Counteraction by Nitric Oxide Synthase Inhibitor of Neurochemical Alterations of Dopaminergic System in 6-OHDA-Lesioned Rats Under l-DOPA Treatment

Abstract

Nitric oxide synthase inhibitors reduce L-3, (Del-Bel et al., Cell Mol Neurobiol 25(2):371-392, 2005) 4-dihydroxyphenylalanine (L-DOPA)-induced abnormal motor effects subsequent to depletion of dopaminergic neurons in rodents and non-human primates. The present study used quantitative high-performance liquid chromatography to analyze, for the first time, dopamine metabolism in striatum of rats in order to elucidate the mechanism of action of the nitric oxide synthase inhibitors. Adult male Wistar rats received unilateral microinjection of saline (sham) or 6-hydroxydopamine (6-OHDA-lesioned) in the medial forebrain bundle. Past 3 weeks, rats were treated during 21 days with L-DOPA/benserazide (30 mg/kg/7.5 mg/kg, respectively, daily). On the 22nd day rats received an intraperitoneal (i.p.) injection of either vehicle or 7-nitroindazole, a preferential neuronal nitric oxide synthase inhibitor before L-DOPA. Abnormal involuntary movements and rotarod test were assessed as behavioral correlate of motor responses. Lesion intensity was evaluated through tyrosine hydroxylase immunohystochemical reaction. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and an extent of dopamine striatal tissue levels/dopamine metabolism were measured in the striatum. Lesion with 6-OHDA decreased dopamine, DOPAC, and DOPAC/dopamine ratio in the lesioned striatum. L-DOPA treatment induced abnormal involuntary movements and increased DOPAC/dopamine ratio (nearly five times) in the lesioned striatum. L-DOPA-induced dyskinesia was mitigated by 7-nitroindazole, which also decreased dopamine turnover, dopamine and DOPAC levels. Our results revealed an almost two times increase in dopamine content in the non-lesioned striatum of 6-OHDA-lesioned rats. Reduction of striatal DOPAC/dopamine ratio in dyskinetic rats may suggest an increase in the dopamine availability. Our data confirm contribution of nitrergic transmission in the pathogenesis of L-DOPA-induced dyskinesia with potential utilization of nitric oxide synthase inhibitors for treatment.

Intrinsic exercise capacity is related to differential monoaminergic activity in the rat forebrain

“…All dissections were performed in both cerebral hemispheres and by the same researcher. The high concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the CPu and ACC were similar to previous reports in the striatum (Del-Bel et al, 2014) and further confirmed the accuracy of the dissections. The brain areas were immediately stored at −80 • C until assay to measure DA, DOPAC, 5-HT, and 5-hydroxyindoleacetic (5-HIAA) Values are expressed as mean ± SEM.…”

The preferential nNOS inhibitor 7-nitroindazole and the non-selective one NG-nitro-l-arginine methyl ester administered alone or jointly with l-DOPA differentially affect motor behavior and monoamine metabolism in sham-operated and 6-OHDA-lesioned rats

“…Also prolongation of L-DOPA activity by 7-NI would be considered to be a beneficial effect due to avoidance of pulsatile stimulation of striatal postsynaptic DA receptors, that is one of the main cause of L-DOPA-induced dyskinesia (Huot et al, 2013). Consistently with our results, Del- Bel et al (2014) reported that 7-NI, decreasing DA turnover, simultaneously reduced L-DOPA induced DA dyskinesia. However, L-NAME that was also described to reduce L-DOPA-induced dyskinesia (Padovan-Neto et al, 2009;Takuma et al, 2012) did not affect DA turnover in our study.…”

Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors

“…Some studies have shown the effectiveness of 7-NI in reducing L-DOPA-induced dyskinesia (LID) in rats lesioned with 6-hydroxydopamine (6-OHDA) [49,50]. Corroborating these previous findings, the present study showed that 7-NI at doses of 1-10 mg/kg was able to attenuate the orofacial dyskinesia induced by reserpine.…”