所致大鼠实验性脑缺血模型,线栓所致大鼠实验性脑缺血-再灌注模型,按50 mg·kg^-1·wt^-1灌胃给予丹参酮ⅡA、丹酚酸B及其等质量混合物,观察相应缺血指标。双侧颈总动脉结扎模型尚测定脑组织中相关生化指标,包括一氧化氮（NO）、一氧化氮合酶（NOS）、钠-钾ATP酶（Na^＋-K^＋ATPase）、钙-镁ATP酶（Ca^2＋-Mg^2＋ATPase）、丙二醛（MDA）。结果：丹参酮ⅡA及混合物对急性心肌缺血的作用优于丹酚酸B,尤其是对垂体后叶素所致的一过性心肌缺血;丹酚酸B仅在缺血时间较长的冠脉结扎模型中表现一定作用。在两种脑缺血模型中,丹酚酸B及混合物均表现较好的拮抗作用,该作用与丹酚酸B强抗氧化能力和对Ca^2＋-Mg^2＋ATPase降低的抑制有关。结论：丹参酮ⅡA、丹酚酸B在心脑缺血的治疗中具有不同的作用特点,在相关药物应用时,应根据临床需要进行恰当选择;二者对心、脑缺血均有一定的协同作用,提示其联合用药可提高疗效,提升药物的临床价值。     

丹酚酸胶囊对急性心肌缺血犬的保护作用

目的：观察丹酚酸胶囊的抗心肌缺血作用。方法：56只体重为（12±2）kg的健康Beagle犬,雌雄兼用,随机分为假手术组,模型对照组、高（100mg／kg）、中（50mg／kg）、低（25mg／kg）剂量的丹酚酸胶囊组,丹参片组（275mg／kg）,地奥心血康胶囊组（100mg／kg）。采用结扎冠状动脉前降支法致Beagle犬急性心肌缺血,经十二指肠给药后,用心外膜电图标测法计算心肌缺血程度,硝基四氮唑蓝（NBT）组织化学染色法测定心肌梗死面积,检测血清中磷酸肌酸激酶（CK）和乳酸脱氢酶（LDH）,观察丹酚酸胶囊对心肌缺血损伤的保护作用。结果：丹酚酸胶囊可明显降低心肌缺血程度（∑-ST）,减少心肌缺血范围（N-ST）,缩小心肌梗死面积（MIS）,并能显著降低血清CK和LDH活力,明显减轻心肌细胞损伤程度。结论：丹酚酸胶裳对急性心肌缺血犬具有明显的保护作用。     

Protective effect of vinconate on ischemia-induced neuronal damage in the rat hippocampus.

The protective effect of vinconate, a vinca alkaloid derivative, on ischemia-induced neuronal damage was investigated using a model of rat forebrain ischemia caused by occlusion of four vessels. Hippocampal cell loss was observed histologically and neurochemically 5 days after 10 min of ischemia. Treatment with vinconate (50 and 200 mg/kg i.p.) before cerebral ischemia significantly suppressed neuronal cell loss in the hippocampal CA1 region and the decrease in the content of neuroactive amino acids in the hippocampus. The release of neuroactive amino acids in the hippocampus was significantly increased by cerebral ischemia. Pretreatment with vinconate (50 and 200 mg/kg i.p.) significantly attenuated the increased release of glutamic acid and aspartic acid, but not the release of gamma-aminobutyric acid (GABA), taurine and glycine. This suppressive effect of vinconate was antagonized by scopolamine (10(-5) M). The addition of vinconate (10(-11)-10(-4) M) had no effect on the binding of [3H]MK-801. These results indicate that pretreatment with vinconate attenuates the ischemia-induced release of excitatory amino acids into the extracellular space of the hippocampus via the stimulation of presynaptic muscarinic acetylcholine receptors. The present results also suggest that this suppressive effect of vinconate on the release of excitatory amino acids (glutamic acid and aspartic acid) may play a crucial role in the protective action of this agent against ischemia-induced neuronal damage in the hippocampus.     

Bioavailability of salvianolic acid B in conscious and freely moving rats

Salvianolic acid B is an herbal ingredient isolated from Salvia miltiorrhiza. The aim of this study was to apply an automated blood sampling system coupled to a simple liquid chromatographic system to determine the bioavailability of salvianolic acid B in stress-free rats. The plasma sample (25 microl) was vortex-mixed with 50 microl of internal standard solution (chloramphenicol 10 microg/ml in acetonitrile) to achieve protein precipitation. Salvianolic acid B in the rat plasma was separated using a reversed-phase C18 column (250 mm x 4.6 mm, 5 microm) with a mobile phase of acetonitrile-methanol-20mM NaH(2)PO(4) (adjusted to pH 3.5 with H(3)PO(4)) (20:10:70 v/v/v) containing 0.1mM 1-octanesulfonic acid, and the flow-rate of 1 ml/min. The UV detection wavelength was 286 nm. The concentration-response relationship from the present method indicated linearity over a concentration range of 0.5-200 microg/ml. Intra- and inter-assay precision and accuracy of salvianolic acid B fell well within the predefined limits of acceptability (<15%). The plasma sample of salvianolic acid B was further identified by LC-MS/MS in the negative ion mode using mass transition m/z 358.2 to the product ion m/z 196.9. After salvianolic acid B (100mg/kg, i.v.; 500 mg/kg, p.o.) was given in conscious and freely moving rats, the AUC were 5030+/-565 and 582+/-222 min microg/ml for intravenous (100 mg/kg) and oral (500 mg/kg) doses, respectively. The oral bioavailability of salvianolic acid B in freely moving rats was calculated to be 2.3%.     

鬼针草总黄酮通过ERK1/2/NF-κB通路减轻局灶性脑缺血大鼠认知功能障碍

摘要：目的 探讨鬼针草总黄酮（TFB）对局灶性脑缺血大鼠认知功能的影响及可能的作用机制。方法 72只大 鼠随机分为假手术组、模型组、阳性对照组（1 mg/kg尼莫地平）、低剂量TFB组（25 mg/kg）、中剂量TFB组（50 mg/kg）、 高剂量TFB组（100 mg/kg）,每组12只。采用改良线栓法建立局灶性脑缺血大鼠模型。Morris水迷宫实验检测大鼠 学习和记忆能力,尼氏染色观察大鼠海马组织病理结构变化,酶联免疫吸附法检测海马组织脑源性神经营养因子 （BDNF）、神经生长因子（NGF）、白介素-1β（IL-1β）、白介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）含量,Western blot 检测海马组织细胞外信号调节蛋白激酶（ERK）1/2、p-ERK1/2、核转录因子（NF）-κB p65和p-NF-κB p65蛋白表达。 结果 与假手术组比,模型组大鼠逃避潜伏期延长,穿越平台次数减少,海马组织BDNF和NGF含量均降低,IL-1β、 IL-6和TNF-α含量以及p-ERK1/2和p-NF-κB p65蛋白表达水平均升高（P＜0.05）。与模型组比,第2天之后高剂量 TFB组和阳性对照组大鼠平均逃避潜伏期均降低（P＜0.05）,中、高剂量TFB组和阳性对照组大鼠穿越平台次数增 加,海马组织BDNF和NGF含量升高（P＜0.05）,IL-1β、IL-6和TNF-α含量以及p-ERK1/2和p-NF-κB p65蛋白表达 水平均降低,具有剂量依赖性（P＜0.05）。阳性对照组和高剂量TFB组大鼠各检测指标比较差异无统计学意义（P＞ 0.05）。结论 TFB可改善局灶性脑缺血大鼠的认知功能,其作用机制可能与抑制ERK1/2/NF-κB信号通路的传导 有关。     

Salvianolic acid B protects the memory functions against transient cerebral ischemia in mice

The objective of this work was to study the protective effects of salvianolic acid B (Sal B) on the dysfunctions of learning and memory induced by transient cerebral ischemia in mice. The mechanisms of its actions also were researched both in vivo and in vitro. The model of dysfunction of learning and memory induced by transient cerebral ischemia in mice was used. One trail passive avoidance tests were used to evaluate the learning and memory functions and experiments in vitro were employed to observe the antioxidative effects of Sal B. Cerebral transient ischemia would impair the function of memory in mice. In step down test. the error number and latency were 2.63 and 120.5 in control group and were 1.35 and 234.4 respectively in sham operated group (p < 0.05). In Sal B treated groups, the error number was less and latency was longer significantly than those of control group. Meanwhile. 3 and 10 mgkg(-1) of Sal B iv. reduced the malondialdehyde contents in cortex, hippocampus and striatum of cerebral transient ischemia rat ion vivo. Sal B 10--100 nmol L(-1) also inhibited lipid-peroxidation and scavenged free hydroxyl radicals in vitro. As conclusion. Sal B ameliorated learning and memory dysfunctions induced by cerebral transient ischemia. Its actions might be related to its antioxidant activity.     

Effect of obzidan on cerebral blood flow in acute cerebral ischemia

The effect of obsidan on the local cerebral circulation was studied in cats with normal brain circulation and under acute cerebral ischemia. It was demonstrated that obsidan (0.2 mg/kg) increased local cerebral circulation, while on being given in a dose of 1 mg/kg it lowered it in cats with normal brain circulation. In animals with stroke (both on the side with normal circulation and on the side of cerebral ischemia) obsidan (0.2 mg/kg) significantly decreased the local cerebral circulation and destroyed autoregulation of the brain circulation.     

dl-3-正丁基苯酞对内皮素诱导脑缺血大鼠行为学的改善研究

目的探讨dl-3-正丁基苯酞对内皮素诱导脑缺血大鼠行为学的改善作用及其作用机制。方法采用向纹状体、皮层注射内皮素-1制作大鼠脑缺血模型。大鼠随机分为假手术组、模型组和dl-3-正丁基苯酞组。dl-3-正丁基苯酞组每日ig 70 mg/kg,起始于缺血后1周,持续给药2周。采用平衡木实验、粘性标签试验和圆筒试验评价神经功能恢复情况,应用免疫荧光技术观察海马齿状回新生神经细胞的情况。结果 dl-3-正丁基苯酞对脑缺血大鼠运功功能的恢复有明显的改善,明显促进海马齿状回的新生神经细胞增多,增加双皮质素(DCX)阳性细胞总树突长度。结论 dl-3-正丁基苯酞不仅能够对脑缺血后大鼠的运动功能有明显的改善,而且促进脑缺血后大鼠的神经再生,对脑缺血所致的神经细胞损坏的治疗提供参考。     

Neuroprotective properties of 5-HT1A receptor agonists in rodent models of focal and global cerebral ischemia.

5-Hydroxytryptamine1A (5-HT1A) receptor agonists have been shown to inhibit the activity of hippocampal, cortical, and dorsal raphé neurons. We tested urapidil and a new 5-HT1A agonist, CM 57493 [4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridine ], for their neuroprotective activity in models of focal and global cerebral ischemia in rodents. After middle cerebral artery-occlusion (MCA-0) in mice, the infarct size was reduced dose dependently by both urapidil and CM 57493. In MCA-occluded rats, CM 57493 (1 and 5 mg/kg) reduced the cortical infarct volume by 30% and application of 10 mg/kg CM 57493 led to a 40% reduction in the cortical infarct volume. The striatal damage could not be influenced by CM 57493 treatment. Furthermore, 1 and 5 mg/kg CM 57493 significantly reduced the neuronal damage within the CA1 sector of the rat hippocampus after 10 min of forebrain ischemia followed by 7 days of recovery. Measurement of cerebral and rectal temperature revealed that the neuroprotective effect of CM 57493 was not caused by a hypothermic effect. We assume that the neuroprotective activity of 5-HT1A agonists is mediated by an inhibitory action on neurons.     

巴曲抗栓酶对沙土鼠脑缺血再灌注期间纹状体多巴胺含量的影响

目的 :研究巴曲抗栓酶 [batroxobin(DF 52 1) ]对沙土鼠脑缺血再灌注期间纹状体多巴胺(dopamine ,DA)和海马ATP含量变化的影响。方法 :阻断沙土鼠双侧颈总动脉制备前脑缺血再灌注模型 ,沙土鼠 4 0只分成 5组 ,假手术组、脑缺血组、对照组、巴曲抗栓酶Ⅰ组 (8BU·kg- 1)和巴曲抗栓酶Ⅱ组 (16BU·kg- 1) ,每组 8只。沙土鼠于脑缺血10min或再灌注 6 0min时处死 ,分别测定各组海马ATP ,ADP ,AMP含量和纹状体多巴胺的含量。结果 :脑缺血组海马ATP含量和纹状体DA含量均明显低于假手术组。对照组 (0 .9%氯化钠注射液 )再灌注 6 0min时纹状体DA与海马ATP含量明显高于脑缺血组 ,但明显低于巴曲抗栓酶Ⅰ ,Ⅱ组。结论 :巴曲抗栓酶可促进脑缺血再灌注期间海马ATP含量的恢复和减少纹状体多巴胺的释放     

Cerebral ischemia in gerbils: improvement of survival after postischemic treatment with oligo-prostaglandin B

Gerbils were subjected to bilateral carotid artery occlusion for either 15 or 20 min. After ischemia the animals were injected i.p. with oligo-prostaglandin B (oligo-PGB; trimer of 16,16'-dimethyl-15-dehydro-prostaglandin B1) dissolved in 4% sodium-bicarbonate, or with the vehicle. The dosing regimen of oligo-PGB was 0.5, 1, 2, 5, 10 mg/kg injected 5 min postischemia, or 1 mg/kg injected 30, 60, 90, 120 min after ischemia, or 10 mg/kg injected 5 min and 24 h postischemia. Behaviour of the animals and their mortality were studied for 14 days after ischemia. Administration of the drug did not affect recovery of the electrical activity in the brain and did not reduce the number of postischemic seizures. Following 15 min ischemia, administration of oligo-PGB resulted in statistically valid improvement of survival (P less than 0.04 or better) in all treatment groups. After 20 min ischemia only the double injection (10 mg/kg at 5 min and 24 h postischemia) resulted in a substantial survival improvement (64%, P less than 0.005). The mechanism of the drug action is unknown but, based on the available data, the authors believe it to be related to the modification of arachidonic acid metabolism in the late postischemic period.     

Possible role of opioids and KATP channels in neuroprotective effect of postconditioning in mice

The present study was designed to investigate the possible role of opioids and K(ATP) channels in ischemic postconditioning-induced reversal of global cerebral ischemia and reperfusion (I/R) induced neuronal injury. Mice were subjected to global ischemia by bilateral carotid artery occlusion for 10 min followed by reperfusion for 24 h, to produce neuronal injury. Ischemic postconditioning was induced by three episodes of carotid artery occlusion and reperfusion of 10 s each, immediately after global ischemia. Morphine postconditioning was induced by administration of morphine (5 mg/kg i.v.), 5 min prior to reperfusion. Naloxone (5 mg/kg i.v.), opioid receptor antagonist, and glibenclamide (5 mg/kg i.v.), K(ATP) channel blocker were administered 10 min before global ischemia. Extent of cerebral injury was assessed by measuring cerebral infarct size using triphenyl tetrazolium chloride (TTC) staining. Short-term memory was evaluated using the elevated plus maze test, while degree of motor incoordination was evaluated using inclined beam-walking, rota-rod and lateral push tests. Bilateral carotid artery occlusion followed by reperfusion resulted in significant increase in infarct size, impairment in short-term memory and motor co-ordination. Ischemic/morphine postconditioning significantly attenuated I/R induced neuronal injury and behavioural alterations. Pretreatments with naloxone and glibenclamide attenuated the neuroprotective effects of ischemic/morphine postconditioning. It may be concluded that ischemic/morphine postconditioning protects I/R induced cerebral injury via activating opioid receptor and K(ATP) channel opening.