OXCARBAZEPINE - PRECLINICAL ANTICONVULSANT PROFILE AND PUTATIVE MECHANISMS OF ACTION

Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabolite (MHD) protected mice and rats against generalized tonic-clonic seizures induced by electroshock with EDS, values between 13.5 and 20.5 mg/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therapeutic indices were 4 (OCBZ) and >6 (MHD) for sedation (observation test, mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotorod test, mice). Both compounds were less potent in suppressing chemically induced seizures and did not significantly influence rat kindling development. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OCBZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum-induced chronically recurring partial seizures. In vitro, OCBZ and MHD suppressed sustained high-frequency repetitive firing of sodium-dependent action potentials in mouse neurons in cell culture with equal potency (medium effective concentration 5 X 10(-8) M/L). This effect is probably due in part to a direct effect on sodium channels. Patch-clamp studies on rat dorsal root ganglia cells revealed that up to a concentration of 3 X 10(-4) M, MHD did not significantly interact with L-type calcium currents, whereas OCBZ diminished them by about 30% at the concentration of 3 X 10(-4) M. In biochemical investigations, no brain neurotransmitter or modulator receptor site responsible for the anticonvulsant mechanism of action of OCBZ and MHD was identified. MHD and both of its enantiomers were of equal anticonvulsant profile and potency in rodent screening tests, with ED(50) values ranging from 13 to 34 and 32 to 46 mg/kg p.o. in the electroshock and pentylenetetrazol test in mice, respectively. In addition, all three compounds showed a very similar profile of unwanted side effects. In vitro, they inhibited penicillin-induced epileptic-like discharges in the CA3 area of rat hippocampal slices with equal potency and efficacy at concentrations of 100-500 mu m. This effect was attenuated when the potassium-channel blocker 4-aminopyridine was added to the bath fluid, thus indicating that potassium channels may also contribute to the antiepileptic activity of OCBZ.