Axonal Regeneration and Neuroinflammation: Roles for the Translocator Protein 18 kDa

Abstract

).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.

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

“…All these features have led to propose TSPO as a promising pharmacological target and a strategic diagnostic tool. Several synthetic ligands with nanomolar/subnanomolar binding affinity to TSPO have been developed [3] and some of these are under investigation in Alzheimer's disease [4], multiple sclerosis [5], neurotrauma [6], neuroinflammation [7], anxiety disorders [8], cardiovascular diseases [9], and cancer [10]. Clinical trials for some TSPO ligands are concluded (Clinical Trials.gov Identifier: NCT00108836) or are currently recruiting participants (NCT01547780), and the marketed Etifoxine, a TSPO ligand, is already clinically approved for the treatment of anxiety-related disorders (Stresam Ò , Biocodex, Gentilly, France).…”

Mitochondrial regulation of macrophage cholesterol homeostasis

“…Signaling via TSPO also reduced the production of reactive oxygen species, cytokines, and chemokines in microglia, and promoted phagocytic activity [158][159][160]; TSPO ligands have also proved useful in reducing inflammation and severity of disease in a murine model of multiple sclerosis [161]. Indeed, TSPO has been proposed as a novel target for Alzheimer's disease and neurologic disorders [162][163][164][165], pain [166], vascular disease [153,[155][156][157], and cancer [167], although it is not clear at present how many of the effects ascribed to TSPO are related to its proposed role in mitochondrial cholesterol trafficking. Further, caution is obviously needed in interpreting the reported effects of TSPO and its ligands, given the lack of phenotype recently reported in healthy TSPO(-/-) mice [111,132,133]: it remains to be seen whether loss of TSPO will contribute to macrophage dysfunction in the context of specific disease pathologies.…”

Double Application of Translocator Protein Ligands and RAW Cells Inflammatory Milieu

“…A number of reports show an increase in the number of TSPO binding sites in the central and peripheral nervous systems during inflammation as well as neuroprotective effects by TSPO ligands (Ferzaz et al, 2002;Wilms et al, 2003;Mattner et al, 2011;Girard et al, 2012;Daugherty et al, 2013;Mattner et al, 2013;Bae et al, 2014;Morato et al, 2014). Because the principal effector cells in neuroinflammatory and neuro-degenerative disorders are microglia, monocyte-derived macrophages, macrophages in the perivascular space, the choroid plexus and the meninges (Bogie et al, 2014), the use of the RAW cell line (derived from murine macrophages) was an appropriate choice for this study.…”