EP2 receptor agonist ONO-AE1-259-01 attenuates pentylenetetrazole- and pilocarpine-induced seizures but causes hippocampal neurotoxicity

Abstract

Epilepsy is a common and devastating neurological disease affecting more than 50 million people worldwide. Accumulating experimental and clinical evidence suggests that inflammatory pathways contribute to the development of seizures in various forms of epilepsy. In this context, while the activation of the PGE EP2 receptor causes early neuroprotective and late neurotoxic effects, the role of EP2 receptor in seizures remains unclear. We investigated whether the systemic administration of the highly selective EP2 agonist ONO-AE1-259-01 prevented acute pentylenetetrazole (PTZ)- and pilocarpine-induced seizures. The effect of ONO-AE1-259-01 on cell death in the hippocampal formation of adult male mice seven days after pilocarpine-induced status epilepticus (SE) was also evaluated. ONO-AE1-259-01 (10μg/kg, s.c.) attenuated PTZ- and pilocarpine-induced seizures, evidenced by the increased latency to seizures, decreased number and duration of seizures episodes and decreased mean amplitude of electrographic seizures. ONO-AE1-259-01 and pilocarpine alone significantly increased the number of pyknotic cells per se in all hippocampal subfields. The EP2 agonist also additively increased pilocarpine-induced pyknosis in the pyramidal cell layer of CA1 but reduced pilocarpine-induced pyknosis in the granule cell layer of the dentate gyrus (DG). Although the systemic administration of ONO-AE1-259-01 caused a significant anticonvulsant effect in our assays, this EP2 agonist caused extensive cell death. These findings limit the likelihood of EP2 receptor agonists being considered as novel potential anticonvulsant drugs.

Cyclooxygenase-2 (COX-2) inhibitors: future therapeutic strategies for epilepsy management

“…EP2 antagonism using 3-aryl-acrylamide derivatives attenuated SE-induced neuroinflammation and neuronal injury in rodents [55, 89–91]. Conflictingly, few other studies found systemic administration of EP2 agonists to have significant anticonvulsant effect to PTZ- and pilocarpine-induced seizures [92, 93]. This dual effect of EP2 modulation on neuronal activity depends on the latency to seizure onset and thus shows neuroprotection within a tightly regulated therapeutic window [94, 95].…”

Novel drugs and early polypharmacotherapy in status epilepticus

“…-Transforming growth factor β signaling (TGF-β), which regulates albumin uptake into astrocytes. -Cyclooxygenase-2 (COX-2), responsible for the synthesis of prostaglandins [115]. -NOX2 (a NADPH oxidase), which generates reactive oxygen and nitrogen species (ROS/RNS) that can cause oxidative stress and contribute to SE-induced cytokine production [116].…”

Inflammation: A Network in the Pathogenesis of Status Epilepticus

“…Recent evidence has shown that PGE2 mediates inflammation and brain damage mainly through EP2 receptors in SE (Du et al, 2016 ). Activation of EP2 receptors plays a dual role: early stimulation is associated with neuroprotection, whereas late stimulation increases neurotoxicity (Dey et al, 2016 ; Santos et al, 2017 ). In this context, pretreatment with EP2 receptor agonists can reduce SE.…”