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Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats

Authors

  • Charles Mills,

    1. Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
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  • Milan Makwana,

    1. Centre for Perinatal Brain Protection and Repair, Department of Obstetrics and Gynaecology, University College London, London WC1E 6HX, UK
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  • Adam Wallace,

    1. Centre for Perinatal Brain Protection and Repair, Department of Obstetrics and Gynaecology, University College London, London WC1E 6HX, UK
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  • Susanna Benn,

    1. Cecil B. Day Laboratory for Neuromuscular Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
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  • Helmut Schmidt,

    1. Pharmazentrum Frankfurt, Institut fur Klinische Pharmakologie/Zentrum fur Arzneimittelforschung, Entwicklung und Sicherheit, Klinikum der Johann Wolfgang Goethe-Universitat Frankfurt am Main, 60590, Germany
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  • Irmgard Tegeder,

    1. Pharmazentrum Frankfurt, Institut fur Klinische Pharmakologie/Zentrum fur Arzneimittelforschung, Entwicklung und Sicherheit, Klinikum der Johann Wolfgang Goethe-Universitat Frankfurt am Main, 60590, Germany
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  • Michael Costigan,

    1. Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
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  • Robert H Brown Jr,

    1. Cecil B. Day Laboratory for Neuromuscular Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
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  • Gennadij Raivich,

    1. Centre for Perinatal Brain Protection and Repair, Department of Obstetrics and Gynaecology, University College London, London WC1E 6HX, UK
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  • Clifford J. Woolf

    1. Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
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  • *

    Present address: Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.

Dr C. Mills, at *present address below.
E-mail: cmills@neurocrine.com

Abstract

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.

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