Translocator Protein as a Promising Target for Novel Anxiolytics

Abstract

Neurosteroids are able to rapidly control the excitability of the central nervous system, acting as regulators of type A receptors for GABA. Over the last two decades, many authors have confirmed that neurosteroid level alterations occur in psychiatric disorders, including anxiety disorders. More recently, investigators have manipulated neurosteroidogenesis in an effort to correct neuronal excitation and inhibition imbalances, which may lie at the root of neuropsychiatric conditions. In line with this strategy, emerging data have demonstrated that a promising target for therapy of anxiety disorders is the Translocator Protein (TSPO). TSPO is a five transmembrane domain protein (18 kDa) that is expressed predominantly in steroid-synthesizing tissues. At the subcellular level, TSPO is localized at contact sites between the outer and inner mitochondrial membranes and mediates the rate-limiting step of neurosteroidogenesis. Brain concentrations of neurosteroids can be affected by selective TSPO activation. Indeed, TSPO drug ligands are able to stimulate the primary neurosteroid formations that enhance GABAA receptor activity, pregnenolone and allopregnenalone, both in in vitro steroidogenic cells and in vivo animal models. A spectrum of TSPO ligands has been shown to exert anxiolytic actions when administered in rodents. Some TSPO drug ligands could potentially reach clinical development. For example, recent evidence has shown that the selective TSPO ligand, XBD173 (AC-5216, Emapunil), exerts anxiolytic effects not only in animal models, but also in human volunteers. Herein, we review the current literature regarding the central nervous system biology of TSPO, a promising molecular target, in combination with its available ligands.

Midazolam Ameliorates the Behavior Deficits of a Rat Posttraumatic Stress Disorder Model through Dual 18 kDa Translocator Protein and Central Benzodiazepine Receptor and Neurosteroidogenesis

“…The TSPO, which is located mainly in the outer mitochondrial membrane (OMM) in peripheral tissues and the central nervous system (CNS), processes the availability of neurosteroids in the brain by modulating cholesterol [15]. Several studies have shown that TSPO ligands effectively treated depression and anxiety disorders through the modulation of the neurosteroid synthesis [16], [17]. Midazolam, a ligand for TSPO and CBR, has also induced anxiolytic-like and antidepressant effects [18], [19].…”

Translocator protein: pharmacology and steroidogenesis

“…Extending our work on gonadal and adrenal steroidogenesis, we demonstrated that brain neurosteroid synthesis was under the control of TSPO drug ligands and endogenous DBI [39], suggesting TSPO ligands may serve as pharmacological means to regulate neurosteroidogenesis [40]. Changes in neurosteroid levels are associated with a variety of psychopathological conditions [41] and induction of neurosteroid formation by TSPO ligands has been a vibrant field of research [40], though the precise cells responsible for synthesis of neurosteroids and TSPO ligand site of action remains to be elucidated.…”

Estradiol Modulates Translocator Protein (TSPO) and Steroid Acute Regulatory Protein (StAR) via Protein Kinase A (PKA) Signaling in Hypothalamic Astrocytes

“…In the 3xTgAD mouse model of Alzheimer's disease, TSPO activation was shown to enhance steroidogenesis and neuroprotection (70). Moreover, activation of TSPO has been shown to have anxiolytic actions potentially due to an increase in synthesis of neurosteroids with sedative properties (64, 71, 72). Patients with posttraumatic stress disorder have lower levels of TSPO, and stimulation of TSPO improved behavioral deficits in a mouse model of posttraumatic stress disorder (73–75).…”