2-APB and CGP-37157 as neuroprotective agents against the toxicity and uptake of 1-methyl-4-phenylpyridinium in dopaminergic MN9D cell
Le, Viet; Mapa, Mapa; Wimalasena, Kandatege From Abstracts of Papers, 254th ACS National Meeting & Exposition, Washington, DC, USA, August 20-24, 2017 (2017), BIOL-64
Parkinson's disease (PD) is characterized by the death of dopaminergic neurons in the substania nigra, a region in the midbrain. The cause of this dopaminergic cell death is unknown and current therapies have not been able to halt or slow down the progression of this disease, although the quality of life for patients with PD undergoing therapies has significantly improved. Thus, a great deal of attention has garnered to the neuroprotective agents as a means to slow down the PD progression. Neurotoxin 1-methyl-4-phenylpyridinium (MPP+) has been commonly used as an exptl. model of PD and it has been shown to perturb the calcium homeostasis that is thought to assocd. with PD. Therefore, it could be an effective mol. target for the neuroprotective agents for the protection of dopaminergic neuron. Here, we show that 2-aminoethyl diphenylborinate (2-APB), a blocker of inositol 1,4,5-triphosphate (IP3) receptor which release calcium from the endoplasmic reticulum, and CGP-37157, a blocker of mitochondrial sodium/calcium exchanger, do not inhibit the uptake of MPP+ into dopaminergic MN9D cells, but significantly protect these cells from the toxicity of MPP+. On the other hand, plasma membrane calcium-channel inhibitors such as benzamil and verapamil inhibit the uptake of MPP+ into MN9D cells, but do not protect these cells from the toxicity of MPP+. These findings suggest that MPP+ indirectly exert its toxicity effect by perturbing the intracellular calcium level that may lead to dopaminergic cell death and 2-APB and CPG-37157 modulate the calcium-dependent pathways and stores underlying neuroprotection against the toxicity of MPP+. A better understanding of the mol. mechanism that protects dopaminergic neurons may lead to a new therapeutic target and improved treatment of PD.