title: 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 (30mg/kg plus benserazide 7.5mg/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 (30mg/kg, i.p.), 30min 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 0.48mm). 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.
authors: Department of Behavioral Neuroscience, Medical School, University of Sao Paulo, Ribeirão Preto, SP, Brazil.
authors: Fernando Eduardo
authors: FE
authors: Padovan-Neto
authors: Nádia Rubia
authors: NR
authors: Ferreira
authors: Danielle
authors: D
authors: de Oliveira-Tavares
authors: Daniele
authors: D
authors: de Aguiar
authors: Célia Aparecida
authors: CA
authors: da Silva
authors: Rita
authors: R
authors: Raisman-Vozari
authors: Elaine
authors: E
authors: Del Bel
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D016627:Oxidopamine; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000978:Antiparkinson Agents; C064269:FOSB protein, human; D007191:Indazoles; D016760:Proto-Oncogene Proteins c-fos; D007980:Levodopa; D016627:Oxidopamine; D052248:Nitric Oxide Synthase Type I; C080122:7-nitroindazole