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目的探讨orexin-1受体(OX1R)和orexin-2受体(OX2R)拮抗剂对睡眠剥夺(SD)的戊四氮(PTZ)致疒间大鼠癫疒间发作及脑组织病理学变化的影响。方法雄性Wistar大鼠48只,随机分为正常对照(NC)组、PTZ组、SD+PTZ(SD)组、SD+PTZ+二甲基亚砜(DMSO)组、SD+PTZ+OX1R拮抗剂SB334867(SB)组和SD+PTZ+OX2R拮抗剂TCS OX229(TCS)组。采用改良多平台SD法,SD前及SD 48 h分别给予相应组大鼠侧脑室注射DMSO、SB或TCS。SD 72 h给予各组腹腔注射PTZ 50 mg/kg诱导癫疒间发作;观察各组大鼠癫疒间发作的潜伏期、发作等级评分、发作持续时间及死亡率;应用常规染色法观察海马的病理学变化,免疫荧光法(BrdU标记)观察神经细胞增殖的变化。结果 (1)与PTZ组比较,SD组及DMSO组疒间性发作的潜伏期明显缩短,发作等级评分、持续时间及死亡率明显增加(均P<0.001),海马CA3区神经元损害加重,海马齿状回门区和颗粒细胞下层BrdU阳性细胞数显著增多(P<0.001);SD组与DMSO组间差异无统计学意义。(2)与SD组比较,SB组和TCS组大鼠疒间性发作的潜伏期明显延长,发作等级评分、持续时间及死亡率明显下降(均P<0.05),海马CA3区神经元损害明显减轻,齿状回门区和颗粒下层BrdU阳性细胞数减少(均P<0.05);TCS组的变化较SB组更显著(P<0.05～0.01)。结论 Orexin受体拮抗剂尤其是OX2R拮抗剂可通过减轻海马CA3区神经元的损害和抑制齿状回区细胞增殖减轻SD对PTZ诱导癫疒间发作的不利影响。
Objective To investigate the effects of orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R) antagonists on epileptic seizures and brain histopathological changes in pentylenetetrazole (PTZ) -induced epileptic rats induced by sleep deprivation influences. Methods Forty-eight male Wistar rats were randomly divided into normal control group (NC), PTZ group, SD + PTZ (SD) group, SD + PTZ + DMSO group, SD + PTZ + OX1R antagonist SB334867 (SB) group and the SD + PTZ + OX2R antagonist TCS OX229 (TCS) group. Using modified multi-platform SD method, DMSO, SB or TCS were injected into the lateral ventricle of the rats in the corresponding groups before and at 48 h after SD. SD 72 h were given intraperitoneal injection of PTZ 50 mg / kg induced epilepsy seizures; epileptic seizures were observed in each group of incubation period, seizure grade, duration of seizure and mortality; the use of conventional staining observed hippocampal disease Neutrophil proliferation was observed by immunocytochemistry (BrdU labeling). Results (1) Compared with PTZ group, the latent period of intersympathetic seizure was significantly shortened in SD group and DMSO group, and the seizure grade, duration and mortality were significantly increased (both P <0.001) The numbers of BrdU positive cells in dentate gyrus and granulosa cells were significantly increased (P <0.001). There was no significant difference between SD group and DMSO group. (2) Compared with SD group, the latency of intersexual seizure in SB group and TCS group was significantly prolonged, seizure grade score, duration and mortality were significantly decreased (all P <0.05), neuronal damage in hippocampal CA3 area was significantly reduced (P <0.05 ~ 0.01). The number of BrdU positive cells in the dentate gyrus and granular layer decreased (all P <0.05). The changes in TCS group were more significant than those in SB group (P <0.05 ~ 0.01). Conclusion Orexin receptor antagonists, especially OX2R antagonists, can reduce the detrimental effects of SD on PTZ-induced epileptic seizures by alleviating neuronal damage in hippocampal CA3 region and inhibiting dentate gyrus cell proliferation.