 | NITRIC OXIDE: NOVEL ACTIONS, DELETERIOUS EFFECTS, AND CLINICAL POTENTIAL
Copyright © 2002 by the New York Academy of Sciences
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Annals of the New York Academy of Sciences 962:332-346 (2002)
© 2002 New York Academy of Sciences
p38 MAP Kinase Is Involved in Lipopolysaccharide-Induced Dopaminergic Neuronal Cell Death in Rat Mesencephalic Neuron-Glia Cultures
GWANG-HO JEOHNa,
CYNTHIA L. COOPERb,
BELINDA WILSONa,
RAYMOND C.C. CHANGa,
KYUNG-JIN JANGc,
HYOUNG-CHUN KIMb,
BIN LIUa AND
JAU-SHYONG HONGa
aNeuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, North Carolina, U.S.A.
bDivision of Science, Truman State University, Kirksville, Missouri, U.S.A.
cDepartment of Pharmacy, Kangwon National University, Chuncheon, 200-701, Korea
Address for correspondence: J.S. Hong, Neuropharmacology Section, LPC, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709, U.S.A. Voice: 919-541-2358; fax: 919-541-0841.
hong3{at}niehs.nih.gov
Ann. N.Y. Acad. Sci. 962: 332-346 (2002).
Immune stimulants, such as the bacterial endotoxin, lipopolysaccharide (LPS), the human immunodeficiency virus-1 coat protein gp120, or ß-amyloid peptides, lead to glial activation and production of various immune mediators, such as nitric oxide (NO) and proinflammatory cytokines in the brain. These mediators appear to contribute to neuronal cell death in neurodegenerative diseases. However, the signaling pathways, which mediate the neurotoxic effect by the endotoxin, are not understood. The purpose of this study was to determine the role of mitogen-activated protein kinase (MAPK) in LPS-induced neurodegeneration using mesencephalic dopaminergic neuron/glia cultures. We have found that the p38 MAPK is important in LPS-induced death of mesencephalic neurons in rat neuron-glia mixed cultures. Upon treatment with 10 ng/ml LPS, the number of dopaminergic neurons decreased by 80% within 48 h, preceded by a significant production of NO by glia. Neuroprotection by selective inhibition of p38 MAPK activity paralleled a decrease in LPS-induced inducible nitric oxide synthase (iNOS) expression. These events were significantly reduced by the selective p38 MAPK inhibitor, SB202190, but not by the inactive analogue SB202474. Inhibition of iNOS activity and NO production by treatment with GW274150 was also neuroprotective. Although the p38 MAPK inhibitor afforded significant neuroprotection from LPS toxicity in the neuron-glia mixed culture, it failed to protect dopaminergic neurons from 6-hydroxy-dopamine-induced toxicity, which acts directly on dopaminergic neurons by inducing hydroxyl radical formation from the mitochondria. The results suggest that p38 MAPK in glia plays a significant role in the LPS-induced death of mesencephalic neurons through induction of nitric oxide synthase and resulting NO production.
Key Words: neurotoxicity • glia • lipopolysaccharide • endotoxin • nitric oxide • p38 MAP kinase • SB202190 • GW274150 • iNOS Abbreviations: ABC avidin-biotin-peroxidase complex. • DAB 3,3'-diaminobenzidine. • GW274150 (S)-2-amino-(1-iminoethylamino)-5-thioheptanoic acid. • iNOS inducible nitric oxide synthase. • LPS lipopolysaccharide. • MAPK mitogen-activated protein kinase. • NO nitric oxide. • 6-OHDA 6-hydroxy-dopamine. • PBSphosphate buffered saline. • PCRpolymerase chain reaction.
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