OXCARBAZEPINE - PRECLINICAL ANTICONVULSANT PROFILE AND PUTATIVE MECHANISMS OF ACTION

Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabol ite (MHD) protected mice and rats against generalized tonic-clonic sei zures induced by electroshock with EDS, values between 13.5 and 20.5 m g/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therape utic indices were 4 (OCBZ) and >6 (MHD) for sedation (observation test , mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotoro d test, mice). Both compounds were less potent in suppressing chemical ly induced seizures and did not significantly influence rat kindling d evelopment. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OC BZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum -induced chronically recurring partial seizures. In vitro, OCBZ and MH D suppressed sustained high-frequency repetitive firing of sodium-depe ndent action potentials in mouse neurons in cell culture with equal po tency (medium effective concentration 5 X 10(-8) M/L). This effect is probably due in part to a direct effect on sodium channels. Patch-clam p studies on rat dorsal root ganglia cells revealed that up to a conce ntration of 3 X 10(-4) M, MHD did not significantly interact with L-ty pe 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 antic onvulsant mechanism of action of OCBZ and MHD was identified. MHD and both of its enantiomers were of equal anticonvulsant profile and poten cy 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 tes t in mice, respectively. In addition, all three compounds showed a ver y similar profile of unwanted side effects. In vitro, they inhibited p enicillin-induced epileptic-like discharges in the CA3 area of rat hip pocampal slices with equal potency and efficacy at concentrations of 1 00-500 mu m. This effect was attenuated when the potassium-channel blo cker 4-aminopyridine was added to the bath fluid, thus indicating that potassium channels may also contribute to the antiepileptic activity of OCBZ.