Modulation of monoamine oxidase (MAO) expression in neuropsychiatric disorders: genetic and environmental factors involved in type A MAO expression

Abstract

Monoamine oxidase types A and B (MAO-A, MAO-B) regulate the levels of monoamine neurotransmitters in the brain, and their dysfunction may be involved in the pathogenesis and influence the clinical phenotypes of neuropsychiatric disorders. Reversible MAO-A inhibitors, such as moclobemide and befloxatone, are currently employed in the treatment of emotional disorders by inhibiting the enzymatic degradation of dopamine, serotonin and norepinephrine in the central nervous system (CNS). It has been suggested that the irreversible MAO-B inhibitors selegiline and rasagiline exert a neuroprotective effect in Parkinson's and Alzheimer's diseases. This effect, however, is not related to their inhibition of MAO activity; in animal and cellular models, selegiline and rasagiline protect neuronal cells through their anti-apoptotic activity and induction of pro-survival genes. There is increasing evidence that MAO-A activity, but not that of MAO-B, is implicated in the pathophysiology of neurodegenerative disorders, but also in gene induction by MAO-B inhibitors; on the other hand, selegiline and rasagiline increase MAO-A mRNA, protein, and enzyme activity levels. Taken together, these results suggest that each MAO subtype exerts effects that modulate the expression and activity of the other isoenzyme. The roles of MAO-A and -B in the CNS should therefore be re-evaluated with respect to the "type-specificity" of their inhibitors, which may not be unconditional during chronic treatment. Mao-a expression, in particular, may be implicated in pathogenesis and phenotypes in neuropsychiatric disorders. MAO-A expression is modified by mao polymorphisms affecting its transcriptional efficiency, as well as by mutations and polymorphism of parkin, Sirt1, FOXO, microRNA, presenilin-1, and other regulatory proteins. In addition, childhood maltreatment has been shown to have an impact upon adolescent social behavior in children with mao-a polymorphisms of low transcriptional activity. Low MAO-A activity may increase the levels of serotonin and norepinephrine, resulting in disturbed neurotransmitter system development and behavior. This review discusses genetic and environmental factors involved in the regulation of MAO-A expression, in the contexts of neuropsychiatric function and of the regulation of neuronal survival and death.

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β‐amyloid in ageing and Alzheimer's disease

“…Previously, it was reported that MAO‐B activity is significantly increased in specific brain regions in ageing (Fowler et al ., ; Strolin Benedetti and Dostert, ; Cohen, ) and AD (Hirvonen et al ., ) and may contribute to neurodegenerative processes, secondary to ROS production. Furthermore, MAO‐A activity and gene expression have been found to be up‐regulated in different brain areas of AD patients (Burke et al ., ; Emilsson et al ., ; Naoi et al ., ). It was suggested that decreased levels of the CNS monoamines, such as dopamine, noradrenaline and 5‐HT (Adolfsson et al ., ) and an altered monoaminergic neurotransmitter system (e.g.…”

Monoamine Oxidase Is Overactivated in Left and Right Ventricles from Ischemic Hearts: An Intriguing Therapeutic Target

“…Oxidative deamination of MAO substrates that produces hydrogen peroxide and the corresponding aldehyde is selectively prevented by propargylamines (clorgyline and deprenyl) [5]. Many studies have extensively highlighted the role of MAO activity in the central nervous system [6–8]; however, its relevance in other organs, including the heart, has been investigated only recently. Increasing evidence suggests that, in rodent cardiomyocytes, MAO activity may contribute to NE- and 5-HT-induced hypertrophy, to apoptosis, and to the stimulation of cell glucose uptake by hydrogen peroxide generation [9–13].…”

Sculpting Cerebral Cortex with Serotonin in Rodent and Primate

“…Following the discovery of the lack of MAOA in Norrie disease [217], abnormal regulation of the enzymes implicated in 5-HT metabolism has been known for long to be associated with neuropsychiatric diseases (recently reviewed by Naoi et al [218]). However, it is not known whether the alteration in prenatal or post-natal human life induces such illness.…”