Milacemide, the selective substrate and enzyme-activated specific inhibitor of monoamine oxidase B, increases dopamine but not serotonin in caudate nucleus of rhesus monkey

Abstract

Treatment of healthy male rhesus monkeys with milacemide 2(n-pentylaminoacetamide hydrochloride, 100 mg/kg, 21 days), the specific enzyme-activated inhibitor of monoamine oxidase B, resulted in a significant increase of dopamine (DA) in the caudate nucleus. There was a concomitant reduction of dihydroxyphenylacetic acid (dopac) and homovanilic acid (HVA) in the same region. Although serotonin (5-HT) and its oxidatively deaminated metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the striatum, pons and hippocampus were unchanged, significant increases in frontal cortex, temporal cortex and visual cortex 5-HT were noted. However, noradrenaline (NA) was unchanged in the brain regions examined. The alteration in caudate nucleus dopamine metabolism, resulting from milacemide treatment can be explained by the observation that in this tissue the predominant form of monoamine oxidase (MAO) is type B. Thus, although DA is a substrate for both enzyme forms in monkey brain, similar to what has been reported in human brain, its inactivation is primarily dependent on MAO-B activity. The ability of milacemide to specifically inhibit MAO-B in the brain makes it a natural choice as adjuvant to l-dopa for the treatment of Parkinson's disease.