5-HT6受体拮抗剂SB271046对大鼠癫痫后认知功能障碍的作用被引量：3

The role of 5-HT6 receptor antagonist on cognitive dysfunction in rats with epilepsy

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摘要目的 5-羟色胺6受体(5-hydroxy trptamine 6 receptor,5-HT6R)拮抗剂能够改善精神病和阿尔茨海默病导致的认知功能障碍。文中探讨其对癫痫后认知功能障碍的作用及其相关机制。方法将SD大鼠按照完全随机设计分为正常组(n=25)、癫痫组(n=30)、SB271046治疗组(n=30),后癫痫组和SB271046组均进行癫痫造模。癫痫造模3 d后SB271046治疗组给予10 mg/kg SB271046(5-HT6R拮抗剂)口服治疗。采用水迷宫以及Western blot检测各组大鼠的学习记忆能力以及分子水平变化。结果与正常组比较,癫痫组大鼠找到平台所需时间、游泳距离明显延长(P<0.05);与癫痫组比较,SB271046治疗组大鼠第2-5天逃离潜伏期缩短,第3-5天游泳距离缩短(P<0.05)。与癫痫组比较,正常组、SB271046治疗组大鼠穿越平台次数明显增多(P<0.05)。癫痫组大鼠脑组织5-HT6R表达较对照组明显升高,并且持续到28 d(P<0.05)。与癫痫组大鼠5-HT6R、p-Fyn、p-ERK1/2相对表达水平(0.21±0.04、1.16±0.40、0.82±0.18)比较,正常组、SB271046治疗组5-HT6R(0.06±0.02,0.12±0.04),p-Fyn(0.30±0.07,0.52±0.09),p-ERK1/2(0.17±0.06,0.43±0.14)表达均降低(P<0.05)。结论5-HT6R拮抗剂SB271046可以改善癫痫后认知功能障碍,其机制可能与抑制5-HT6R,p-Fyn,p-ERK1/2通路有关。 Objective 5-HT6 receptor antagonist can improve cognitive impairment caused by schizophrenia and Alzheimer disease. The study was to investigate the role of 5- HT6 R in the cognitive dysfunction caused by epilepsy and its potential mechanism.Methods Male Sprague-Dawley rats( 200- 250 g) were involved in our study. All the rats were randomly divided into three groups: negative control group( n = 25),epilepsy group( n = 30) and SB271046group( n = 30). Rats in epilepsy group and SB271046 group were given pilocarpine to induce epilepsy. Three days later, the rats in SB271046 group were given SB271046( highly selective 5-HT6 R antagonist,10 mg/kg,orally) till water maze test or sample collection. Morris water maze and western blot were used to detect the learning and memory ability and the change of molecular in all the rats. Results The results showed that the learning and memory ability of rats in SB271046 group extremely reduced compared with the rats in negative control group( escape latency: 90.95±21.69 vs 59.36±16.75,P<0.001; 75.50±23.83 vs 23.21±7.78,P<0.001; 74.59±24.09 vs 19.56±6.64,P<0.001; 59.78± 24.99 vs 17.70± 7.21,P<0.001; 55.88±28.48 vs 17.99±4.86,P<0.001; platform crossovers: 0.79±0.86 vs 2.88±1.41,P<0.001). After the administration of SB271046,the rats showed improved learning and memory ability( escape latency: 78.63± 25.40 vs 90.95± 21.69,P> 0.05; 51. 71 ±21.40 vs 75.50±23.83,P = 0.002; 39.14±17.40 vs 74.59±24.09,P<0.001; 32.21±13.21 vs 59.78±24.99,P< 0.001; 30.72± 17.01 vs55.88±28.48,P = 0.002; platform crossovers: 1.80±1.21 vs 0.79±0.86,P = 0.04),and the expression of 5-HT6 R,p-Fyn,p-ERK1/2 decreased significantly. Conclusion 5-HT6 receptor antagonist--SB271046 can improve cognitive impairment induced by epilepsy and its mechanism may be involved with the inhibition of 5-HT6 R,p-Fyn,p-ERK1/2 pathway.