Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperExtension of the neuroprotective time window for thiazolidinediones in ischemic stroke is dependent on time of reperfusion
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Rats
Male Wistar rats, 250–300 g, were obtained from Charles River (Wilmington, MA, USA). Animals were housed and cared for in the Animal Resource Center and allowed free access to food and water before and after surgery. All procedures were approved by the Institutional Animal Care and Use Committee of Case Western Reserve University and in accordance with the guidelines specified in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All efforts were made to
Dose response curves for pioglitazone and rosiglitazone
Several doses of pioglitazone and rosiglitazone were tested in a pre-treatment paradigm in order to efficiently identify the optimal doses for neuroprotection. Subsequent experiments utilized more clinically relevant post-MCAO treatment times. Maximal reduction in infarction volume by pioglitazone was achieved using a dose of 1 mg/kg and for rosiglitazone at 0.1 mg/kg dissolved in DMSO and injected i.p. 24 h before and at the time of MCAO (Fig. 1). These doses are consistent with the potency of
Discussion
This study builds on our previous work demonstrating that TZDs reduce infarction volume and improve long term neurologic function in a rodent model of ischemia (Sundararajan et al., 2005, Victor et al., 2006) and specifically addresses optimal dosing paradigms including factors that influence the time window of efficacy. The current data indicate TZDs are protective at clinically relevant doses, independent of any effects on systemic blood pressure or CBF. Importantly, reperfusion, and
Acknowledgments
The authors would like to thank the technical assistance of Kimberly Deininger and Youzhi Kuang. In addition, the authors are indebted to the many helpful discussions with Drs. David Lust, Joseph LaManna and Dennis Landis, without their insight the current study would not have happened. This work was funded by the NINDS/NIH (K08 NS-041594; SS) and GlaxoSmithKline (GL and SS) and Takeda Pharmaceuticals (SS).
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