Anti-dyskinetic effect of the neuronal nitric oxide synthase inhibitor is linked to decrease of FosB/DeltaFosB expression

Rodents with lesion of dopaminergic pathway when receiving repeated L-3,4-dihydroxiphenylalanine (L-DOPA) treatment develop abnormal involuntary movements called dyskinesia. We demonstrated that nitric oxide synthase (NOS) inhibitors mitigate L-DOPA-induced dyskinesia in rodents. The aim of the present study was to verify if the in vivo preferential neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI) affect the expression of the transcription factor FosB/Delta FosB in the lesioned striatum, an indicator of neuronal activity associated with dyskinesia. Male Wistar rats with unilateral microinjection (medial forebrain bundle) of either the neurotoxin 6-hydroxidopamine (6-OHDA; n = 4-6/group) or saline (sham; n=6/group) were provided with L-DOPA (30 mg/kg plus benserazide 7.5 mg/kg/day, oral gavage), once a day during 22 days. 6-OHDA-lesioned animals developed abnormal involuntary movements (AIMs) classified as axial, limb, orofacial and locomotive dyskinesia and presented FosB/Delta FosB increase in the dopamine-depleted striatum. Administration of 7-NI (30 mg/kg, i.p.), 30 min prior to L-DOPA reduced the severity of AlMs (approximate to 65% for axial, limb and orofacial and 74% for locomotive AIMs scores), without interfering with the rotarod performance. Simultaneously, 7-NI attenuated the expression of FosB/Delta FosB in dopamine-depleted striatum (approximate to 65% in medial and approximate to 54% in lateral striatum, bregma 0.48 mm). FosB/Delta FosB expression in lateral striatum was correlated with L-DOPA-induced dyskinesia. The findings described here corroborate a new approach to the management of L-DOPA-therapy in Parkinson's disease (PD) treatment. Crown Copyright (C) 2013 Published by Elsevier Ireland Ltd. All rights reserved.