c-Jun N-terminal kinase inhibition and alpha-tocopherol protect midbrain dopaminergic neurons from interferon-gamma/lipopolysaccharide-induced injury without affecting nitric oxide production.
Interferon-gamma (IFN-gamma)/lipopolysaccharide (LPS) induces delayed dopaminergic neuron loss in midbrain slice cultures, because of nitric oxide production resulting from p38 mitogen-activated protein kinase (p38 MAPK)-dependent induction of inducible nitric oxide synthase (iNOS). In this study, we show that inhibition of c-Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase, protects dopaminergic neurons from IFN-gamma/LPS-induced degeneration. In contrast to a p38 MAPK inhibitor, SB203580, however, a JNK inhibitor, anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), did not suppress IFN-gamma/LPS-induced iNOS expression and nitric oxide production. Involvement of NADPH oxidase-derived superoxide production in dopaminergic neurodegeneration was not obvious, in that superoxide dismutase/catalase or manganese 3-methoxy-N,N'-bis(salicylidene)ethylenediamine chloride (EUK-134), a superoxide dismutase/catalase mimetic, did not afford neuroprotection. Moreover, the NADPH oxidase inhibitors apocynin and diphenylene iodonium were protective against IFN-gamma/LPS cytotoxicity only at concentrations that suppressed nitric oxide production. Notably, alpha-tocopherol effectively prevented IFN-gamma/LPS-induced dopaminergic neuron degeneration, without affecting iNOS induction and nitric oxide production. These results underscore the neuroprotective potential of JNK inhibitor and alpha-tocopherol, in the sense that both agents could rescue dopaminergic neurons under inflammatory conditions associated with robust increases in nitric oxide production.
Shibata
Haruki
H
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Katsuki
Hiroshi
H
Okawara
Mitsugi
M
Kume
Toshiaki
T
Akaike
Akinori
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004298:Dopamine / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000633:toxicity; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents; D009569:Nitric Oxide / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D013481:Superoxides / Q000378:metabolism; D024502:alpha-Tocopherol / Q000494:pharmacology*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D013481:Superoxides; D009569:Nitric Oxide; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D024502:alpha-Tocopherol; D004298:Dopamine