Brain Monoamine Oxidase B Activity and Amino Acid Precursor Treatment of Parkinson’s Disease, Depression and Epilepsy

Abstract

The importance of monoamine oxidase (MAO) A and B in maintaining the cytoplasmic levels of monoamines (dopamine, noradrenaline, serotonin and phenylethylamine) low within the aminergic neurones and their role in cytoplasmic release mechanism are well established. Animal behavioural and biochemical studies have shown that MAO in the brain is in excess and inhibition of enzyme by more than 80 % is required for amino release into “function”. The alteration in brain concentrations of dopamine and serotonin after L-dopa (L-dihydroxyphenylalamine) and L-tryptophan treatments respectively, are not as obvious as those seen in animals pretreated with selective MAO inhibitors. Therefore, enzyme inhibition and amino acid precursor loading would appear to be obvious and logical choice for treatment of Parkinson’s disease and depressive illness, where alterations in dopamine and serotonin metabolism have been implicated in their pathophysiology. The therapeutic success of 1-deprenyl (MAO-B inhibitor) in combination with L-dopa or L-5-hydroxytryptophan for the management of Parkinson’s disease and depression has manifested itself in the predominance of MAO-B in the extrapyramidal regions and raphe nucleus of human brain. The apparent potentiation of the pharmacological activities of the neurotransmitters, derived from amino acids precursors, by MAO-B inhibitor is supported by the clinical data, since neither treatment alone appears to be as effective. MAO-B is an enzyme capable of oxidizing a variety of primary, secondary and tertiary aliphatic and aromatic monoamines. This property of MAO-B lends itself to the oxidation of inert amines, including the Parkinson inducing compound, MPTP (N-methyl-4-phenyl-1, 2,3,6-tetrahydropridine), and the anticonvulsant, milacemide (2-n-pentylaminoacetamide) to neuroactive metabolites. Precursor amino acid treatment of neurological disorders, where inhibitory neurotransmitters GABA and glycine are implicated have not been successful, since, these amino acids hardly cross the blood brain barrier (BBB). However, the potent glycine-derivative anticonvulsant, milacemide, readily crosses the BBB where it is actively converted to glycineamide, followed by glycine. In vitro and in vivo studies have demonstrated that the major (80–90 %) route of its metabolism is solely mediated by MAO-B and is the only one so far identified in the brain. The oxidation of milacemide is selectively inhibited by MAO-B rather than MAO-A inhibitors. Milacemide, therefore, behaves as a prodrug and opens a new avenue for the development of similar drugs derived from other amino acids. Thus, just as in the case with “dopamine replacement” therapy of Parkinson’s disease by L-dopa, similar therapeutic approaches can be envisaged for the treatment of neurological disorders involving alterations in inhibitory amino acid neurotransmitters.