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

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 PGE2 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.

Alpha melanocyte stimulating hormone (α-MSH) does not modify pentylenetetrazol- and pilocarpine-induced seizures.

AIMS: Alpha-melanocyte stimulating hormone (α-MSH) is a pro-opiomelanocortin (POMC)-derived peptide involved in different neurological functions that also exerts anti-inflammatory effects, including in the central nervous system (CNS). Although inflammation has been implicated in seizures and epilepsy, no study has systematically investigated whether α-MSH modifies seizures. Therefore, in the current study we determined whether α-MSH alters pentylenetetrazol (PTZ)- and pilocarpine-induced seizures. MAIN METHODS: Adult male Swiss mice were injected with α-MSH (1.66, 5 or 15 µg/3 µL, intracerebroventricular (i.c.v.)) or systemic (0.1, 0.3 or 1 mg/kg, intraperitoneally (i.p.)). Five to sixty minutes after the injection of the peptide, animals were injected with PTZ (60 mg/kg, i.p.) or pilocarpine (370 mg/kg, i.p.). Latency to myoclonic jerks and tonic-clonic seizures, number of seizure episodes, total time spent seizing and seizure intensity, assessed by the Racine and Meurs scales were recorded. Interleukin 1 beta (IL-1ß) levels in the hippocampus were measured by a commercial enzyme-linked immunoabsorbent assay (ELISA). KEY FINDINGS: Neither intracerebroventricular (1.66, 5 or 15 µg/3 µL, i.c.v.) nor systemic (0.1, 0.3 or 1 mg/kg, i.p.) administration of α-MSH altered PTZ- and pilocarpine-induced seizures. IL-1ß levels in the hippocampi were not altered by α-MSH, PTZ or pilocarpine. SIGNIFICANCE: Although inflammation has been implicated in seizures and epilepsy and α-MSH is a potent anti-inflammatory peptide, our results do not support a role for α-MSH in seizure control.