Villar-Cheda Begoña, Dominguez-Meijide Antonio, Valenzuela Rita, Granado Noelia, Moratalla Rosario, Labandeira-Garcia Jose L
Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Centre on Neurodegenerative Diseases (CIBERNED), Spain.
Networking Research Centre on Neurodegenerative Diseases (CIBERNED), Spain; Instituto Cajal CSIC (Consejo Superior de Investigaciones Científicas), Madrid, Spain.
Neurobiol Aging. 2014 Jul;35(7):1726-38. doi: 10.1016/j.neurobiolaging.2014.01.017. Epub 2014 Jan 17.
It is not known whether the aging-related decrease in dopaminergic function leads to the aging-related higher vulnerability of dopaminergic neurons and risk for Parkinson's disease. The renin-angiotensin system (RAS) plays a major role in the inflammatory response, neuronal oxidative stress, and dopaminergic vulnerability via type 1 (AT1) receptors. In the present study, we observed a counterregulatory interaction between dopamine and angiotensin receptors. We observed overexpression of AT1 receptors in the striatum and substantia nigra of young adult dopamine D1 and D2 receptor-deficient mice and young dopamine-depleted rats, together with compensatory overexpression of AT2 receptors or compensatory downregulation of angiotensinogen and/or angiotensin. In aged rats, we observed downregulation of dopamine and dopamine receptors and overexpression of AT1 receptors in aged rats, without compensatory changes observed in young animals. L-Dopa therapy inhibited RAS overactivity in young dopamine-depleted rats, but was ineffective in aged rats. The results suggest that dopamine may play an important role in modulating oxidative stress and inflammation in the substantia nigra and striatum via the RAS, which is impaired by aging.
目前尚不清楚多巴胺能功能与衰老相关的下降是否会导致多巴胺能神经元与衰老相关的更高易损性以及患帕金森病的风险。肾素-血管紧张素系统（RAS）通过1型（AT1）受体在炎症反应、神经元氧化应激和多巴胺能易损性中起主要作用。在本研究中，我们观察到多巴胺与血管紧张素受体之间存在反向调节相互作用。我们观察到，在成年早期多巴胺D1和D2受体缺陷小鼠以及成年早期多巴胺耗竭大鼠的纹状体和黑质中，AT1受体过表达，同时伴有AT2受体的代偿性过表达或血管紧张素原和/或血管紧张素的代偿性下调。在老年大鼠中，我们观察到老年大鼠多巴胺和多巴胺受体下调以及AT1受体过表达，而在年轻动物中未观察到代偿性变化。左旋多巴治疗可抑制成年早期多巴胺耗竭大鼠的RAS过度活跃，但对老年大鼠无效。结果表明，多巴胺可能通过RAS在调节黑质和纹状体的氧化应激和炎症中起重要作用，而RAS会因衰老而受损。
