Present address: Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.
Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats
Article first published online: 10 MAR 2008
© The Authors(2008)
European Journal of Neuroscience
Volume 27, Issue 4, pages 937–946, February 2008
How to Cite
Mills, C., Makwana, M., Wallace, A., Benn, S., Schmidt, H., Tegeder, I., Costigan, M., Brown, R. H., Raivich, G. and Woolf, C. J. (2008), Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats. European Journal of Neuroscience, 27: 937–946. doi: 10.1111/j.1460-9568.2008.06065.x
- Issue published online: 10 MAR 2008
- Article first published online: 10 MAR 2008
- Received 18 July 2007, revised 6 October 2007, accepted 22 December 2007
- cell death;
- peripheral benzodiazepine rece ptor;
- PK 11195
The translocator protein (18 kDa; TSPO), formerly known as the peripheral benzodiazepine receptor, is an outer mitochondrial membrane protein that associates with the mitochondrial permeability transition pore to regulate both steroidogenesis and apoptosis. TSPO expression is induced in adult dorsal root ganglion (DRG) sensory neurons after peripheral nerve injury and a TSPO receptor ligand, Ro5-4864, enhances DRG neurite growth in vitro and axonal regeneration in vivo. We have now found that TSPO is induced in neonatal motor neurons after peripheral nerve injury and have evaluated its involvement in neonatal and adult sensory and motor neuron survival, and in adult motor neuron regeneration. The TSPO ligand Ro5-4864 rescued cultured neonatal DRG neurons from nerve growth factor withdrawal-induced apoptosis and protected neonatal spinal cord motor neurons from death due to sciatic nerve axotomy. However, Ro5-4864 had only a small neuroprotective effect on adult facial motor neurons after axotomy, did not delay onset or prolong survival in SOD1 mutant mice, and failed to protect adult DRG neurons from sciatic nerve injury-induced death. In contrast, Ro5-4864 substantially enhanced adult facial motor neuron nerve regeneration and restoration of function after facial nerve axotomy. These data indicate a selective sensitivity of neonatal sensory and motor neurons to survival in response to Ro5-4864, which highlights that survival in injured immature neurons cannot necessarily predict success in adults. Furthermore, although Ro5-4864 is only a very weak promoter of survival in adult neurons, it significantly enhances regeneration and functional recovery in adults.