Neuroprotection by PGE2 receptor EP1 inhibition involves the PTEN/AKT pathway.
The prostanoid synthesizing enzyme cyclooxygenase-2 (COX-2) is involved in the mechanisms of cerebral ischemia, an effect mediated by prostaglandin E2 through activation of EP1 receptors. Thus, inhibition of EP1 receptors is neuroprotective in models of ischemic stroke, but the molecular mechanisms of the effect have not been fully elucidated. We used oxygen glucose deprivation (OGD) in hippocampal slices as an injury model to investigate whether the neuroprotection afforded by EP1 receptor inhibition involves the PI3K/AKT survival pathway. EP1 receptor inhibition with SC51089 or SC51322 reduced the hippocampal damage produced by ODG by 28+/-2% and 32+/-3%, respectively (p<0.05). OGD induced a transient reduction of AKT activity that was partly counteracted by SC51089. LY294002 blocked the increase in phospho-AKT evoked by SC51089 and abolished the associated protective effect. The AKT activation induced by SC51089 was associated with phosphorylation of PTEN, the phosphatase that negatively regulates AKT. Furthermore, SC51089 attenuated the mitochondrial translocation of the proapoptotic protein BAD. These data indicate that EP1 receptor inhibition improves the survival of hippocampal slices by preventing the attenuation in AKT activity induced by OGD, and by reducing the mitochondrial translocation of BAD. The findings provide evidence for a link between EP1 receptors and the PI3K/AKT survival pathway and shed light on the molecular mechanisms of the prosurvival effect of EP1 receptor inhibition.
Zhou
Ping
P
Division of Neurobiology, Weill Cornell Medical College, New York, NY 10021, USA. piz2001@med.cornell.edu
Qian
Liping
L
Chou
Tsu
T
Iadecola
Costantino
C
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006834:Hydrazines / Q000494:pharmacology; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010077:Oxazepines / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000502:physiology*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D006834:Hydrazines; D018696:Neuroprotective Agents; D010077:Oxazepines; C545636:Ptger1 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; C086836:SC 51089; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D015232:Dinoprostone