Amine oxidases and their inhibitors: what can they tell us about neuroprotection and the development of drugs for neuropsychiatric disorders?

Although monoamine oxidase (MAO) inhibitors are not used as extensively as other antidepressants, they continue to have an important place in the armamentarium of drugs used to treat psychiatric and neurological disorders. Interest in MAO inhibitors has also increased in recent years because of numerous reports of their neuroprotective/neurorescue properties. Such studies have resulted in a better understanding of possible mechanisms of neuroprotection; stimulated the development of new drugs, such as rasagiline; provided important clues for the development of other drugs for neuropsychiatric disorders; and contributed to the recent surge of interest in possible neuroprotective actions of psychiatric drugs in general. Intriguingly, they have also demonstrated that the MAO inhibitors currently available are multifaceted, since, in many cases, the neuroprotection seems to be independent of their MAO inhibition. Studies on semicarbazidesensitive amine oxidase (SSAO) and its inhibition have also provided exciting results that are relevant to neuropsychiatric disorders and associated diabetes and cardiovascular disease. These findings are outlined briefly below. Tranyclypromine, an irreversible, nonselective MAO inhibitor, has not been investigated as extensively as some of the other MAO inhibitors with regard to neuroprotection, but it has been reported to cause an increase in messenger ribonucleic acid (mRNA) for brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (AMP) response element binding protein (CREB) 11 in the rat brain hippocampus — effects that could lead to neurogenesis. l-Deprenyl (l-N-propargyl,N-methylamphetamine, selegiline), a selective irreversible MAO-B inhibitor, was originally developed in the hope that it would be an effective antidepressant without the pressor effect (“cheese effect”), which can occur in patients on irreversible MAO-A inhibitors when foods containing tyramine are ingested. It turned out to be a poor antidepressant drug, except at higher doses, at which it also inhibited MAO-A (although recent reports indicate that transdermal administration allows doses of l-deprenyl to be used that are sufficient to inhibit brain MAO-A and produce an antidepressant effect without substantially inhibiting MAO-A in the gut). l-Deprenyl is used in Parkinson’s disease and has more recently been reported to be of some use in Alzheimer’s disease (AD), although a recent Cochrane review did not report evidence of clinically meaningful benefit in AD. l-Deprenyl is remarkable in that it has been demonstrated to have neuroprotective or neurorescue properties in a wide variety of neurotoxicity tests in vivo and in vitro. A direct result of research on l-deprenyl has been the development of rasagiline, a structurally related drug (both contain an N-propargyl group), which has now been approved for use in Parkinson’s disease in many countries. Rasagiline has an advantage over l-deprenyl of not being metabolized to lamphetamine and l-methamphetamine. The mechanisms of neuroprotective action of these N-propargyl drugs appear to be complex. In a recent review, Youdim and colleagues indicated that l-deprenyl and rasagiline interact with the outer mitochondrial membrane, preventing neurotoxin-induced collapse of mitochondrial membrane potential and permeability transition and the opening of the voltage-dependent anion channel; these effects are proposed to be the result of upregulation of antiapoptotic B-cell leukemia/lymphoma 2 (BCL2) protein. l-Deprenyl and rasagiline have also been shown to downregulate proapoptotic proteins such as BCLassociated death promoter (BAD) and BCL-associated protein X (BAX) and to prevent the activation and nuclear localization of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an initiator of apoptotic cascades, in response to neurotoxins and reactive oxygen species. Many of the effects of these N-propargyl drugs and the consequent neuro-