title: Gö6976 protects mesencephalic neurons from lipopolysaccharide-elicited death by inhibiting p38 MAP kinase phosphorylation.
abstract: Glial activation is associated with inflammation-related neuron degeneration in the brain. A variety of protein kinases are assumed to contribute to the expression of inflammation-related products, such as nitric oxide (NO) and proinflammatory cytokines, however, the mechanisms of glial activation and glia-mediated neurotoxicity remain unclear. We found that the indolocarbazole, Gö6976, originally known as a selective protein kinase C (PKC) inhibitor, protects neurons from glia-mediated damage and suppresses lipopolysaccharide (LPS)-induced microglial production of inflammatory factors. The purpose of the study we report here was to determine the mechanism underlying the neuroprotective effect of Gö6976 in mesencephalic neuron/glia cultures. Gö6976 suppressed LPS-induced neurotoxicity in mesencephalic neuron/glia cultures and the protective effect of Gö6976 paralleled the suppression of p38 mitogen activated protein kinase (MAPK) activation and inhibition of NO production. Gö6976 did not directly inhibit the activity of p38 MAPK; rather, the inhibitor suppressed the phosphorylation of p38 MAPK, suggesting that the target of Gö6976 is a signaling event upstream of p38 MAPK. Although Gö6976 was originally known to be a selective PKC inhibitor, the neuroprotection was not mediated through its reputed effects on PKC activity. This paper demonstrates that the neuroprotective effect of Gö6976 against LPS-induced damage is mediated through the inhibition of proinflammatory factors, such as NO from microglia, by inhibiting the phosphorylation of p38 MAPK.
authors.affiliation: Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Gwang-Ho
authors.initials: GH
authors.lastname: Jeohn
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Cooper
authors.forename: Kyung-Jin
authors.initials: KJ
authors.lastname: Jang
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D016923:Cell Death; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; C081021:Go 6976; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases