Journal
JOURNAL OF NEUROTRAUMA
Volume 28, Issue 6, Pages 983-993Publisher
MARY ANN LIEBERT INC
DOI: 10.1089/neu.2010.1685
Keywords
inflammation; pioglitazone; peroxisome proliferator-activated receptor-gamma; rosiglitazone; traumatic brain injury
Funding
- Takeda Pharma, Germany
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Inflammatory and ischemic processes contribute to the development of secondary brain damage after mechanical brain injury. Recent data suggest that thiazolidinediones (TZDs), a class of drugs approved for the treatment of non-insulin-dependent diabetes mellitus, effectively reduces inflammation and brain lesion by stimulation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The present study investigates the influence of the TZD pioglitazone and rosiglitazone on inflammation and secondary brain damage after experimental traumatic brain injury (TBI). A controlled cortical impact (CCI) injury was induced in male C57BL/6 mice to investigate following endpoints: (1) mRNA expression of PPAR-gamma and PPAR-gamma target genes (LPL, GLT1, and IRAP/Lnpep), and inflammatory markers (TNF-alpha, IL-1 beta, IL-6, and iNOS), at 15 min, 3 h, 6 h, 12 h, and 24 h post-trauma; (2) contusion volume, neurological function, and gene expression after 24 h in mice treated with pioglitazone (0.5 and 1 mg/kg) or rosiglitazone (5 and 10 mg/kg IP at 30 min post-trauma); and (3) the role of PPAR-gamma to mediate protection was determined in animals treated with pioglitazone, the PPAR-gamma inhibitor T0070907, and a combination of both. Inflammatory marker genes, but not PPAR-gamma gene expression, was up-regulated after trauma. Pioglitazone reduced the histological damage and inflammation in a dose-dependent fashion. In contrast, rosiglitazone failed to suppress inflammation and histological damage. PPAR-gamma and PPAR-gamma target gene expression was not induced by pioglitazone and rosiglitazone. In line with these results, pioglitazone-mediated protection was not reversed by T0070907. The results indicate that the neuroprotective effects of pioglitazone are not solely related to PPAR-gamma-dependent mechanisms.
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