C‐Jun N‐terminal kinase inhibition and α‐tocopherol protect midbrain dopaminergic neurons from interferon‐γ/lipopolysaccharide‐induced injury without affecting nitric oxide production

Interferon‐γ (IFN‐γ)/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‐γ/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‐γ/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‐γ/LPS cytotoxicity only at concentrations that suppressed nitric oxide production. Notably, α‐tocopherol effectively prevented IFN‐γ/LPS‐induced dopaminergic neuron degeneration, without affecting iNOS induction and nitric oxide production. These results underscore the neuroprotective potential of JNK inhibitor and α‐tocopherol, in the sense that both agents could rescue dopaminergic neurons under inflammatory conditions associated with robust increases in nitric oxide production. © 2005 Wiley‐Liss, Inc.