Etifoxine improves peripheral nerve regeneration and functional recovery

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 51; pp. 20505 - 20510
• Main Authors: Girard, Christelle, Liu, Song, Cadepond, Françoise, Adams, David, Lacroix, Catherine, Verleye, Marc, Gillardin, Jean-Marie, Baulieu, Etienne-Emile, Schumacher, Michael, Schweizer-Groyer, Ghislaine
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23-12-2008; National Acad Sciences
• Subjects: Animals; Axons; Biological Sciences; Carrier Proteins - antagonists & inhibitors; Cell growth; Drug therapy; GABA-A Receptor Antagonists; Ligands; Locomotion; Macrophages; Male; Molecules; Motor ability; Motor Activity; Nerve Regeneration - drug effects; Nerves; Neurons; Oxazines - pharmacology; Oxazines - therapeutic use; PC12 Cells; Peripheral Nerve Injuries; Peripheral nerves; Peripheral Nerves - physiology; Rats; Rats, Sprague-Dawley; Receptors; Receptors, GABA-A; Recovery of Function - drug effects; Regeneration; Sciatic nerve; Sensation; Tissue engineering; Vehicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0811201106

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.