Etifoxine improves peripheral nerve regeneration and functional recovery
Posted: Tue Dec 23, 2008 2:49 pm
http://www.pnas.org/content/early/2008/12/15/0811201106
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Etifoxine improves peripheral nerve regeneration and functional recovery
1. Christelle Girarda,
2. Song Liub,
3. Françoise Cadeponda,
4. David Adamsa,c,
5. Catherine Lacroixc,
6. Marc Verleyed,
7. Jean-Marie Gillardind,
8. Etienne-Emile Baulieua,1,
9. Michael Schumachera,1, and
10. Ghislaine Schweizer-Groyera
+Author Affiliations
1.
aUnité Mixte de Recherche 788, Institut National de la Santé et de la Recherche Médicale, and Université Paris-Sud 11, 94276 Le Kremlin-Bicêtre Cedex, France;
2.
bU622, Institut Pasteur, 75015 Paris, France;
3.
cAssistance Publique–Hôpitaux de Paris, Service de Neurologie, Hôpital de Bicêtre, 94276 Le Kremlin-Bicêtre Cedex, France; and
4.
dService de Pharmacologie, Biocodex, 60200 Compiègne, France
1.
Contributed by Etienne-Emile Baulieu, November 5, 2008 (sent for review October 17, 2008)
Abstract
Peripheral nerves show spontaneous regenerative responses, but recovery after injury or peripheral neuropathies (toxic, diabetic, or chronic inflammatory demyelinating polyneuropathy syndromes) is slow and often incomplete, and at present no efficient treatment is available. Using well-defined peripheral nerve lesion paradigms, we assessed the therapeutic usefulness of etifoxine, recently identified as a ligand of the translocator protein (18 kDa) (TSPO), to promote axonal regeneration, modulate inflammatory responses, and improve functional recovery. We found by histologic analysis that etifoxine therapy promoted the regeneration of axons in and downstream of the lesion after freeze injury and increased axonal growth into a silicone guide tube by a factor of 2 after nerve transection. Etifoxine also stimulated neurite outgrowth in PC12 cells, and the effect was even stronger than for specific TSPO ligands. Etifoxine treatment caused a marked reduction in the number of macrophages after cryolesion within the nerve stumps, which was rapid in the proximal and delayed in the distal nerve stumps. Functional tests revealed accelerated and improved recovery of locomotion, motor coordination, and sensory functions in response to etifoxine. This work demonstrates that etifoxine, a clinically approved drug already used for the treatment of anxiety disorders, is remarkably efficient in promoting acceleration of peripheral nerve regeneration and functional recovery. Its possible mechanism of action is discussed, with reference to the neurosteroid concept. This molecule, which easily enters nerve tissues and regulates multiple functions in a concerted manner, offers promise for the treatment of peripheral nerve injuries and axonal neuropathies.
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Etifoxine improves peripheral nerve regeneration and functional recovery
1. Christelle Girarda,
2. Song Liub,
3. Françoise Cadeponda,
4. David Adamsa,c,
5. Catherine Lacroixc,
6. Marc Verleyed,
7. Jean-Marie Gillardind,
8. Etienne-Emile Baulieua,1,
9. Michael Schumachera,1, and
10. Ghislaine Schweizer-Groyera
+Author Affiliations
1.
aUnité Mixte de Recherche 788, Institut National de la Santé et de la Recherche Médicale, and Université Paris-Sud 11, 94276 Le Kremlin-Bicêtre Cedex, France;
2.
bU622, Institut Pasteur, 75015 Paris, France;
3.
cAssistance Publique–Hôpitaux de Paris, Service de Neurologie, Hôpital de Bicêtre, 94276 Le Kremlin-Bicêtre Cedex, France; and
4.
dService de Pharmacologie, Biocodex, 60200 Compiègne, France
1.
Contributed by Etienne-Emile Baulieu, November 5, 2008 (sent for review October 17, 2008)
Abstract
Peripheral nerves show spontaneous regenerative responses, but recovery after injury or peripheral neuropathies (toxic, diabetic, or chronic inflammatory demyelinating polyneuropathy syndromes) is slow and often incomplete, and at present no efficient treatment is available. Using well-defined peripheral nerve lesion paradigms, we assessed the therapeutic usefulness of etifoxine, recently identified as a ligand of the translocator protein (18 kDa) (TSPO), to promote axonal regeneration, modulate inflammatory responses, and improve functional recovery. We found by histologic analysis that etifoxine therapy promoted the regeneration of axons in and downstream of the lesion after freeze injury and increased axonal growth into a silicone guide tube by a factor of 2 after nerve transection. Etifoxine also stimulated neurite outgrowth in PC12 cells, and the effect was even stronger than for specific TSPO ligands. Etifoxine treatment caused a marked reduction in the number of macrophages after cryolesion within the nerve stumps, which was rapid in the proximal and delayed in the distal nerve stumps. Functional tests revealed accelerated and improved recovery of locomotion, motor coordination, and sensory functions in response to etifoxine. This work demonstrates that etifoxine, a clinically approved drug already used for the treatment of anxiety disorders, is remarkably efficient in promoting acceleration of peripheral nerve regeneration and functional recovery. Its possible mechanism of action is discussed, with reference to the neurosteroid concept. This molecule, which easily enters nerve tissues and regulates multiple functions in a concerted manner, offers promise for the treatment of peripheral nerve injuries and axonal neuropathies.
