Synergistic effect of docosahexaenoic acid on anticonvulsant activity of valproic acid and lamotrigine in animal seizure models.

Add-on therapy is a common strategy to improve efficacy and tolerability of antiepileptic drugs (AEDs). Anticonvulsant potential and appropriate safety of docosahexaenoic acid (DHA) makes it a promising candidate for combination therapy. We evaluated influence of DHA on anticonvulsant activity of AEDs phenytoin, valproate, and lamotrigine in maximal electroshock (MES), pentylenetetrazole (PTZ), and kindling models of epilepsy. The dose-response to DHA was obtained 15 min after intracerebroventricular (i.c.v.) injection in PTZ model of clonic seizures in mice, MES model of tonic seizures in mice, and kindling model of complex partial seizures in rats. The dose-response curve of valproate (30 min after i.p. injection to mice) in PTZ, phenytoin (60 min after i.p. injection to mice) in MES, and lamotrigine (60 min after i.p. injection to rats) in kindling models were obtained. Dose-response curves of the AEDs were then achieved in the presence of ED25 of DHA. DHA had no anticonvulsant effect in the MES model. However, it showed a dose-dependent protective effect against PTZ (ED50 = 0.13 μM) and kindled seizures (ED50 = 1.08 mM). DHA at ED25 caused a 3.6-fold increase in potency of valproate as its ED50 value from 117.5 (98.3-135.3) decreased to 32.5 (21.6-44.1) mg/kg. Moreover, a 4.9-fold increase in potency of lamotrigine occurred, as its ED50 value from 13.10 (11.50-14.9) decreased to 2.65 (0.8-5.6) mg/kg. CompuSyn analysis indicated synergistic anticonvulsant interaction between DHA and both valproate and lamotrigine. Co-administration strategy of the safe and inexpensive anticonvulsant compound DHA with AEDs should be favorably regarded in clinical studies of epilepsy treatment.