Monoamine oxidase-B inhibitors as potential neurotherapeutic agents: An overview and update

This article provides an update about catecholamine metabolism, with emphasis on correcting common misconceptions relevant to catecholamine systems in health and disease. Importantly, most metabolism of catecholamines takes place within the same cells where the amines are synthesized. This mainly occurs secondary to leakage of catecholamines from vesicular stores into the cytoplasm. These stores exist in a highly dynamic equilibrium, with passive outward leakage counterbalanced by inward active transport controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes depends on the dynamics of vesicular-axoplasmic monoamine exchange and enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol, not 3,4-dihydroxymandelic acid. Subsequent extraneuronal O-methylation consequently leads to production of 3-methoxy-4-hydroxyphenylglycol, not vanillylmandelic acid. Vanillylmandelic acid is instead formed in the liver by oxidation of 3-methoxy-4-hydroxyphenylglycol catalyzed by alcohol and aldehyde dehydrogenases. Compared to intraneuronal deamination, extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism. The single largest source of metanephrines is the adrenal medulla. Similarly, pheochromocytoma tumor cells produce large amounts of metanephrines from catecholamines leaking from stores. Thus, these metabolites are particularly useful for detecting pheochromocytomas. The large contribution of intraneuronal deamination to catecholamine turnover, and dependence of this on the vesicular-axoplasmic monoamine exchange process, helps explain how synthesis, release, metabolism, turnover, and stores of catecholamines are regulated in a coordinated fashion during stress and in disease states.

Oestrogen use by postmenopausal women has many health benefits, but findings on the effect of oestrogen in Alzheimer's disease are conflicting. Oestrogen promotes the growth and survival of cholinergic neurons and could decrease cerebral amyloid deposition, both of which may delay the onset or prevent Alzheimer's disease. To investigate whether use of oestrogen during the postmenopausal period affects the risk of Alzheimer's disease, we studied 1124 elderly women who were initially free of Alzheimer's disease, Parkinson's disease, and stroke, and who were taking part in a longitudinal study of ageing and health in a New York City community. Relative risks and age-at-onset distributions were calculated from simple and adjusted Cox proportional hazards models. Standard annual clinical assessments and criterion-based diagnoses were used in follow-up (range 1-5 years). Overall, 156 (12.5%) women reported taking oestrogen after onset of menopause. The age at onset of Alzheimer's disease was significantly later in women who had taken oestrogen than in those who did not and the relative risk of the disease was significantly reduced (9/156 [5.8%] oestrogen users vs 158/968 [16.3%] nonusers; 0.40 [95% Cl 0.22-0.85], p < 0.01), even after adjustment for differences in education, ethnic origin, and apolipoprotein-E genotype. Women who had used oestrogen for longer than 1 year had a greater reduction in risk; none of 23 women who were taking oestrogen at study enrolment has developed Alzheimer's disease. Oestrogen use in postmenopausal women may delay the onset and decrease the risk of Alzheimer's disease. Prospective studies are needed to establish the dose and duration of oestrogen required to provide this benefit and to assess its safety in elderly postmenopausal women.