H_(3)R拮抗剂GSK189254改善Aβ大鼠学习记忆障碍及其机制初探

Histamine H_(3) antagonist GSK189254 ameliorates learning and memory deficits and its mechanism in Aβ1-42 Alzheimer′s disease rat model

目的研究组胺H_(3)受体(histamine H_(3) receptor,H_(3)R)拮抗剂GSK189254对阿尔茨海默病(Alzheimer′s disease,AD)大鼠学习记忆行为的影响并探讨其可能机制。方法选取20只成年雄性Wistar大鼠,分为对照组(n=8)、Aβ1-42组(n=6)和Aβ1-42+H_(3)R拮抗剂组(n=6)。Aβ1-42组动物侧脑室注射β淀粉样蛋白1-42(β-amyloid,Aβ1-42,0.67 g·L^(-1),5μL),连续14 d。Aβ1-42+H_(3)R拮抗剂组除同前侧脑室注射14 dAβ1-42外,同时连续28 d给予GSK189254(1 g·L^(-1),5μL)。停药1 d后,所有动物行Morris水迷宫、Y迷宫以及新事物识别行为检测。次日,以生理盐水经动物心脏灌流后取脑,左侧脑以4%多聚甲醛固定后进行免疫组化染色;右侧脑分离海马与前额叶皮层,应用高效液相串联质谱(HPLC-MS/MS)和qPCR法检测各种神经递质的含量与炎症因子的表达。结果H_(3)R拮抗剂GSK189254可以改善Aβ1-42诱导的AD大鼠学习记忆障碍行为与神经元损伤,不同程度增加海马与前额叶皮层内多种神经递质的含量,以五羟色胺(5-HT)最为明显;GSK189254虽可以降低多种炎症因子的表达,但并无明显影响。结论H_(3)R拮抗剂GSK189254可通过增加海马内5-HT释放改善AD大鼠学习记忆能力的缺失。

Aim To determine the effect of histamine H_(3) receptor(H_(3)R)antagonist GSK189254 on the learning and memory behaviors in Aβ1-42 induced Alzheimer′s disease(AD)rats and its potential mechanism.Methods Twenty male adult Wistar rats were randomly assigned into three groups including control group(n=8),Aβ1-42 group(n=6),and Aβ1-42+H_(3)R antagonist group(n=6).The animals in Aβ1-42 group were injected withβ-amyloid 1-42(0.67 g·L^(-1),5μL,ICV)for 14 days.Besides,Aβ1-42,GSK189254(1 g·L^(-1),5μL,ICV)was also administrated for 28 days in the animals of Aβ1-42+H_(3)R antagonist group.The water maze,Y maze,and novel object recognition behavioral tests were performed to assess the abilities of learning and memory of all animals.After that,animals were transcardially perfused with 0.9%saline.Rat brains were excised,bisected and the left hemispheres were fixed in 4% paraformaldehyde for the following immunohistochemical staining,while the hippocampus and prefrontal cortex of right hemisphere were dissected to detect the levels of a few neurotransmitters by with HPLC-MS/MS and the expressions of inflammatory factors by qPCR.Results The H_(3)R antagonist GSK189254 ameliorated the learning and memory deficits of AD rats and the degeneration of neurons.GSK189254 increased the levels of a few neurotransmitters in hippocampus and prefrontal cortex,but only hydroxytryptamine(5-HT)increased significantly.In addition,GSK189254 decreased the expression of a few inflammatory factors,but no statistically significant difference was found.Conclusions The H_(3)R antagonist GSK189254 may ameliorate the learning and memory deficits of Aβ1-42 induced AD rats by increasing the 5-HT level in hippocampus.The present study reveals the possible anti-AD effect of H_(3)R antagonist GSK189254 and its underlying mechanism.