DIPHENYLPIPERAZINES ENHANCE REGENERATION AFTER FACIAL-NERVE INJURY

Immature rat facial motoneurons are very sensitive to injury with near ly 80% dying during the first week after axotomy. This motoneuron deat h is apoptotic, similar to that induced in neurons after tropic factor withdrawal. The diphenylpiperazines, flunarizine and cinnarizine, pro tect dorsal root ganglion neurons from death after withdrawal of troph ic support, i.e., nerve growth factor withdrawal, in vitro. Similarly, the monoamine oxidase inhibitor, deprenyl, promotes survival of facia l motoneurons after axotomy. These pharmacological agents were assesse d both alone and in combination for their ability to prevent death in non-nerve growth factor dependent CNS motoneurons after facial nerve a xotomy in newborn rats. Long-term experiments were done with the diphe nylpiperazines to evaluate potential enhancement of regeneration. Faci al nerve transection resulted in 78% neuronal loss in the injured comp ared with the contralateral, uninjured nucleus. Systemic administratio n of diphenylpiperazines for 1 week after facial nerve transection dou bled the number of surviving motoneurons from 23% to 47%. Similar resu lts were obtained with deprenyl. Combinations of diphenylpiperazines a nd deprenyl provide a similar degree of neuronal protection 1 week aft er injury as that obtained by either agent alone. We assessed the abil ity of diphenylpiperazines to Protect facial motoneurons from death ov er a prolonged period and enhance subsequent regeneration. Motor neuro n counts in rats treated with diphenylpiperazines for 1 month after in jury and assessed 2 months later demonstrated long-term enhancement of neuronal protection with an increase of 45% in the number of horserad ish peroxidase-labelled motoneurons. The diphenylpiperazines group had similar to 80% more regenerated myelinated axons in the distal facial nerve than the control group. Thus, diphenylpiperazine treatment duri ng the first month after injury provides long-term protection of non-n erve growth factor dependent CNS motoneurons with subsequent potentiat ion of long-term facial nerve regeneration.