Substance P prevents 1-methyl-4-phenylpyridiniuminduced cytotoxicity through inhibition of apoptosis via neurokinin-1 receptors in MES23.5 cells

Abstract

[Sar9, Met(O2)11] termed Substance P (SP), is an effective and selective agonist for the neurokinin-1 (NK-1) receptors, which are synthetic peptides, similar in structure to SP. SP is an important neurotransmitter or neuromodulator mediated by neurokinin receptors, namely the SP receptor in the central nervous system. The excitatory effects induced by SP may be selectively inhibited by a neurokinin-1 receptor antagonist, such as SR140333B. It has been proposed that Parkinson's disease (PD) is primarily caused by the loss of trophic peptidergic neurotransmitter, possibly SP, which may lead to the degeneration of neurons. In previous studies, 1-methyl-4-phenylpyridinium (MPP+) has been frequently utilized to establish animal or cell models of PD. In the present study, to further investigate the effects of SP in PD, MPP+ was employed to investigate the promising anti-apoptotic effects of SP, and examine the underlying mechanisms of the pathology in the MES23.5 dopaminergic cell line. The results indicated that MPP+-triggered apoptosis was prevented by treatment with SP. SP treatment also decreased the MPP+-triggered Ca2+ influx, caspase-3 re-activity, reactive oxygen species production and mitochondrial membrane potential decrease. Treatment with MPP+ also induced phosphorylation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. In addition, treatment with SP inhibited the MPP+-triggered neurotoxicity in MES23.5 cells. However, no changes were observed in SR140333B+SP+MPP+-treated MES23.5 cell lines. In conclusion, SP could protect the cells from MPP+-induced cytotoxicity by inhibiting the apoptosis via NK-1 receptors.