SB-399885阻断5-羟色胺6受体/雷帕霉素靶蛋白途径对精神分裂症大鼠认知和记忆障碍的改善作用

SB-399885 blocks HTR6/mTOR pathway to improve cognitive and memory impairment in rats with schizophrenia

目的研究5-羟色胺6受体(HTR6)拮抗剂SB-399885通过阻断HTR6/雷帕霉素靶蛋白(mTOR)途径对精神分裂症大鼠认知和记忆障碍的作用。方法将40只SD大鼠随机分为4组:空白对照组、精神分裂症模型组(SZ组)、SZ+SB-399885组(10 mg/kg)、阳性对照组(SZ+利培酮,0.1 mg/kg),每组各10只大鼠。采用MK-801建立SZ大鼠模型。新物体辨别实验检测大鼠视觉识别记忆,Morris水迷宫实验检测大鼠认知能力,被动回避实验检测大鼠学习记忆能力,乙酰胆碱酯酶(AChE)活性测定试剂盒检测大鼠海马和大脑皮质AChE活性,TUNEL染色法检测大鼠海马CA1区神经细胞凋亡情况,Western blot检测大鼠海马HTR6/mTOR途径相关蛋白的表达。结果5-HT6受体拮抗剂SB-399885和利培酮均能显著改善SZ大鼠视觉识别记忆障碍、认知障碍和学习记忆障碍(均P<0.05)。与SZ组比较,SZ+SB-399885组大鼠海马AChE活性[(0.008±0.001)μmol/(min·mg)]、神经细胞凋亡率[(21.75±4.45)%]、HTR6蛋白表达(0.56±0.10)和mTOR活性(0.41±0.05)均显著降低(均P<0.05);阳性对照组大鼠海马和大脑皮质AChE活性显著降低(均P<0.05),大鼠海马神经细胞凋亡率[(19.28±5.22)%]、HTR6蛋白表达(0.40±0.10)和mTOR活性(0.33±0.05)均显著降低(均P<0.05)。结论5-HT6受体拮抗剂SB399885可能通过阻断HTR6/mTOR途径改善精神分裂症大鼠认知和记忆障碍。

Objective To investigate the effect of 5-HT6 receptor antagonist SB-399885 on cognitive and memory impairment in rats with schizophrenia by blocking the HTR6/mTOR pathway.Methods A total of 40 SD rats were randomly divided into 4 groups:blank control group,schizophrenia model group(SZ group),SZ+SB-399885 group(10 mg/kg),positive control group(SZ+risperidone,0.1 mg/kg),with 10 rats in each group.The SZ rat model was established using MK-801.The new object discrimination experiment was used to detect the visual recognition memory of rats.The Morris water maze test was used to detect the cognitive ability of rats.The passive avoidance test was used to detect the learning and memory ability of rats.The AChE activity assay kit was used to detect the activity of AChE in hippocampus and cerebral cortex of rats.TUNEL staining method was used to detect the neuronal apoptosis in the hippocampal CA1 region of rats.Western blot was used to detect the expression of HTR6/mTOR pathway-related proteins in rat hippocampus.Results Both 5-HT6 receptor antagonists SB-399885 and risperidone could significantly improve visual recognition and memory impairment,cognitive impairment and learning and memory impairment in SZ rats(P<0.05).Compared with SZ group,the hippocampal AChE activity[(0.008±0.001)μmol/(min·mg)],the neuronal apoptosis rate(21.75±4.45)%,HTR6 protein expression(0.56±0.10)and mTOR activity(0.41±0.05)in the SZ+SB399885 group was significantly reduced(P<0.05).The AChE activity in hippocampus and cerebral cortex of positive control group rats was significantly reduced(P<0.05).The neuronal apoptosis rate(19.28±5.22)%,HTR6 protein expression(0.40±0.10),and mTOR activity(0.33±0.05)were significant decreased(P<0.05)in positive control group.Conclusions The 5-HT6 receptor antagonist SB-399885 may improve cognitive and memory impairment in schizophrenic rats by blocking the HTR6/mTOR pathway.