Etifoxine improves peripheral nerve regeneration and functional recovery.
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.
Girard
Christelle
C
Unité 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.
Liu
Song
S
Cadepond
Françoise
F
Adams
David
D
Lacroix
Catherine
C
Verleye
Marc
M
Gillardin
Jean-Marie
JM
Baulieu
Etienne-Emile
EE
Schumacher
Michael
M
Schweizer-Groyer
Ghislaine
G
D000818:Animals; D001369:Axons; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D058787:GABA-A Receptor Antagonists; D008124:Locomotion; D008264:Macrophages; D008297:Male; D009043:Motor Activity; D009416:Nerve Regeneration / Q000187:drug effects*; D010078:Oxazines / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A; D020127:Recovery of Function / Q000187:drug effects; D012677:Sensation
D002352:Carrier Proteins; D058787:GABA-A Receptor Antagonists; D010078:Oxazines; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; C002125:etifoxine