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KMID : 0880520080440030162
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Chonnam Medical Journal
2008 Volume.44 No. 3 p.162 ~ p.168
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Protective Effects of K6PC-5, A Sphingosine Kinase Activator, Against 1-methyl-4-phenylpyridinium-induced Dopaminergic Neuronal Cell Death
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Jang Su-Jeong
Kim Song-Hee
Choi Seung-Sik
Park Jong-Seong
Jeong Han-Seong
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Abstract
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Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metaolite, regulates multiple cellular responses such as Ca2＋ signaling, cellular growth and survival, and differentiation. Sphingosine kinase (SphK) is a key enzyme in modulating the levels of S1P and is emerging as an important regulating enzyme. Here we have investigated whether K6PC-5, a newly synthesized SphK activator, plays a neuroprotective role by activating cell survival systems such as protein kinase C, phosphatidylinositol-3-kinase (PI3K), and acting on the anti-apoptotic and the pro-apoptotic genes in SN4741 dopaminergic cells. 1-methyl-4-phenylpyridinium is a neurotoxin that selectively inhibits the mitochondrial functions of dopaminergic neurons in the substantia nigra pars compacta. In the present study, we found that MPP＋ induced a decrease in SN4741 mouse dopaminergic cell viability. K6PC-5 restored the reduced phospho-PKC and phospho-PI3K activities caused by MPP＋ toxicity. In addition, gene expression analysis revealed that K6PC-5 prevented both the MPP＋- induced expression of the pro-apoptotic gene mRNA, Bax, and the decrease of the anti-apoptotic gene mRNA, bcl-w. These results suggest that the neuroprotective mechanism of K6PC-5 against MPP＋-induced apoptotic cell death includes stimulation of PKC and PI3K, and modulation of cell survival and death genes.
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KEYWORD
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K6PC-5 compound, Sphingosine kinase-1, 1-methyl-4-phenylpyridinium, Parkinson disease, Dopaminergic agents
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