阿立哌唑改善帕金森病伴发抑郁模型大鼠行为学及能量代谢

Aripiprazole Improves Ethology and Energy Metabolism in Rats with Parkinson’s Disease Depression

目的探究阿立哌唑(Aripiprazole)对帕金森病抑郁症(PDD)大鼠行为学及能量代谢的影响。方法采用6-羟基多巴胺(6-OHDA)纹状体双靶点注射法及慢性不可预见性温和应激法(CUMS)制备PDD大鼠模型,将60只大鼠随机分为5组:健康对照组、模型组(PDD组)、低、中、高剂量(1.25、2.5、5 mg/kg)Aripiprazole处理组。通过旷场实验、蔗糖溶液偏好实验及Y迷宫实验观察大鼠行为,采用Longa法评价大鼠神经功能损伤程度,试剂盒检测脑组织5-羟色胺(5-HT)和5-羟吲哚乙酸(5-HIAA)的含量,苏木精-伊红(HE)染色观察脑组织病理变化,TUNEL染色观察脑组织细胞凋亡,试剂盒检测血清乳酸脱氢酶(LDH)含量、Na^(+)-K^(+)-ATP酶、Ca^(2+)-Mg^(2+)-ATP酶活力,蛋白印迹法检测凋亡标记分子[生存素(Survivin)、B淋巴细胞瘤(Bcl-2)、Bcl-2相关X蛋白(Bax)]及代谢相关调节因子[腺苷酸活化蛋白激酶α1(AMPKα1)、过氧化物酶体增殖物激活受体γ辅激活因子1α(PGC-1α)和葡萄糖转运蛋白4(GLUT4)]的表达。结果与PDD组比较,中、高剂量Aripiprazole处理可显著降低PDD模型大鼠犯错次数、脑神经功能缺损评分、脑组织细胞凋亡指数、脑组织Bax/Bcl-2表达及血清LDH含量;并提高旷场移动路程、蔗糖偏好指数及新异臂进入次数,提高脑组织5-HT、5-HIAA含量及Survivin、p-AMPKα1/AMPKα1、PGC-1α及GLUT4表达,并提高血清Na^(+)-K^(+)-ATP酶、Ca^(2+)-Mg^(2+)-ATP酶活力(均P<0.05)。结论阿立哌唑可改善帕金森病抑郁症大鼠抑郁样行为,其机制可能与增加单胺类神经递质、抑制脑组织细胞凋亡、改善能量代谢有关。

Objective To explore the effects of Aripiprazole on ethology and energy metabolism in rats with Parkinson's disease depression(PDD).Methods PDD rat models were prepared by 6 hydroxydopamine(6 OHDA)striatal double target in-jection and chronic unpredictable mild stress(CUMS).Sixty rats were randomly divided into healthy control group,model(PDD)group,low dose,medium dose and highr dose Aripiprazole groups(1.25,2.5,5 mg/kg).The ethology conditions of rats were observed by open field test,sucrose preference test and Y-maze test.The nerve function damage was evaluated by Longa method.The contents of 5-hydroxytryptamine(5-HT)and 5-hydroxyindoleacetic acid(5-HIAA)were detected by kits.The pathological changes of brain tissues were observed by HE staining.The apoptosis of brain tissue was observed by TUNEL staining.The activities of serum lactate dehydrogenase(LDH),Na^(+)-K^(+)-ATP enzyme and Ca^(2+)-Mg^(2+)-ATP enzyme were detected by kits.The expression levels of apoptosis marker molecules(Survivin,Bcl-2,Bax)and metabolism-related regulatory factors(AMPKal,PGC-1a,GLUT4)were detected by W estern blotting.Results Compared with PDD group,times of mistakes,score of neurological deficits,apoptosis index of brain tissue,levels of Bax/Bc-2 and LDH were significantly decreased in mediumdose and high-dose A ripiprazole groups.Travel distance in open field test,sucrose preference index,times of visits in extraneous arm were increased(all P<0.05).And expression levels of 5-HT,5-HIAA,Survivin,Na^(+)-K^(+)-ATP enzyme,Ca^(2+)-Mg^(2+)-ATP enzyme,p-AMPKal/AMPKal,PGC-1a and GLUT4 were increased(all P<0.05).Conclusion Aripiprazole can improve depression-like behaviors in PDD rats,and the mechanism may be related to increasing monoamine neurotransmitters,inhibiting apoptosis of brain tissue and improving energy metabolism.