The effect of nNOS inhibitors on toxin-induced cell death in dopaminergic cell lines depends on the extent of enzyme expression

Nitric oxide is linked with neurodegeneration in Parkinson's disease (PD) through the involvement of both inducible (iNOS) and neuronal nitric oxide synthase (nNOS). While non-selective NOS inhibitors are neuroprotective, the role of nNOS has not been determined using selective NOS inhibitors. The present study investigated the neuroprotective effect of selective iNOS and nNOS inhibitors on MPP+- and MG-132-induced cell death in cell lines with differing levels of nNOS expression. Inhibition of endogenously expressed nNOS by 7-NI and ARR17477 enhanced the toxicity of MPP+ and MG-132 in N1E-115 cells, whereas in transfected SH-SY5Y cells overexpressing nNOS, ARR17477 and 7-NI protected against MPP+- and MG-132-induced cell death. In contrast, inhibition of iNOS by 1400W was ineffective in preventing MPP+ and MG-132 toxicity in these cell lines. These results suggest a dual role for NOS in dopaminergic cell viability. nNOS is protective against toxic insult when produced endogenously. When nNOS is overexpressed, it becomes neurotoxic to cells suggesting that inhibition of nNOS may be a promising strategy to prevent cell death in PD.

► The effect of NOS inhibitors on toxin-induced cell death in cell lines was examined.
► NOS activity and cell viability in cell culture were determined.
► Inhibition of endogenously expressed nNOS enhances toxicity.
► Inhibition of overexpressed nNOS protects against toxin-induced cell death.
► A dual role for NOS in dopaminergic cell viability is suggested.