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Diphenylpiperazines enhance regeneration after facial nerve injury
1Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
Immature rat facial motoneurons are very sensitive to injury with nearly 80% dying during the first week after axotomy. This motoneuron death is apoptotic, similar to that induced in neurons after tropic factor withdrawal. The diphenylpiperazines, flunarizine and cinnarizine, protect dorsal root ganglion neurons from death after withdrawal of trophic support, i.e., nerve growth factor withdrawal, in vitro. Similarly, the monoamine oxidase inhibitor, deprenyl, promotes survival of facial motoneurons after axotomy. These pharmacological agents were assessed both alone and in combination for their ability to prevent death in non-nerve growth factor dependent CNS motoneurons after facial nerve axotomy in newborn rats. Long-term experiments were done with the diphenylpiperazines to evaluate potential enhancement of regeneration. Facial nerve transection resulted in 78% neuronal loss in the injured compared with the contralateral, uninjured nucleus. Systemic administration of diphenylpiperazines for 1 week after facial nerve transection doubled the number of surviving motoneurons from 23% to 47%. Similar results were obtained with deprenyl. Combinations of diphenylpiperazines and deprenyl provide a similar degree of neuronal protection 1 week after injury as that obtained by either agent alone. We assessed the ability of diphenylpiperazines to protect facial motoneurons from death over a prolonged period and enhance subsequent regeneration. Motor neuron counts in rats treated with diphenylpiperazines for 1 month after injury and assessed 2 months later demonstrated long-term enhancement of neuronal protection with an increase of 45% in the number of horseradish peroxidase-labelled motoneurons. The diphenylpiperazines group had approximately 80% more regenerated myelinated axons in the distal facial nerve than the control group. Thus, diphenylpiperazine treatment during the first month after injury provides long-term protection of non-nerve growth factor dependent CNS motoneurons with subsequent potentiation of long-term facial nerve regeneration.
Insights
Diphenylpiperazines and deprenyl protect immature rat facial motoneurons from death after injury. These drugs also enhance long-term facial nerve regeneration, offering a promising therapeutic approach for nerve injury.
Area of Science:
- Neuroscience
- Regenerative Medicine
Background:
- Immature rat facial motoneurons exhibit high susceptibility to axotomy-induced apoptosis.
- Pharmacological agents like diphenylpiperazines and deprenyl have shown neuroprotective effects in other neuronal models.
Purpose of the Study:
- To evaluate the neuroprotective efficacy of diphenylpiperazines and deprenyl in preventing motoneuron death after facial nerve axotomy.
- To assess the long-term effects of diphenylpiperazines on neuronal survival and facial nerve regeneration.
Main Methods:
- Facial nerve axotomy was performed in newborn rats.
- Systemic administration of diphenylpiperazines and/or deprenyl was administered post-axotomy.
- Neuronal survival was quantified using horseradish peroxidase labeling at various time points.
- Regenerated myelinated axons in the distal facial nerve were assessed.
Main Results:
- Diphenylpiperazines and deprenyl significantly increased facial motoneuron survival by approximately 24% one week after axotomy.
- Long-term treatment with diphenylpiperazines (1 month) demonstrated sustained neuroprotection and enhanced facial nerve regeneration, with an 80% increase in regenerated axons.
- Combined treatment did not yield superior neuroprotection compared to individual agents.
Conclusions:
- Diphenylpiperazines provide significant long-term neuroprotection for non-nerve growth factor-dependent central nervous system motoneurons following injury.
- Diphenylpiperazine treatment potentiates long-term regeneration of the facial nerve, suggesting therapeutic potential for nerve repair.