5-羟色胺1A受体激动剂8-OH-DPAT对癫痫合并抑郁大鼠的干预作用及其机制研究

摘要

目的 探讨5-羟色胺1A(5-HT1A)受体激动剂8-OH-DPAT对癫痫合并抑郁大鼠的干预作用及其机制.方法 成年级SD大鼠160只,随机选取8只为正常对照组,其余大鼠采用匹罗卡品诱导慢性癫痫大鼠模型.25 d后通过体质量与摄食量测量及旷场试验筛选出癫痫合并抑郁模型大鼠32只,随机分为模型组、卡马西平(CBZ)组、CBZ+ 8-OH-DPAT低剂量组(8-OH-DPAT低剂量组)及CBZ+ 8-OH-DPAT高剂量组(8-OH-DPAT高剂量组)；分别给予CBZ 100 mg/kg、CBZ +8-OH-DPAT 0.1mg/(kg·d)、CBZ+ 8-OH-DPAT 1 mg/(kg·d).连续治疗7d后,进行癫痫发作的Racine分级、体质量、摄食量测量及旷场试验；采用荧光实时定量聚合酶链反应测定大鼠海马齿状回神经生长因子(NGF) mRNA表达,免疫组化染色观察苔藓纤维出芽(M FS).结果 治疗后,与正常对照组比较,模型组、CBZ组、8-OH-DPAT低、高剂量组的体质量与摄食量明显下降,海马NGF mRNA表达与Timm评分明显增高(均P＜0.05).与模型组比较,CBZ组、8-OH-DPAT低、高剂量组的体质量、摄食量及旷场试验评分明显提高,Racine分级、海马NGF mRNA表达与Timm评分明显下降(均P＜0.05)；其中8-OH-DPAT高剂量组上述改变更明显(均P＜0.05).结论 高剂量的5-HT1A受体激动剂8-OH-DPAT能抑制癫痫合并抑郁大鼠海马齿状回的MFS和神经生长因子的表达,促进海马神经重塑.这可能是5-HT1A受体激动剂抗癫痫、抗抑郁的分子机制之一.%Objective To study intervention effect and its mechanism of 5-hydroxytryptamine 1A (5-HT1A)receptor agonist 8-OH-DPAT on epileptic rats with depression.Methods Eight rats were randomly selected from 160 adult SD rats as normal control (NC) group,the other rats were induced epilepsy with pilocarpine.After 25 d,32 epileptic rats with depression were selected by the body weight and food intake measurements and open field test,and were randomly divided into model group,carbamazepine (CBZ) group,CBZ + 8-OH-DPAT low dose group(8-OH-DPAT low dose group) and CBZ + 8-OH-DPAT high dose group(8-OH-DPAT high dose group).The rats in each group were respectively treated with normal saline,CBZ 100 mg/kg,CBZ +8-OH-DPAT 0.1 mg/(kg · d),CBZ +8-OH-DPAT 1 mg/(kg · d).Racine classification,body weight and food intake and open field test were measured 7 d after continuous coursetreatment.The expression of nerve growth factor(NGF) mRNA was measured with fluorescence quantitative PCR,mossy fiber sprouting (MFS)was observed with Timm staining.Results Compared with the NC group after treatment,weights,food intake in model group,CBZ group,8-OH-DPAT low and high dose groups were significantly decreased ; the expression of the NGF mRNA and timm scores were significantly increased (all P ＜0.05).Compared with model group,weight,food intake,open-field test scores in CBZ group,8-OH-DPAT low and high dose groups were remarkably increased; Racine classification,the expression of NGF mRNA and Timm scores were remarkably decreased (all P ＜ 0.05).The above changes were more obvious in the 8-OH-DPAT high dose group(all P ＜ 0.05).Conclusion High doses of 5-HT1A receptor agonist 8-OH-DPAT can inhibit MFS and NGF expression of hippocampal dentate gyms in epileptic rats with depression,to promote hippocampal neural remodeling.That may be one of the molecular mechanisms of antidepressants and antiepileptic by 5-HT1A receptors agonist.