Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke

Fan Yang1, Rachita K Sumbria2, Dong Xue3, Chuanhui Yu3, Dan He3, Shuo Liu1, Annlia Paganini-Hill3, Mark Fisher4

1Departments of Anatomy & Neurobiology, School of Pharmacy, Keck Graduate Institute, Claremont, California
2Neurology, and Department of Biopharmaceutical Sciences, School of Pharmacy, Keck Graduate Institute, Claremont, California
3Neurology, School of Pharmacy, Keck Graduate Institute, Claremont, California
4Departments of Anatomy & Neurobiology, Neurology, and Pathology & Laboratory Medicine, University of California, Irvine, California, School of Pharmacy, Keck Graduate Institute, Claremont, California

Abstract


PURPOSE: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS: Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS: Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p<0.01) and 138% (p<0.05) of control in the ligation and embolic models, respectively. PDE4D knockout rats subjected to embolic stroke showed no change in infarct size compared to wild-type control. CONCLUSIONS: Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis.

 

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J Pharm Pharm Sci, 17 (3): 362-370, 2014

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