title: Nitric oxide synthase inhibition decreases l-DOPA-induced dyskinesia and the expression of striatal molecular markers in Pitx3(-/-) aphakia mice.
abstract: 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-DOPA-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.
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, 28002 Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Solís
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, 28002 Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Espadas
authors.affiliation: Department of Morphology, Physiology and Pathology, School of Odontology, University of Sao Paulo, Campus Ribeirao Preto, Brazil.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Del-Bel
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, 28002 Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: moratalla@cajal.csic.es.
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity; D001545:Benserazide / Q000627:therapeutic use; D002452:Cell Count; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000633:toxicity; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D007191:Indazoles / Q000627:therapeutic use*; D007980:Levodopa / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008981:Molsidomine / Q000008:administration & dosage; D020030:Nitric Oxide Donors / Q000008:administration & dosage; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
chemical_list: D000978:Antiparkinson Agents; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D007191:Indazoles; D020030:Nitric Oxide Donors; D014157:Transcription Factors; C433629:homeobox protein PITX3; D007980:Levodopa; D001545:Benserazide; D008981:Molsidomine; C080122:7-nitroindazole
keywords: Abnormal involuntary movements; FosB; Histone3; Molsidomine; NO/cGMP; Nitrergic system; Parkinson disease; Pitx3 deficient aphakia mice; Striatum; Zaprinast; l-DOPA