Glyceryl nonivamide (GLNVA), a
vanilloid receptor (VR) agonist, has been reported to have
calcitonin gene-related peptide-associated vasodilatation and to prevent
subarachnoid hemorrhage-induced
cerebral vasospasm. In this study, we investigated the
neuroprotective effects of GLNVA on activated microglia-like cell mediated- and proparkinsonian
neurotoxin 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in human dopaminergic
neuroblastoma SH-SY5Y cells. In coculture conditions, we used
lipopolysaccharide (LPS)-stimulated BV-2 cells as a model of activated microglia. LPS-induced neuronal death was significantly inhibited by
diphenylene iodonium (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 it lacked protection in DPI-pretreated cultures. GLNVA also decreased LPS activated microglia induced overexpression of
neuronal nitric-oxide synthase (nNOS) and
glycoprotein 91 phagocyte
oxidase (gp91(
phox)) on SH-SY5Y cells. Pretreatment of BV-2 cells with GLNVA diminished LPS-induced
nitric oxide production, overexpression of
inducible nitric-oxide synthase (iNOS), and gp91(
phox) and intracellular
reactive oxygen species (iROS). GLNVA also reduced
cyclooxygenase (COX)-2 expression, inhibitor of nuclear factor (
NF)-kappaB (
IkappaB)alpha/
IkappaBbeta degradation,
NF-kappaB activation, and the overproduction of
tumor necrosis factor-alpha,
interleukin (IL)-1beta, and
prostaglandin E2 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 up-regulated
heme oxygenase-1 expression. 6-OHDA-induced overexpression of nNOS, iNOS, COX-2, and gp91(
phox) 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.