Selective inhibition of monoamine oxidase A or B reduces striatal oxidative stress in rats with partial depletion of the nigro-striatal dopaminergic pathway

Abstract

Partial lesion (50%) of the nigro-striatal dopaminergic pathway induces compensatory increase in dopamine release from the remaining neurons and increased extracellular oxidative stress (OS(-ec)) in the striatum. The present study was designed to explore the role of monoamine oxidase types A and B (MAO-A, MAO-B) in producing this increased oxidative stress. Lesion of the dopaminergic pathways in the CNS was produced in rats by intra-cerebroventricular injection of 6-hydroxydopamine (6-OHDA; 250 μg) and striatal microdialysis was carried out 5 weeks later. Striatal OS(ec) was determined by measurement of oxidized derivatives of the marker molecule N-linoleyl-tyrosine. Striatal tissue MAO-A activity was unchanged by 6-OHDA lesion but MAO-B activity was increased by 16%, together with a 45% increase in glial cell content. The selective MAO-B inhibitor rasagiline (0.05 mg/kg s.c. daily for 14 days) did not affect microdialysate dopamine concentration [DA(ec)] in sham-operated rats, but decreased OS(ec) by 30%. In lesioned rats, rasagiline decreased [DA(ec)] by 42% with a 49% reduction in OS(ec). The decrease in [DA(ec)] was reversed by the dopamine D2 receptor antagonist sulpiride (10 mg/kg s.c.). The selective MAO-A inhibitor clorgyline (0.2 mg/kg s.c. daily for 14 days) increased striatal [DA(ec)] by 72% in sham-operated rats with no change in OS(ec). In lesioned rats clorgyline increased [DA(ec)] by 66% and decreased OS(ec) by 44%. Rasagiline and clorgyline were effective to a similar extent in reduction of tissue levels of 7-ketocholesterol and the ratio GSSG/GSH, indicative of reduced intracellular oxidative stress level. This data implies that gliosis in our 6-OHDA animals together with inhibition of glial cell MAO-B by rasagiline causes an increase in local levels of dopamine at the presynaptic receptors, and a reduction in dopamine release (and in [DA(ec)]) by presynaptic inhibition. Moreover, inhibition of MAO-A or MAO-B reduces the enhanced level of oxidative stress in the lesioned striatum, and while both clorgyline and rasagiline reduced DA oxidative metabolism, rasagiline possesses an additional antioxidant property, not only that resulting from MAO inhibition.