The effects of ajmaline on human platelet aggregation, arachidonate metabolism and platelet activating factor (PAF)-induced lethality in rabbits were examined. Platelet aggregation induced by several stimuli (ADP, collagen, and PAF) was inhibited by increasing concentrations of ajmaline. The potency of ajmaline was higher when PAF was employed as stimulating agent in comparison with other agonists (IC50 70, 270 and 380 microM for PAF, ADP and collagen, respectively) whereas ajmaline had no effect against arachidonic acid-induced aggregation. In contrast however, ajmaline inhibited arachidonate metabolism by platelet homogenates. The formation of both thromboxane A2 and 12-hydroxy-eicosatetraenoic acid was inhibited by ajmaline with comparable potencies. Pretreatment of rabbits with ajmaline (50 mg kg-1) completely abolished the lethal effects of PAF (11 micrograms kg-1) given intravenously (P < 0.001). In addition, ajmaline at doses ranging from 50 to 100 mg kg-1 inhibited carrageenan-induced rat paw oedema (P < 0.001). In this test ajmaline was three times more potent than aspirin. In the light of these results we conclude that ajmaline, a known anti-arrhythmic agent is a PAF antagonist and a dual inhibitor of platelet cyclo-oxygenase and lipoxygenase enzymes with anti-inflammatory properties.
Monoamine oxidase (MAO) performs deamination of amines and is found bound to the outer mitochondrial membrane at high‐concentration in neuronal cells. There are two isoforms of MAO: MAO_A which oxidizes serotonin, noradrenaline and adrenaline, and MAO_B which oxidizes dopamine, b‐phenylethylamine (PEA), and benzylamine. Alterations in MAO activity can occur in some central and peripheral nervous system diseases. More specifically, heightened MAO_B activity in the brain occurs in Alzheimer's disease, Huntington's disease, Parkinson's disease and normal aging. Abnormal MAO_A activity has found to be associated with depression, anxiety and psychiatric disorders. Drugs have been developed and continue to be developed for both MAO_A and MAO_B as targets. MAO_A is inhibited by clorgyline and MAO_B is potently inhibited by both deprenyl and pargyline. Using these inhibitors as controls, a fluorescent activity assay was performed with commercially available catechins (green tea extracts), serotonin, and benzylamine substrates for MAO_A and MAO_B respectively, to investigate and confirm recent studies suggesting that green tea catechins (polyphenols) may be preventative for certain degenerative diseases and emotional illnesses utilizing MAOs as a target. Using a fluorescent assay, the Km value of serotonin to MAO_A was 1.75 μM and the Km value of benzylamine to MAO_B was 0.75 μM. The IC50 of clorgyline to MAO_A was 3.25 nM and that of deprenyl to MAO_B was 7.25 nM, in close agreement with the literature. The commercial catechins tested were found to have IC50s in the low‐to‐mid μM range (~50–750 μM). Efforts to purify catechins are underway to repeat these studies. Molecular docking of specific catechins into the MAO_A and MAO_B active sites resulted in binding constants in the low μM range (in agreement with experimentally determined Km values for natural substrates). Crystallization studies of MAO/catechin complexes are in progress.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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