2型糖尿病大鼠认知行为的改变及新型褪黑素受体激动剂Neu-P11的调节作用

目的 评价2型糖尿病大鼠认知功能的变化和新型褪黑素受体激动剂Neu-P11的调节作用及其作用机制.方法 采用高脂饲料喂养2月联合腹腔注射链脲佐菌素(STZ)建立2型糖尿病大鼠模型,分为正常对照组、模型组和Neu-P11组,各8只;正常对照组和模型组每日1次灌胃生理盐水,Neu-P11组每日1次灌胃Neu-P11 (5 mg/kg).第25天进行情绪唤醒实验,第32天进行旷场实验,第34天收集24 h尿液测定尿游离肾上腺皮质激素(CORT)水平,第35天断头处死大鼠并收集躯干血测定血清促肾上腺皮质激素释放激素(CRH)、促肾上腺皮质激素(ACTH)和CORT水平.结果 模型组情绪唤醒实验综合得分低于正常对照组(P＜0.05),而Neu-P11组与模型组比较差异无统计学意义(P＞0.05).模型组中央格停留时间长于对照组(P＜0.05),水平运动得分和垂直运动得分低于正常对照组(P＜0.01);Neu-p11组中央格停留时间短于模型组(P＜0.05),垂直运动得分高于模型组(P＜0.05).模型组尿CORT水平显著高于正常对照组(P＜0.01).Neu-P11组血清CRH、CORT及尿CORT水平低于模型组(P ＜0.05,P＜0.01),而血清ACTH水平高于模型组(P＜0.05).结论 新型褪黑素受体激动剂Neu-P11可改善2型糖尿病大鼠的认知功能障碍,降低下丘脑-垂体-肾上腺轴功能亢进可能是其主要的作用机制.

Changes of Cognitive Function Type 2 Diabetes Mellitus Rats and Regulated Effect of New Melatonin Receptor Agonist Neu-P11

Objective To evaluate changes of cognitive function in type 2 diabetes mellitus (T2DM) rats and regulated effect of new melatonin receptor agonist Neu-P11 and its mechanism of action.Methods T2DM rat models were established by high fat diet for 2 months combined with Streptozotocin (STZ) by intraperitoneal injection,and the rats were divided into control group,model group and Neu-P11 group (n =8 for each group).Control and model groups were lavaged with normal saline (1 time/d),while Neu-P11 group was lavaged with Neu-P11 (5 mg/kg,1 time/d).Emotional awaken test was performed at 25th d after treatment;open field test was performed at 32thd after treatment;urine within 24h was collected at 34th d after treatment to detect urinary freeing corticosterone (CORT) level;all rats were sacrificed by decapitation at 35th d after treatment and trunk blood was collected to detect plasma corticotropin release hormone (CRH),adrerrmrticotropic hormone (ACTH) and CORT levels.Results In model group,score of emotional awaken test was significantly lower than that in control group (P ＜ 0.05),but there was no significant difference in the score between Neu-P11 and model groups (P ＞ 0.05).Compared with those in control group,in model group,residence time in central zone was longer (P ＜ 0.05),while scores of horizontal movement and vertical movement were significantly lower (P ＜ 0.01).In Neu-p11 group,residence time in central zone was shorter (P ＜ 0.05),while vertical movement score was significantly higher than those in model group (P ＜ 0.05).Urinary CORT level in model group was significantly higher than that in control group (P ＜ 0.01).In Neu-P11 group,serum CRH,CORT and urinary CORT levels were significantly lower (P ＜ 0.01,P ＜ 0.05),while serum ACTH level was significantly higher than those in model group (P ＜0.05).Conclusion New melatonin receptor agonist Neu-P11 may improve cognitive dysfunction in T2DM rats,and decreasing hyperfunctioning of hypothalamus-pituitary-adrenal may be the main mechanism of action.