INVOLVEMENT OF PGE2-EP1 SIGNALING IN THE PTZ-INDUCED EPILEPTIC SEIZURE AND ITS NEUROINFLAMATION-ASSOCIATED EXACERBATION

Abstract Background Epilepsy is one of the most common neurological disorders. Neuroinflammation and an enhanced excitability via NMDA receptor are known to be involved in the pathophysiology of epilepsy. The cyclooxygenase (COX)/prostaglandin E2 (PGE2) signaling pathway plays a critical role in the neuroinflammation. Among PGE2 receptors (EP1-4), EP1 contributes to NMDA receptor-mediated neuronal excitability. Aims & Objectives We aimed to investigate whether the PGE2-EP1 signaling is involved in the epileptic seizures induced by pentylenetetrazol (PTZ) in mice. Method Pentylenetetrazol (PTZ) was administered to mice every other consecutive day and seizures were evaluated. Co-administration of lipopolysaccharide (LPS) with PTZ and seizure scores were evaluated. Brains were removed and PGE2-related gene mRNA was measured by real-time PCR. Results Chronic administration of PTZ exacerbated epileptic seizures and increased expression of EP1 but not cyclooxygenases (COXs) and microsomal prostaglandin E synthases (mPGESs). The exacerbation of seizure was attenuated in the EP1-knockout mice. Co-administration of lipopolysaccharide (LPS) with PTZ increased body-temperature associated with enhanced expression of COX-2 and mPGES-1 and exacerbated epileptic seizures. This exacerbated seizure was also attenuated in the EP1- knockout mice. Discussion & Conclusion These data suggested that PGE2-EP1 signaling may have critical roles in the pathophysiology of epilepsy and its exacerbation with neuroinflammation. In conclusion, EP1 receptors may be attractive therapeutic target for epileptic seizure.