Molsidomine, a nitric oxide donor, modulates rotational behavior and monoamine metabolism in 6-OHDA lesioned rats treated chronically with L-DOPA

Abstract

Some biochemical and histological studies of Parkinson's disease patients' brains and 6-OHDA-lesioned rats suggest that dopaminergic dennervation of the striatum leads to the nitrergic system hypofunction in this structure. Hence, recently the modulation of nitric oxide (NO)- soluble guanylyl cyclase-cyclic GMP signaling is considered to be a new target for the treatment of Parkinson's disease. The aim of our study was to examine the impact of chronic combined treatment with low doses of the NO donor molsidomine (2 and 4mg/kg) and L-DOPA (12.5 and 25mg/kg) on rotational behavior and monoamine metabolism in the striatum (STR) and substantia nigra (SN) of unilaterally 6-OHDA-lesioned rats. Chronic administration of molsidomine at a dose of 2mg/kg jointly with 25mg/kg of L-DOPA significantly decreased the number of contralateral rotations when compared to L-DOPA alone. Other combinations of the examined drug doses were less effective. The tissue DA levels in the ipsilateral STR and SN after the last chronic doses of molsidomine (2mg/kg) and L-DOPA (12.5 or 25mg/kg), were significantly higher than after L-DOPA alone. Chronic L-DOPA treatment alone or jointly with a lower dose of molsidomine decreased 5-HT levels and accelerated its catabolism in the examined structures. However, combination of a higher dose of molsidomine with L-DOPA (25mg/kg) did not reduce 5-HT content while its catabolism was less intensive. The obtained results show that low doses of molsidomine can modulate rotational behavior and tissue DA and 5-HT concentrations in the STR and SN of 6-OHDA-lesioned rats treated chronically with L-DOPA.

Keywords: 3,4-dihydroxyphenylacetic acid; 5-HIAA; 5-HT; 5-hydroxyindoleacetic acid; 6-OHDA; 6-OHDA animal model of Parkinson’s disease; 6-hydroxydopamine hydrochloride; ANOVA; DA; DOPAC; Dopamine and serotonin metabolism; HPLC; HVA; L-DOPA; MAO; Molsidomine; Nitric oxide; PD; Parkinson’s disease; Rotational behavior; SNc; SNr; STR; analysis of variance; dopamine; high-pressure liquid chromatography; homovanillic acid; monoamine oxidase; serotonin; striatum; substantia nigra pars compacta; substantia nigra pars reticulate.