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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 13, 2006; DOI: 10.1124/jpet.106.113472

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*Substance via MeSH
Medline Plus Health Information
*Pain
*Spinal Cord Injuries


Received for publication September 7, 2006.
Revised December 11, 2006.
Accepted for publication December 11, 2006.

Thiazolidinedione Class of PPAR{gamma} Agonists Prevent Neuronal Damage, Motor Dysfunction, Myelin loss, Neuropathic Pain and Inflammation Following Spinal Cord Injury in Adult Rats

Seung-Won Park 1, Jae-Hyuk Yi 2, Guruwattan Miranpuri 2, Irawan Satriotomo 2, Kellie Bowen 2, Daniel K. Resnick 2, Raghu Vemuganti 2*

1 Univeristy of Wisconsin 2 University of Wisconsin

* Address correspondence to: E-mail: vemugant{at}neurosurg.wisc.edu

Abstract

Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). TZDs were shown to induce neuroprotection after cerebral ischemia by blocking inflammation. As spinal cord injury (SCI) induces massive inflammation that precipitates secondary neuronal death, we currently analyzed the therapeutic efficacy of TZDs pioglitazone and rosiglitazone following SCI in adult rats. Both pioglitazone and rosiglitazone (1.5 mg/ Kg; i.p.; 4 doses at 5 min, 12h, 24h, and 48h) significantly decreased the lesion size (by 57 to 68%, p<0.05), motor neuron loss (by 3 to 10 fold, p<0.05), myelin loss (by 66 to 75%, p<0.05), astrogliosis (by 46 to 61%, p<0.05) and microglial activation (by 59 to 78%, p<0.05) after SCI. TZDs significantly enhanced the motor function recovery (at 7 days after SCI, the motor scores were 37 to 45% higher in the TZD groups over vehicle group; p<0.05); but the treatment was effective only when the first injection was given by 2h after SCI. At 28-days after SCI, chronic thermal hyperalgesia was decreased significantly (by 31 to 39%; p<0.05) in the pioglitazone group compared to vehicle group. At 6h after SCI, pioglitazone group showed significantly less induction of inflammatory genes (IL6 by 83%, IL1{beta} by 87%, MCP1 by 75%, ICAM1 by 84% and Egr1 by 67%) compared to vehicle group (p<0.05 in all cases). Pioglitazone also significantly enhanced the post-SCI induction of neuroprotective heat-shock proteins and anti-oxidant enzymes. Pretreatment with a PPAR{gamma} antagonist GW9662 prevented the neuroprotection induced by pioglitazone.


Key words: CNS injury, Inflammation, Neuronal death, Nuclear hormone receptor, Pioglitazone, Transcription factor


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