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Non-invasive Imaging and Analysis of Cerebral Ischemia in Living Rats Using Positron Emission Tomography with 18F-FDG
Published on: December 28, 2014
Altered PPARgamma expression and activation after transient focal ischemia in rats
N A Victor1, E W Wanderi, J Gamboa
1Department of Neurology, Case Western Reserve University, 11100 Euclid Ave., Cleveland, Ohio 44106, USA.
Abstract:
Stroke is a devastating disease with limited treatment options. Recently, we found that the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists troglitazone and pioglitazone reduce injury and inflammation in a rat model of transient cerebral ischemia. The mechanism of this protection is unclear, as these agents can act through PPAR-gamma activation or through PPAR-gamma-independent mechanisms. Therefore, we examined PPAR-gamma expression, DNA binding and transcriptional activity following stroke. In addition, we used a PPAR-gamma antagonist, T0070907, to determine the role of PPAR-gamma during ischemia. Using immunohistochemical techniques and real-time PCR, we found low levels of PPAR-gamma mRNA and PPAR-gamma immunoreactivity in nonischemic brain; however, PPAR-gamma expression dramatically increased in ischemic neurons, peaking 24 h following middle cerebral artery occlusion. Interestingly, we found that in both vehicle- and agonist-treated brains, DNA binding was reduced in the ischemic hemisphere relative to the contralateral hemisphere. Expression of a PPAR-gamma target gene, lipoprotein lipase, was also reduced in ischemic relative to nonischemic brain. Both DNA binding and lipoprotein lipase expression were increased by the addition of the PPAR-gamma agonist rosiglitazone. Finally, we found that rosiglitazone-mediated protection after stroke was reversed by the PPAR-gamma antagonist T0070907. Interestingly, infarction size was also increased by T0070907 in the absence of PPAR-gamma agonist, suggesting that endogenous PPAR-gamma ligands may mitigate the effects of cerebral ischemia.
Insights
Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists show promise in reducing stroke injury. This study reveals that PPARgamma activation is crucial for this protective effect, suggesting potential therapeutic strategies for stroke treatment.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Stroke remains a significant cause of disability with limited therapeutic options.
- Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have demonstrated neuroprotective effects in preclinical stroke models.
- The precise mechanisms underlying PPARgamma agonist-mediated protection in cerebral ischemia are not fully elucidated.
Purpose of the Study:
- To investigate the role of PPARgamma expression, DNA binding, and transcriptional activity in a rat model of transient cerebral ischemia.
- To determine the contribution of PPARgamma activation versus independent mechanisms in stroke protection.
- To evaluate the therapeutic potential of modulating PPARgamma activity during ischemic stroke.
Main Methods:
- Utilized immunohistochemistry and real-time PCR to assess PPARgamma mRNA and protein levels in ischemic and non-ischemic brain regions.
- Employed a PPARgamma antagonist (T0070907) to block receptor activity.
- Measured DNA binding activity and expression of a PPARgamma target gene (lipoprotein lipase).
Main Results:
- PPARgamma expression significantly increased in ischemic neurons post-stroke.
- Despite increased expression, PPARgamma DNA binding and target gene activity were reduced in the ischemic hemisphere.
- PPARgamma agonist rosiglitazone enhanced DNA binding and target gene expression, conferring protection that was reversed by the antagonist T0070907.
- T0070907 alone increased infarction size, suggesting a protective role for endogenous PPARgamma ligands.
Conclusions:
- PPARgamma activation plays a critical role in mediating the neuroprotective effects of agonists against cerebral ischemia.
- Endogenous PPARgamma ligands may offer intrinsic protection against ischemic stroke.
- Targeting PPARgamma represents a promising therapeutic strategy for stroke treatment.
