Therapy with central active catechol-O-methyltransferase (COMT)-inhibitors: is addition of monoamine oxidase (MAO)-inhibitors necessary to slow progress of neurodegenerative disorders?

Summary Neurotrophic factors, like e.g. nerve growth factor (NGF), neurotrophin 3 (NT-3) or brain-derived neurotrophic factor (BDNF) promote the survival and function of neurones in the peripheral and central nervous system. Dopamine or other biogenic amines induce the biosynthesis of neurotrophic factors in glial and neuronal cells. Therefore inhibition of enzymes, like the extraneuronal and neuronal located MAO or the predominantly glial situated COMT, which both metabolize catecholamines, may induce an increased biosynthesis of neurotrophic factors. Due to clinical studies especially MAO-B-inhibitors appear to slow the progression of neurological deficits in Parkinson's disease and the cognitive decline in Alzheimer's disease. On the one hand inhibition of COMT alone may also slow the metabolisation of biogenic amines in glial cells and may consequently induce synthesis of neurotrophic factors in glial cells. But on the other hand in vivo and in vitro studies show, that COMT-inhibitors may intensify the metabolisation of catecholamines in neurones by MAO, what may cause an enhanced generation of free radicals. This increase of free radicals may induce lipid peroxidation of membranes and therefore cause accelerated neuronal and glial cell death. For that reason we conclude, that centrally active COMT-inhibitors may only be used together with MAO-inhibitors in the neuroprotective treatment of neurodegenerative disorders. Medical treatment with both inhibitors will have to be performed very carefully due to cytotoxic effects of high catecholamine levels on neuronal and glial cells and due to possible prolongation or potentiation of the activity of several noradrenergic drugs in the periphery.