CEP-1347 KT7515 PREVENTS MOTOR NEURONAL PROGRAMMED CELL-DEATH AND INJURY-INDUCED DEDIFFERENTIATION IN-VIVO/

CEP-1347, also known as KT7515, a derivative of a natural product indo locarbazole, inhibited motor neuronal death in vitro, inhibited activa tion of the stress-activated kinase JNK1 (c-jun NH terminal kinase) in cultured spinal motor neurons, but had no effect on the mitogen-activ ated protein kinase ERK1 in these cells. Results reported here profile the functional activity of CEP-1347/KT7515 in vivo in models of motor neuronal death or dedifferentiation. Application of CEP-1347/KT7515 t o the chorioallantoic membrane of embryonic chicks rescued 40% of the lumbar motor neurons that normally die during the developmental period assessed. Peripheral administration of low doses (0.5 and 1 mg/kg dai ly) of CEP-1347/KT7515 reduced death of motor neurons of the spinal nu cleus of the bulbocavernosus in postnatal female rats, with efficacy c omparable to testosterone. Strikingly, daily administration of CEP-134 7/KT7515 during the 4-day postnatal window of motor neuronal death res ulted in persistent long-term motor neuronal survival in adult animals that received no additional CEP-1347/KT7515. In a model of adult moto r neuronal dedifferentiation following axotomy, local application of C EP-1347/KT7515 to the transected hypoglossal nerve substantially reduc ed the lass of choline acetyl transferase immunoreactivity observed 7 days postaxotomy compared to untreated animals. Results from these exp eriments demonstrate that a small organic molecule that inhibits a sig naling pathway associated with stress and injury also reduces neuronal death and degeneration in vivo. (C) 1998 John Wiley & Sons, Inc.