Novel Protection by Omega-3-FAs against Strychnine-Induced Tonic-Convulsion in Mice: Synergy with Carbamazepine

Abstract

Background/Aim: The utility of ω-3-FAs (DHA and EPA) against epilepsy was evident in clonic-convulsion animal-models, in their chronic- than acute-modes. However, their efficacy against tonic-convulsion-models remained unclear. Besides, while some-antiepileptics (AEDs), like carbamazepine (CBZ), adversely impacted the bioavailability of dietary ω-3-FAs, it remains unclear whether co-ω-3-FAs may change efficacy/blood-levels of CBZ. This work investigated the capacity of both acute- versus chronic-regimens of  ω-3-FAs to: 1) alleviate the-tonic, strychnine-induced convulsions in mice, and 2) synergize with CBZ-evoked anti-tonic-convulsions, and then further-probe whether this has altered plasma-CBZ levels (clearance). Methods: Both acute (1.0 hr)- and chronic (14 day)-regimens of the  ω-3-FAs, DHA and EPA (120-1000mg/kg p.o.), were administered in a mouse strychnine convulsion-model (2mg/kg i.p.), and seizure frequency, latency and animal-survival were determined versus the positive-control CBZ (12mg/kg p.o). Further, synergy between submaximal-doses of DHA(EPA) and CBZ was verified. Lastly, pharmacokinetic interaction was verified in rats by determining plasma CBZ-levels in the presence- and-absence of ω-3-FAs. Results: Both DHA and EPA dose-dependently enhanced seizure latency (2-folds) and protected mice against strychnine-induced convulsion (up to 75%). Besides, interestingly, similar responses and animal-survival rates obtained in acute and chronic models. Moreover, either DHA or EPA synergized with CBZ effects beyond their individual responses (3.6-4.3 folds, respectively). Such concurrent DHA/CBZ fully protected the mice, while the joint-EPA/CBZ spared only 88% of the animals. Lastly, pharmacokinetic studies revealed that CBZ levels were unchanged with co-administration of ω-3-FAs. Conclusions: The study revealed, for the first-time, that ω-3-FAs significantly delayed seizure/convulsions in a strychnine-tonic mouse-model, both in their acute and chronic regimens. Further, ω-3-FAs synergized with “CBZ”-responses, without altering its plasma levels. These results provide new clues that substantiate the spectrum and clinical utility of ω-3-FAs, alone or with AEDs, against epilepsy.