Prostaglandin E₂ potentiates methylmalonate‐induced seizures

Abstract

SUMMARYPurpose: Methylmalonic acidemias are inherited metabolic disorders characterized by methylmalonate (MMA) accumulation and neurologic dysfunction, including seizures. It is known that metabolic crises in affected patients are precipitated by infections. Although growing evidence supports that inflammation facilitates seizures, it is not known whether inflammatory mediators facilitate MMA-induced seizures. Therefore, in this study we investigate the involvement of cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ) in MMA-induced seizures. Methods: Adult male Wistar rats were implanted with electrodes over the parietal cortex for electroencephalography (EEG) recording and a cannula in the right lateral ventricle. Animals were injected with PGE 2 (100 ng/ 2 ll, i.c.v.) or phosphate-buffered saline (PBS) (2 ll, i.c.v.), 15 min before MMA (2.5 lmol/2.5 ll, i.c.v.) or NaCl (2.5 lmol/2.5 ll, i.c.v.). The anticonvulsant effect of celecoxib (0.2; 2 or 20 mg/kg, p.o., 60 min before MMA) on MMA-induced seizures, and whether PGE 2 (10 or 100 ng/ 2 ll, i.c.v.) prevented the anticonvulsant effect of celecoxib (2 mg/kg, p.o.) were also investigated. Key Findings: PGE 2 decreased the latency to MMAinduced jerks and generalized seizures, and increased the amplitude of generalized seizure EEG recordings. The selective COX-2 inhibitor celecoxib at the dose 2 mg/kg, but not at the dose 20 mg/kg, completely prevented MMA-induced seizures. The protective effect of celecoxib (2 mg/kg) against MMA-induced seizures was prevented by PGE 2 . Significance: These results support a role for PGE 2 in the seizures elicited by MMA, which is in agreement with the view that infections may precipitate and exacerbate neurologic dysfunction in patients with MMA acidemic.

Role of Inflammatory Mediators in the Pathogenesis of Epilepsy

“…mPGES-1-KO mice show little postictal production of PGE 2 , and the lack of increased PGE 2 production resulted in the promotion of neuronal survival following KA injection [64, 68]. Furthermore, the intraventricular injection of PGE 2 decreased the latency to methylmalonate- (MMA-) induced seizures and increased the amplitude of spikes measured by an electroencephalogram (EEG) in rats [69]. Thus, COX-2-coupled PGE 2 production can promote seizures through mechanisms that drive epileptogenesis.…”

Computer-Aided Diagnosis and Localization of Lateralized Temporal Lobe Epilepsy Using Interictal FDG-PET

“…A non-epileptic seizure is defined as the presence of external seizure symptoms and/or signs with no electrographic features characteristic of epilepsy. Long term video-EEG monitoring has shown consistently that roughly one third of patients diagnosed with “medication refractory epilepsy” in fact suffer from NES (Kerr et al, 2012a). Because they don’t suffer from epilepsy, these patients with NES (PWN) are not treated effectively with anti-epileptic drugs (AEDs).…”

“…The gold standard for the differential diagnosis and pre-surgical assessment of epilepsy includes 72 or more hours of video-EEG monitoring (Cragar et al, 2002; LaFrance and Devinsky, 2004). However, 10% of patients admitted for this extensive assessment leave with inconclusive results (Kerr et al, 2012a). Considering that one sixth of PWE are diagnosed with medication refractory epilepsy (Privitera, 2011), improved methods to effectively identify PWN who do not benefit from AEDs effectively could reduce the morbidity and both the financial and social cost of treating epilepsy.…”

Monoterpenoid Terpinen-4-ol Exhibits Anticonvulsant Activity in Behavioural and Electrophysiological Studies

“…The high amplitude (2-3 Hz) activity shown in this figure is a feature of generalized seizures, and thus the seizures elicited by PTZ in the behavioural tests were confirmed by physiological measurements [30]. …”

“…This reduction in the severity of symptoms in the recordings (fewer spikes) was associated with attenuation of the severity of behavioural seizures [30, 31]. These results indicate that 4TRP reduced the severity of paroxystic activity, but its effects were evaluated primarily with respect to generalized seizures.…”