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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 12, 2007; DOI: 10.1124/jpet.107.125955

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Received for publication May 21, 2007.
Revised September 8, 2007.
Accepted for publication September 10, 2007.

Neuroprotective Effects of GLNVA against Microglia-like Cells and 6-OHDA-Induced Neurotoxicity in SH-SY5Y Human Dopaminergic Neuroblastoma Cells

Yi-Chin Lin 1, Hao-Wei Uang 1, Rong-Jyh Lin 1, Ing-Jun Chen 1, Yi-Ching Lo 1*

1 Kaohsiung Medical University

* Address correspondence to: E-mail: yichlo{at}kmu.edu.tw

Abstract

Glyceryl nonivamide (GLNVA), a vanilloid receptor (VR) agonist, has been reported to have calcitonin gene-related peptide (CGRP)-associated vasodilatation and prevent subarachnoid hemorrhage-induced cerebral vasospasm. In this study, we investigated the neuroprotective effects of GLNVA on activated microglia-like cells mediated- and pro-parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA) induced-neurotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells. In co-culture conditions, we employed lipopolysaccharide (LPS) stimulated BV-2 cells as a model of activated microglia. LPS-induced neuronal death was significantly inhibited by DPI, an inhibitor of NADPH oxidase. However, capsazepine, the selective VR1 antagonist, did not block the neuroprotective effects of GLNVA. GLNVA reduced LPS activated microglia-mediated neuronal death but lacked protection in DPI pretreated cultures. GLNVA also decreased LPS activated microglia induced overexpression of nNOS and gp91phox on SH-SY5Y cells. Pretreatment of BV-2 cells with GLNVA diminished LPS-induced nitric oxide production, overexpression of iNOS and gp91phox and intracellular ROS. GLNVA also reduced COX-2 expression, I{kappa}B{alpha}/I{kappa}B{beta} degradation, NF-{kappa}B activation and the overproduction of TNF-{alpha}, IL-1{beta} and PGE2 in BV-2 cells. However, GLNVA augmented anti-inflammatory cytokine IL-10 production on LPS-stimulated BV-2 cells. Furthermore, in 6-OHDA-treated SH-SY5Y cells, GLNVA rescued the changes in condensed nuclear and apoptotic bodies, prevented the decrease in mitochondrial membrane potential and reduced cells death. GLNVA also suppressed accumulation of iROS and upregulated HO-1 expression. 6-OHDA-induced overexpression of nNOS, iNOS, COX-2 and gp91phox was also reduced by GLNVA. In summary, the neuroprotective effects of GLNVA are mediated, at least in part, by decreasing the inflammation- and oxidative stress-associated factors induced by microglia and 6-OHDA.


Key words: 6-OHDA, GLNVA, dopaminergic neuron, lipopolysaccharide, microglia, neuroprotection




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