Fenamate protects against 1-methyl-4-phenylpyridinium-induced apoptosis in dopaminergic MN9D cells
Le, Viet; Mapa, Mapa; Wimalasena, Kandatege From Abstracts of Papers, 256th ACS National Meeting & Exposition, Boston, MA, United States, August 19-23, 2018 (2018), BIOL-83
Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in substania nigra. While the causes of PD under mol. level have not been fully identified, it is necessary to identify the pharmacol. active compds. with neuroprotective properties aimed at protecting dopaminergic cells. Perturbation in calcium homeostasis has been implicated in PD and recently studies suggest that the calcium pathway is assocd. with mitochondrial functions and oxidative stress. 1-methyl-4-phenylpyridinium (MPP+) has been shown to induce dopaminergic cell death by targeting mitochondria that maintains mitochondrial functions including calcium homeostasis. Nevertheless, the mechanism by which MPP+ kills dopaminergic neurons is unclear. Recently, many members of the non-selective non-steroidal anti-inflammatory drugs (NSAID) shown to protect dopaminergic neurons in animal models against PD. NSAIDs are known inhibitors of cycloxygenenase-2 (COX-2), an enzyme responsible for inflammation and pain. Fenamate, one of the NSAID drugs, have been shown to affect a variety of channels including inhibition of transient receptor potential (TRP) channels. However, the action of fenamate on ion channels is not mediated by COX, because selective COX inhibitors were found to have no direct effect on TRP cationic channels. Interestingly, it has been reported that fenamate can modulate intracellular calcium level by inducing the release of calcium from the intracellular stores. Here we show that although fenamate do not inhibit the uptake of MPP+ in dopaminergic MN9D cells, but it significantly protects dopaminergic MN9D cells against MPP+. Fenamate decreases ROS prodn. caused by MPP+. In addn., while MPP+ does not increase the intracellular calcium level in dopaminergic MN9D cells, fenamate increases the intracellular calcium level. Thus, it is possible that the toxicity of MPP+ may be the result of the perturbation of intracellular calcium and the cellular protection could be due to the opposing effects of fenamate to that of MPP+ with respect to the intracellular calcium level. More studies are necessary to gain a better understanding of the mechanism(s) of specific dopaminergic toxicity of MPP+ and the neuroprotective properties of fenamate that may provide clues to the etiol. of sporadic PD.