经鼻施予丙酸睾丸酮对老年运动行为和运动技能的改善及相关机制

In the senile process, testosterone (T) level decreased gradually and the motor behavior and motor performence were impaired in aged male organisms. Aged men or aged male animals often displayed the disturbances of the motor coordination and the body balance. .Currently, testosterone replacement therapies include oral therapy, intramuscular injections and subcutaneous testosterone implants. The administration routes above have been shown some disadvantages.Nasal cavity was a part of respiratory system. The lining mucosa of nasal cavity includes respiratory region and olfactory region. The olfactory cells of olfactory region belong to nerve cells, which contact with rhinencephalon through fila olfactoria. Based on the mucous membrane characteristics of nasal cavity, intranasal delivery of drugs has become preferred method in recent year..Our work group have demonstrated that the impaired behaviors insulted by gonadectomy could be mostly restored by chronic intranasal administration of testosterone. To date, it is not known whether intranasal administration of testosterone propionate to aged male rats ameliorates the impaired motor behavior and motor performance. Therefore, the aged male rats were used as experimental animal models in present study. The influence of intranasal administration of testosterone propionate upon the motor behavior and motor performance was studied by analyzing the motor-related behaviors of rats and the effects of intranasal delivery of testosterone propionate on mensencephalic dopaminergic neurons was analyzed by immunohistochemistry, immunoblotting, HPLC and RT-PCR. It is hoped that intranasal administration of testoeterone propionate could be used in adjutant therapy for impaired motor coordination and the body balance in the senile process.

衰老过程中男性个体睾丸酮水平多呈现不同程度的降低，其运动行为和运动技能逐渐减弱、老年后常表现出运动协调及平衡的障碍。目前针对睾丸酮缺乏的替代疗法均存在一定的缺点。由于鼻腔粘膜的解剖特点，经鼻途径也渐成为近年睾丸酮制剂理想的给药途径。课题组的研究证实，经鼻施予睾丸酮能够恢复去势大鼠的运动行为，经鼻施予丙酸睾丸酮是否能够改善老年大鼠受损的运动行为和运动技能，目前尚不清楚。因此本研究以老年雄性大鼠为动物模型，通过分析老年大鼠运动相关行为的变化，探讨经鼻施予丙酸睾丸酮对运动行为和运动技能的影响，并通过免疫组织化学、免疫印迹、RT-PCR以及高效液相色谱分析法探讨与行为密切相关的中脑多巴胺能神经元所发挥的作用，期望所获结果为经鼻腔施予丙酸睾丸酮辅助治疗衰老过程中出现的运动相关行为障碍提供一定的实验依据。

衰老过程中男性个体睾丸酮水平多呈现不同程度的降低，其运动行为和运动技能逐渐减弱、老年后常表现出运动协调及平衡的障碍。睾丸酮因其亲脂性应很容易入脑，然而外源性睾丸酮的使用受到多种因素的影响，限制了入脑的有效量。鼻腔给药具有无侵害性、可避开肝脏首过效应及给药方便易行等优点。雄激素能够调节脑内多巴胺（DA）能神经体系的功能状态。老年后黑质纹状体和中脑边缘DA能神经元的功能减退，经鼻施予丙酸睾丸酮是否也能够引起相同的作用目前尚不清楚。本研究以老年大鼠为模型，探讨经鼻施予丙酸睾丸酮（TP）对老年大鼠运动行为和运动技能的影响及DA能神经体系参与的机制。本研究发现经鼻施予TP改善衰老引起的旷场行为、倾斜面行为和水平绳行为；增加了衰老大鼠黑质（SN）-尾壳核（CPu）以及腹侧被盖区（VTA）-伏核（Acb）DA能神经体系酪氨酸羟化酶（TH）以及多巴胺转运体（DAT）的表达；增加了CPu和Acb 脑区DA及其代谢产物的表达，海马脑区DA及其代谢产物的表达无明显改变；对SN和VTA脑区TH阳性神经元具有保护作用，经鼻施予TP对脑内DA能体系的作用效果优于皮下注射TP。此外，经鼻施予TP增加衰老大鼠SN、CPu、VTA、Acb和Hip脑区还原型谷胱甘肽的含量，降低丙二醛的含量；增加了SN和VTA脑区核因子E2相关因子2（Nrf2）、血红素氧合酶-1（HO-1）和NAD(P)H醌氧化还原酶1（NQO1）的表达，海马脑区Nrf2、HO-1和NQO1的表达无明显改变，经鼻施予TP对脑内Nrf2、HO-1和NQO1的表达效果优于皮下注射TP。因此，长期经鼻腔施予TP能够增强衰老的中脑DA能神经体系DA能神经活动，这对改善年龄相关的探索行为和运动行为起到非常重要作用。衰老的中脑DA能神经体系的改善很可能与脑内区域性Nrf2-ARE抗氧化应激途径的激活密切相关。