期刊
NEUROBIOLOGY OF DISEASE
卷 73, 期 -, 页码 49-59出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.09.010
关键词
Parkinson disease; L-DOPA; Abnormal involuntary movements; Nitrergic system; NO/cGMP; Pitx3 deficient aphakia mice; FosB; Histone3; Molsidomine; Zaprinast; Striatum
资金
- Spanish Ministerios de Economia y Competitividad [5AF2013-48532-R]
- Sanidad Politica Social e Igualdad (PNSD) [2012/071, CB06/05/0055]
- Comunidad de Madrid [S2011/BMD-2336]
- CONACYT-Mexico doctoral scholarship
Nitric oxide (NO), a gaseous messenger molecule synthesized by nitric oxide synthase (NOS), plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). To study the role of the nitrergic system in L-DOPA-induced dyskinesia (LID), we assessed the effect of the pharmacological manipulation of NO levels and NO/cyclic guanosine monophosphate (cGMP) signaling on LID in the Pitx3(-/-) aphakia mouse, a genetic model of PD. To evaluate the effect of decreased NO signaling on the development of LID, Pitx3(-/-) mice were chronically treated with L-DOPA and 7-nitroindazole (7-NI, a neuronal NOS inhibitor). To evaluate its effect on the expression of established LID, 7-NI was administered acutely to dyskinetic mice. The chronic 7-NI treatment attenuated the development of LID in the Pitx3(-/-) mice, and the sub-acute 7-NI treatment attenuated established dyskinesia without affecting the beneficial therapeutic effect of L-DOPA. Moreover, 7-NI significantly reduced FosB and pAcH3 expression in the acutely and chronically L-DO PA-treated mice. We also examined how increasing NO/cGMP signaling affects LID expression by acutely administering molsidomine (an NO donor) or zaprinast (a cGMP phosphodiesterase 5-PDE5 inhibitor) before L-DOPA in mice with established dyskinesia. Paradoxically, the administration of either of these drugs also significantly diminished the expression of established LID; however, the effect occurred at the expense of the antiparkinsonian L-DOPA properties. We demonstrate that targeting the NO/cGMP signaling pathway reduces dyskinetic behaviors and molecular markers, but only the 7-NI treatment preserved the antiparkinsonian effect of L-DOPA, indicating that NOS inhibitors represent a potential therapy to reduce LID. (C) 2015 Elsevier Inc. All rights reserved.
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