Activation of the inducible cyclooxygenase COX-2 generates significant toxicity in wide range of neurological disease models, in particular cerebral ischemia. However, sustained COX-2 inhibition exerts cardiovascular and cerebrovascular side effects, suggesting that selected downstream prostaglandin receptor signaling pathways may be beneficial. Our previous studies have focused on identifying which prostaglandin receptors mediate COX-2 neurotoxicity and we have determined that although several receptors do promote toxicity, a major finding has been that a larger group of prostaglandin receptors mediates an unexpected and significant protective effect in models of ischemia. Thus, the investigation of prostaglandin receptor pathways downstream of COX-2 has uncovered toxic as well as paradoxically protective signaling pathways, both of which are amenable to therapeutic targeting in models of ischemia. The research objective of this proposal is to expand our investigation of the mechanisms of protection of the PGE2 EP4 receptor, which we have found is significantly cerebroprotective in rodent models of stroke. In this proposal, the cellular substrates and molecular mechanisms that mediate EP4 cerebroprotection with regard to cerebral perfusion and the inflammatory response will be investigated in the murine model of transient focal cerebral ischemia. Genetic strategies using conditional knockout models and pharmacological strategies will be used to identify the cellular substrate(s) mediating protection by this receptor in ischemia and evaluate effects on long term functional outcome measures. Successful completion of these studies will broaden our understanding of endogenous mechanisms of cerebrovascular protection in stroke, and establish the rationale for subsequent investigations in larger animal models of cerebral ischemia to promote accelerated functional recovery, with the long term goal of therapeutic intervention in patients affected by stroke.
Stroke is a major cause of morbidity and mortality. We have identified a prostaglandin receptor that has important protective properties that may be beneficial in stroke recovery. The research objective of this proposal is to examine the protective functions of this receptor in a model of cerebral ischemia.
|Taniguchi, Hidetoshi; Anacker, Christoph; Wang, Qian et al. (2014) Protection by vascular prostaglandin E2 signaling in hypoxic-ischemic encephalopathy. Exp Neurol 255:30-7|
|Taniguchi, Hidetoshi; Anacker, Christoph; Suarez-Mier, Gabriela Beatriz et al. (2011) Function of prostaglandin E2 EP receptors in the acute outcome of rodent hypoxic ischemic encephalopathy. Neurosci Lett 504:185-90|
|Liang, Xibin; Lin, Lu; Woodling, Nathaniel S et al. (2011) Signaling via the prostaglandin Eýýý receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia. J Clin Invest 121:4362-71|
|Andreasson, Katrin (2010) Emerging roles of PGE2 receptors in models of neurological disease. Prostaglandins Other Lipid Mediat 91:104-12|
|Savonenko, A; Munoz, P; Melnikova, T et al. (2009) Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor. Exp Neurol 217:63-73|
|Hyman, Joel M; Firestone, Ari J; Heine, Vivi M et al. (2009) Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. Proc Natl Acad Sci U S A 106:14132-7|
|Li, Jun; Liang, Xibin; Wang, Qian et al. (2008) Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia. Neurosci Lett 438:210-5|
|Liang, X; Wu, L; Wang, Q et al. (2007) Function of COX-2 and prostaglandins in neurological disease. J Mol Neurosci 33:94-9|
|Wu, Liejun; Wang, Qian; Liang, Xibin et al. (2007) Divergent effects of prostaglandin receptor signaling on neuronal survival. Neurosci Lett 421:253-8|
|Liu, Dong; Wu, Liejun; Breyer, Richard et al. (2005) Neuroprotection by the PGE2 EP2 receptor in permanent focal cerebral ischemia. Ann Neurol 57:758-61|