Neuroprotective effects of glyceryl nonivamide against microglia-like cells and 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y human dopaminergic neuroblastoma cells.
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.
Lin
Yi-Chin
YC
Department of Pharmacology and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., Kaohsiung 807, Taiwan.
Uang
Hao-Wei
HW
Lin
Rong-Jyh
RJ
Chen
Ing-Jun
IJ
Lo
Yi-Ching
YC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004298:Dopamine / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C080418:N-(4-O-glycerol-3-methoxybenzyl)nonivamide; D009569:Nitric Oxide; D016627:Oxidopamine; D005990:Glycerol; D002211:Capsaicin; D004298:Dopamine