PRECLINICAL CHARACTERIZATION OF MDL-27,192 AS A POTENTIAL BROAD-SPECTRUM ANTICONVULSANT AGENT WITH NEUROPROTECTIVE PROPERTIES

The compound phenyl)-2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one (MDL 2 7,192) was evaluated in a variety of rodent models to assess its antic onvulsant profile and its potential neuroprotective activity. MDL 27,1 92 demonstrated anticonvulsant activity in a wide range of epilepsy mo dels that are genetically-based (audiogenic seizures in the seizure su sceptible DBA/2J or Frings mouse; spike wave seizures in genetic absen ce epilepsy rats of Strasbourg (GAERS), electrically-based (MES seizur es in mice and rats, corneally-kindled seizures in rats) and chemicall y-based (bicuculline, PTZ, picrotoxin, 3-mercaptopropionic acid, quino linic acid and strychnine). When compared to valproate, orally adminis tered MDL 27,192 was 17-48-fold more potent as an anticonvulsant and s howed a safety index one to three-fold greater. Following a timed intr avenous administration of PTZ to mice, MDL 27,192, but not phenytoin o r carbamazepine, consistently increased the latencies to first twitch and clonus. MDL 27,192 was active in a genetic model of absence epilep sy, the GAERS rat model. These data indicate that MDL 27,192 likely ex erts its anticonvulsant action by affecting seizure spread and by rais ing seizure threshold. MDL 27,192 did not display any signs of toleran ce following subchronic (15 day) administration. In tests of neuroprot ective potential, MDL 27:192 reduced infarct volume in a permanent mid dle cerebral artery occlusion model of focal cerebral ischemia in rats and reduced the loss of hippocampal dentate hilar neurons in an anima l model of unilateral head injury. In summary, MDL 27,192 possesses a broad-spectrum anticonvulsant profile. The potential for reduced toler ance and neuroprotective activity are additional positive features of MDL 27,192's preclinical profile. (C) 1997 Elsevier Science B.V.