title: Pioglitazone reduces secondary brain damage after experimental brain trauma by PPAR-γ-independent mechanisms.
abstract: 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-γ (PPAR-γ). 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-γ and PPAR-γ target genes (LPL, GLT1, and IRAP/Lnpep), and inflammatory markers (TNF-α, IL-1β, 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-γ to mediate protection was determined in animals treated with pioglitazone, the PPAR-γ inhibitor T0070907, and a combination of both. Inflammatory marker genes, but not PPAR-γ gene expression, was upregulated 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-γ and PPAR-γ 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-γ-dependent mechanisms.
authors.affiliation: Department of Anesthesiology, Medical Center of the Johannes Gutenberg-University, Mainz, Germany. thal@uni-mainz.de
authors.forename: Serge C
authors.initials: SC
authors.lastname: Thal
authors.forename: Marius
authors.initials: M
authors.lastname: Heinemann
authors.forename: Clara
authors.initials: C
authors.lastname: Luh
authors.forename: Dana
authors.initials: D
authors.lastname: Pieter
authors.forename: Christian
authors.initials: C
authors.lastname: Werner
authors.forename: Kristin
authors.initials: K
authors.lastname: Engelhard
mesh_terms: D000818:Animals; D001925:Brain Damage, Chronic / Q000188:drug therapy* / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000502:physiology*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone