Fish oil attenuates methylmalonate-induced seizures.

Methylmalonic acidemias are inherited metabolic disorders characterized by methylmalonate (MMA) accumulation and neurological dysfunction, including seizures. Dietary fatty acids are known as an important energy source and reduce seizure activity in selected acute animal models. This study investigated whether chronic treatment with fish oil or with oleic acid attenuates MMA-induced seizures and whether maintenance of Na(+),K(+)-ATPase activity was involved in such an effect. Adult male Wistar rats were given fish oil (85 mg/kg), oleic acid (85 mg/kg) or vehicle (0.42% aqueous Cremophor EL™, 4 mL/kg/body weight/day), p.o., for 75 days. On the 73th day a cannula was implanted in the right lateral ventricle with electrodes over the parietal cortex for EEG recording. On the 76th day the animals were injected with NaCl (2.5 µmol/2.5 µL, i.c.v.), or with MMA (2.5 µmol/2.5 µL, i.c.v.), and seizure activity was measured by electroencephagraphic (EEG) recording with concomitant behavior monitoring. The effect of prostaglandin E2 (PGE2) on Na(+),K(+)-ATPase activity of slices of cerebral cortex from NaCl-injected animals was determined. Fish oil increased the latency to MMA-induced tonic-clonic seizures, reduced the mean amplitude of ictal EEG recordings, and prevented PGE2-induced decrease of Na(+),K(+)-ATPase activity in cortical slices in vitro. Oleic acid decreased mean amplitude of ictal EEG recordings. The results support that fish oil decreases MMA-induced seizures. The decreased sensitivity of Na(+),K(+)-ATPase to the inhibitory effect of PGE2 in fish oil-treated animals may be related to the currently reported anticonvulsant activity.

Prostaglandin E(2) potentiates methylmalonate-induced seizures.

PURPOSE: 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 µl, i.c.v.) or phosphate-buffered saline (PBS) (2 µl, i.c.v.), 15 min before MMA (2.5 µmol/2.5 µl, i.c.v.) or NaCl (2.5 µmol/2.5 µl, 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 µl, 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 MMA-induced 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.