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

Abstract 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/ΔFosB 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/ΔFosB 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 AIMs (≈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/ΔFosB in dopamine-depleted striatum (≈65% in medial and ≈54% in lateral striatum, bregma 0.48 mm). FosB/ΔFosB 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.