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.inflammation ͉ macrophage ͉ axonal growth ͉ Translocator Protein (18 kDa)

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).After a traumatic injury of the nervous system or in the course of a neurodegenerative disease, the speed of axonal regeneration and the control of the inflammatory response are fundamental parameters of functional recovery. Spontaneous regeneration takes place in the peripheral nervous system, although the process is slow and often incomplete. There is currently no efficient treatment for enhancing axonal regeneration, including elongation speed and functional reinnervation. Ligands of the translocator protein 18 kDa (TSPO) are currently under investigation as therapeutic means for promoting neuroprotection, accelerating axonal regeneration and modulating inflammation. The mechanisms of action of TSPO ligands involve the regulation of mitochondrial activity and the stimulation of steroid biosynthesis. In the peripheral nervous system, TSPO expression is strongly up-regulated after injury, primarily in Schwann cells and macrophages, but also in neurones. Its levels return to low control values when nerve regeneration is completed, strongly supporting an important role in regenerative processes. We have demonstrated a role for the benzoxazine etifoxine in promoting axonal regeneration in the lesioned rat sciatic nerve, either after freeze-injury or complete transection. Etifoxine is already clinically approved for the treatment of anxiety disorders (Stresam Ò , Biocodex, Gentilly, France). Daily treatment with etifoxine resulted in a two-fold acceleration in axonal regeneration, as well as in a marked improvement of both the speed and quality of functional recovery. The neuroregenerative effects of etifoxine are likely to be mediated by TSPO, and they may involve an increased synthesis of pregnenolone and its metabolites, such as progesterone. After freeze-injury of the sciatic nerve, administration of etifoxine also strongly reduced the number of activated macrophages and decreased the production of the inflammatory cytokines tumour necrosis factor-a and interleukin-1b. Thus, this drug offers promise for the treatment of peripheral nerve injuries and axonal neuropathies. It may also be used as a lead compound in the development of new TSPO-based neuroprotective approaches.