Clinical & Experimental Neuroscience and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Department of Human Anatomy and Psychobiology, School of Medicine, Regional Campus of International Excellence Campus Mare Nostrum, University of Murcia, E-30100 Murcia, Spain.
Neuropharmacology. 2012 Dec;63(7):1258-67. doi: 10.1016/j.neuropharm.2012.07.031. Epub 2012 Aug 1.
Neuronal nitric oxide synthase (nNOS) is involved in the regulation of diverse intracellular messenger systems in the brain. Nitric Oxide (NO) contributes to inducing signaling cascades that involve a complex pattern of phosphorylation of DARPP-32 (in Thr-34), which controls the phosphoproteins involved in neuronal activation. However, the role of NO in the pathophysiology of Parkinson's disease (PD) and its effect in striatal neurons have been scarcely explored. In the present work, we investigate the effects of a nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI) in the nigrostriatal pathway of striatal 6-hydroxydopamine (6-OHDA) lesioned rats. Our quantitative histological findings show that treatment with 7-NI significantly reduced 6-OHDA-induced dopaminergic damage in the dorsolateral striatum and Substantia Nigra pars compacta (SNpc). Moreover, 6-OHDA lesioned rats show a significant increase of nNOS(+) and Phospho-Thr34-DARPP-32(+) cells, accompanied by a consequent decrease of total DARPP-32(+) cells, which suggests an imbalance of NO activity in the DA-depleted striatum, which is also reflected in behavioral studies. Importantly, these effects are reverted in the group treated with 7-NI. These results show a clear link between the state of phosphorylation of DARPP-32 and parkinsonism, which is regulated by nNOS. This new evidence suggests a prominent role for nitric oxide in the neurotransmitter balance within the basal ganglia in the pathophysiology of experimental parkinsonism.
神经元型一氧化氮合酶（nNOS）参与脑内多种细胞内信使系统的调节。一氧化氮（NO）有助于诱导信号级联反应，涉及 DARPP-32（Thr-34 位）的磷酸化的复杂模式，DARPP-32 控制参与神经元激活的磷酸蛋白。然而，NO 在帕金森病（PD）的病理生理学中的作用及其对纹状体神经元的影响尚未得到充分探索。在本工作中，我们研究了一氧化氮合酶（NOS）抑制剂 7-硝基吲唑（7-NI）在纹状体 6-羟多巴胺（6-OHDA）损伤大鼠黑质纹状体通路中的作用。我们的定量组织学研究结果表明，7-NI 处理可显著减轻 6-OHDA 诱导的背外侧纹状体和黑质致密部（SNpc）多巴胺能损伤。此外，6-OHDA 损伤大鼠 nNOS(+)和磷酸化 Thr34-DARPP-32(+)细胞显著增加，同时总 DARPP-32(+)细胞显著减少，这表明 DA 耗竭纹状体中 NO 活性失衡，这也反映在行为研究中。重要的是，7-NI 处理组可逆转这些影响。这些结果表明 DARPP-32 的磷酸化状态与帕金森病之间存在明确的联系，而 nNOS 调节了 DARPP-32 的磷酸化状态。这一新证据表明，NO 在实验性帕金森病的基底神经节神经递质平衡的病理生理学中具有重要作用。
