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Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with IκBα induction and block of NFκB and iNOS activation
Author(s) -
Dehmer Thomas,
Heneka Michael T.,
Sastre Magdalena,
Dichgans Johannes,
Schulz Jörg B.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02210.x
Subject(s) - pioglitazone , substantia nigra , mptp , pars compacta , dopaminergic , medicine , endocrinology , striatum , nitric oxide synthase , glial fibrillary acidic protein , tyrosine hydroxylase , agonist , dopamine , chemistry , biology , receptor , nitric oxide , diabetes mellitus , type 2 diabetes , immunohistochemistry
Inflammation has been implicated in the pathogenesis of Parkinson's disease (PD). In the chronic 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) model of PD, inducible NO synthase (iNOS) derived nitric oxide (NO) is an important mediator of dopaminergic cell death. Ligands of the peroxisome proliferator‐activated receptor (PPAR) exert anti‐inflammatory effects. We here investigated whether pioglitazone, a PPARγ agonist, protected mice from MPTP‐induced dopaminergic cell loss, glial activation, and loss of catecholamines in the striatum. As shown by western blot, PPARγ was expressed in the striatum and the substantia nigra of vehicle‐ and MPTP‐treated mice. Oral administration of 20 mg/(kg day) of pioglitazone protected tyrosine hydroxylase (TH)‐positive substantia nigra neurons from death induced by 5 × 30 mg/kg MPTP. However, the decrease of dopamine in the striatum was only partially prevented. In mice treated with pioglitazone, there were a reduced activation of microglia, reduced induction of iNOS‐positive cells and less glial fibrillary acidic protein positive cells in both striatum and substantia nigra pars compacta. In addition, treatment with pioglitazone almost completely blocked staining of TH‐positive neurons for nitrotyrosine, a marker of NO‐mediated cell damage. Because an increase in inhibitory protein‐κ‐Bα (IκBα) expression and inhibition of translocation of the nuclear factor kappaB (NFκB) subunit p65 to the nucleus in dopaminergic neurons, glial cells and astrocytes correlated with the protective effects of pioglitazone, our results suggest that pioglitazone sequentially acts through PPARγ activation, IκBα induction, block of NFκB activation, iNOS induction and NO‐mediated toxicity. In conclusion, treatment with pioglitazone may offer a treatment opportunity in PD to slow the progression of disease that is mediated by inflammation.