Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in:Journal of Medicinal Chemistry 58.13 (2016)

Altered synaptic transmission with excess glutamate release has been implicated in the loss of motoneurons occurring in amyotrophic lateral sclerosis (ALS). Hyperexcitability or hypoexcitability of motoneurons from mice carrying the ALS mutation SOD1(G93A) (mSOD1) has also been reported. Here we have investigated the excitability, the ion currents, and the kinetics of the exocytotic fusion pore in chromaffin cells from postnatal day 90 to postnatal day 130 mSOD1 mice, when motor deficits are already established. With respect to wild-type (WT), mSOD1 chromaffin cells had a decrease in the following parameters: 95% in spontaneous action potentials, 70% in nicotinic current for acetylcholine (ACh), 35% in Na(+) current, 40% in Ca(2+)-dependent K(+) current, and 53% in voltage-dependent K(+) current. Ca(2+) current was increased by 37%, but the ACh-evoked elevation of cytosolic Ca(2+) was unchanged. Single exocytotic spike events triggered by ACh had the following differences (mSOD1 vs. WT): 36% lower rise rate, 60% higher decay time, 51% higher half-width, 13% lower amplitude, and 61% higher quantal size. The expression of the α3-subtype of nicotinic receptors and proteins of the exocytotic machinery was unchanged in the brain and adrenal medulla of mSOD1, with respect to WT mice. A slower fusion pore opening, expansion, and closure are likely linked to the pronounced reduction in cell excitability and in the ion currents driving action potentials in mSOD1, compared with WT chromaffin cells.

Since the first generation of MAO inhibitors was developed, more than fifty years ago, this family of drugs has been ups and downs over the last decades. Actually, interest in MAO inhibitors is reviving and the emergence of new advances in the rational design of molecules and new techniques to predict the in vivo behavior has encouraged the research for new drugs with therapeutic potential in this area. The classic MAOIs have been widely used as antidepressants during the two decades after its introduction in clinic. Based on observations made on MAO inhibition by these drugs, it has been postulated hypothesis that have contributed to a better understanding of the mechanism and management of depressive disorders. However, exaggerated concerns about food and drug interactions relegated these drugs from the pharmaceutical landscape. The correct interpretation and the contextualization of side effects and the recent research findings, in which MAO selective inhibitors appear as promising agents in the treatment of emerging and high prevalence diseases, are placing these drugs again into the scientific and pharmacological focus.

These findings suggest that hypertrophic aortic remodeling and abnormal contraction triggered mainly by Ca2+ overload via STIM-1/Orai-1-mediated SOCE through SOCCs are involved hypertension developed by EtOH consumption.

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