STRESS, INDUCIBLE NITRIC OXIDE SYNTASE (iNOS), AND MPTP-INDUCED PARKINSONISM IN TRANSGENIC MICE WITH DYSFUNCTIONAL GLUCOCORTICOID RECEPTOR (GR) FUNCTION

It is generally assumed that stress and glucocorticoids (GCs) have neurotoxic effects and play a central role in neuonal cell loss during aging and following neuropathological insults. However, GCs, by virtue of their interaction with the immune system, exert potent anti-inflammatory and immunosuppressive effects. Hence, after binding to their cytoplasmatic receptor (GR), GCs inhibit the transcription of several cytokines and inflammatory mediators, including nitric oxide, NO, through repression of inducible NO synthase (iNOS), thereby limitng inflammatory reactions. Among several toxic oxidative species, the local generation of toxic concentrations of NO has been implicated in the mechanism of nerve cell death in Parkinson’s disease (PD). Here we have studied the effect of a dysfunctional GR in MPTP (1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine, 35 mg/kg/day i.p. for 5 consecutive days) model of PD in wild type (Wt) and transgenic (Tg) mice expressing GR antisense RNA. Activation of the stress axis was present in both Wt and Tg mice, as revealed by increased plasma corticosterone levels throught the experimental period. In GRdeficient mice, both peripheral and crentral macrophage activation preceeded MPTPinduced dopaminergic neuronal cell loss, as revealed by the sharp increase in nitrites/nitrates (an indirect measure of NO) production in vitro by macrophage and glial cultures, and by iNOS-immunopositivity of striatal astrocytes and microglial cells. Thyrosine hydroxylase (TH) immunohistochemistry documented a dramatic decrease TH-immunoreactivity in triatum and substantia nigra of Tg mice as compared to Wt mice. Neurochemical determinations indicated that striatal loss of dopamine (DA) was greater in Tg as compared to Wt mice 7 days after MPTP, when 3,4- dihydroxyphenylacetic acid (DOPAC)+homovanilic acid (HVA)/DA ratio and dehydroascorbic acid (DHA)/ ascorbic acid (AA) ratio ratio were sharply up-regulated in Tg with respect to Wt mice. These results indicate that long-lasting GR deficiency renders the nigrostriatal DA system highly vulnerable to MPTP-induced DA degeneration, through increased oxidative DA metabolism, pointing to iNOS inducibility as a key risk factor in this murine model of PD.