Nguyen Xuan V, Liu Mei, Kim Hyoung-Chun, Bing Guoying
Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536, USA.
Exp Neurol. 2009 Sep;219(1):228-38. doi: 10.1016/j.expneurol.2009.05.028. Epub 2009 Jun 3.
Dynorphins, endogenous neuropeptides found in striatonigral neurons, have been observed to exhibit dopamine-inhibitory actions and under some circumstances possess intrinsic neurotoxic activity. To test the hypothesis that dynorphin suppression mitigates effects of aging on the striatal dopaminergic system, HPLC quantitation of dopamine and related amines was performed on striatal homogenates of wild-type (WT) mice and mice lacking the prodynorphin (Pdyn) gene at varying ages. Pdyn knockout (KO) mice at 10 and 20 months show significant elevations in striatal dopamine compared to 3-month mice. Differences in tyrosine hydroxylase (TH) immunoreactivity could not account for these findings, but phosphorylation of TH at Ser40, but not Ser31, was enhanced in aged Pdyn KO mice. Systemic administration of MPTP produced significant dopamine depletion in an age-dependent manner, but Pdyn deletion conferred no protection against MPTP-induced dopamine loss, arguing against a mechanism by which Pdyn deletion enhances dopaminergic neuron survival. The above findings demonstrate an age-dependent inhibitory effect of dynorphins on striatal dopamine synthesis via modulation of TH activity.
强啡肽是在纹状体黑质神经元中发现的内源性神经肽，已观察到其具有抑制多巴胺的作用，并且在某些情况下具有内在的神经毒性活性。为了验证强啡肽抑制可减轻衰老对纹状体多巴胺能系统影响的假说，对不同年龄的野生型（WT）小鼠和缺乏前强啡肽（Pdyn）基因的小鼠的纹状体匀浆进行了多巴胺及相关胺类的高效液相色谱定量分析。10个月和20个月大的Pdyn基因敲除（KO）小鼠与3个月大的小鼠相比，纹状体多巴胺水平显著升高。酪氨酸羟化酶（TH）免疫反应性的差异无法解释这些结果，但在老年Pdyn KO小鼠中，TH在Ser40而非Ser31位点的磷酸化增强。全身给予MPTP会以年龄依赖性方式导致显著的多巴胺耗竭，但Pdyn基因缺失并不能保护小鼠免受MPTP诱导的多巴胺损失，这表明Pdyn基因缺失增强多巴胺能神经元存活的机制不成立。上述研究结果表明，强啡肽通过调节TH活性对纹状体多巴胺合成具有年龄依赖性抑制作用。
