Research ReportPPARγ agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms
Introduction
Traumatic brain injury (TBI) is a major disabling condition in young adults all over the world. Several pathological events including inflammation, apoptosis, oxidative stress and excitotoxicity during the acute stage after an injury are known to precipitate the neuronal death and neurological dysfunction (Raghupathi, 2004, Jennings et al., 2008). Hence, therapeutic compounds that can target multiple pathophysiological mechanisms can be extremely useful in preventing post-TBI neuronal death. Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor of nuclear hormone receptor superfamily (Escher and Wahli, 2000). 15-d-Prostaglandin J2 is the natural ligand of PPARγ, while several thiazolidinediones (TZDs) are potent synthetic agonists (Kapadia et al., 2008). As PPARγ plays a significant role in glucose and lipid homeostasis, 2 TZDs rosiglitazone and pioglitazone are currently approved by the United States Food and Drug Administration (FDA) for type-2 diabetes treatment (Sood et al., 2000).
Recent studies showed that both rosiglitazone and pioglitazone are extremely neuroprotective in animal models of acute CNS insults including focal ischemia, spinal cord injury (SCI) and surgical trauma (Sundararajan et al., 2005, Zhao et al., 2005Zhao et al., 2006, Pereira et al., 2006, Collino et al., 2006, Tureyen et al., 2007, Park et al., 2007, McTigue et al., 2007, Hyong et al., 2008). Their efficacy was also shown in animal models of chronic CNS injuries like Parkinson's disease, Amyotrophic lateral sclerosis and Alzheimer's disease (Breidert et al., 2002, Schütz et al., 2005, Pedersen et al., 2006). We currently evaluated the therapeutic potential of rosiglitazone in minimizing secondary lesion expansion, apoptotic markers, infiltration of macrophages/activation of microglia, and the expression of inflammatory, anti-oxidant and heat-shock protein (HSP) genes in adult mice subjected to controlled cortical impact (CCI) injury.
Section snippets
TBI-induced cortical PPARγ expression
At 1 day following CCI injury, the mRNA expression of PPARγ was observed to be upregulated (by 2.1 fold; p < 0.05) in the cortical tissue surrounding the injury epicenter compared to sham control (Fig. 1). Rosiglitazone treatment following CCI injury (6 mg/kg, i.p. at 5 min, 6 h and 12 h) resulted in a significantly higher induction of PPARγ mRNA (by 4.4 fold; p < 0.05) compared to sham (Fig. 1). Whereas, treatment with GW9662 (a PPARγ antagonist; 4 mg/kg, i.p. at 5 min and 12 h) prevented the
Discussion
PPARγ is a transcription factor of nuclear hormone receptor superfamily (Blanquart et al., 2003). The PPAR protein is a complex of several domains including a DNA-binding domain (DBD), a ligand binding domain (LBD) and a D-domain that links DBD and LBD (Escher and Wahli, 2000). In the absence of a ligand, the PPAR will be associated with a corepressor complex to tans-repress the target genes. Whereas, when a specific ligand binds to the LBD, the PPAR complex dimerizes with retinoic
Controlled cortical impact injury and drug administration
TBI was induced in adult male C57BL/6 mice (22–25 g) with a CCI device as described earlier (Rao et al., 2001). All surgical procedures were conducted and animals were cared for according to the animal welfare guidelines (1985 Principles of the Guide for the Care and Use of Laboratory Animals, U.S. Department of Health and Human Services Publ. 85–23) and were approved by the animal care committee of the University of Wisconsin-Madison. In brief, a moderate grade injury was induced through a
Acknowledgments
These studies were partially supported by grants from the United States National Institute of Health (RO1 NS044173 and RO1 NS049448), the American Heart Association (Grant-in-Aid 0350164N) and the faculty start-up funds from the University of Wisconsin to R. Vemuganti.
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