Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders

The translocator protein (18 kDa) (TSPO) is a five transmembrane domain protein that is localized primarily in the outer mitochondrial membrane and is expressed predominantly in steroid-synthesizing tissues, including the brain.TSPO is involved in the translocation of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in the synthesis of steroids and neurosteroids and one of the most well-characterized functions of this protein.TSPO expression seems to be a sensitive biomarker of brain damage and neurodegeneration, particularly of inflammation and reactive gliosis.In response to injury, TSPO expression is strongly upregulated in the peripheral nervous system in Schwann cells, macrophages and neurons. Increased TSPO ligand binding has also been investigated as a molecular in vivo sensor of neuronal damage and inflammation in patients with neurodegenerative diseases of the central nervous system (CNS) that are characterized by neuronal loss in discrete areas.Cholesterol, porphyrins and endozepines are endogenous ligands of TSPO. Classical synthetic ligands of TSPO include the isoquinoline PK-11195 and the benzodiazepine Ro5-4864. Over the past two decades, various additional TSPO ligands have been developed, which can be subdivided into distinct chemical classes.Most of the TSPO ligands were developed primarily as neuroimaging agents and diagnostic tools for brain inflammation associated with various neuropathological conditions.Certain specific TSPO ligands are under development also for the treatment of various neurological and psychiatric disorders. Possible indications include peripheral neuropathies, neurodegenerative or traumatic processes within the CNS, and psychiatric disorders, especially anxiety disorders.There are ongoing trials with TSPO ligands for the treatment of chemotherapy-induced peripheral neuropathy and as an adjunct treatment in amyotrophic lateral sclerosis. Moreover, clinical studies with various TSPO ligands have been performed in patients suffering from diabetic neuropathy, in healthy volunteers undergoing an experimental anxiety challenge and in patients with generalized anxiety disorder. Etifoxine is available in France for the treatment of adjustment disorder with anxiety.Systematic clinical studies involving prolonged administration and safety monitoring and differential treatment regimens are needed to evaluate the therapeutic potential of TSPO ligands in relation to their putative side-effect profile.