Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders?

Abstract

Efficient treatment of stress-related disorders, such as depression, is still a major challenge. The onset of antidepressant drug action is generally quite slow, while the anxiolytic action of benzodiazepines is considerably faster. However, their long-term use is impaired by tolerance development, abuse liability and cognitive impairment. Benzodiazepines act as positive allosteric modulators of ɣ-aminobutyric acid type A (GABA A ) receptors. 3α-reduced neurosteroids such as allopregnanolone also are positive allosteric GABA A receptor modulators, however, through a site different from that targeted by benzodiazepines. Recently, the administration of neurosteroids such as brexanolone or zuranolone has been shown to rapidly ameliorate symptoms in post-partum depression or major depressive disorder. An attractive alternative to the administration of exogenous neurosteroids is promoting endogenous neurosteroidogenesis via the translocator protein 18k Da (TSPO). TSPO is a transmembrane protein located primarily in mitochondria, which mediates numerous biological functions, e.g., steroidogenesis and mitochondrial bioenergetics. TSPO ligands have been used in positron emission tomography (PET) studies as putative markers of microglia activation and neuroinflammation in stress-related disorders. Moreover, TSPO ligands have been shown to modulate neuroplasticity and to elicit antidepressant and anxiolytic therapeutic effects in animals and humans. As such, TSPO may open new avenues for understanding the pathophysiology of stress-related disorders and for the development of novel treatment options.

Impact of Translocator Protein 18 kDa (TSPO) Deficiency on Mitochondrial Function and the Inflammatory State of Human C20 Microglia Cells

“…It is expressed to varying degrees in multiple tissues, with the highest levels of expression found in steroidogenic tissues and relatively low expression in the central nervous system. In the brain, TSPO can be detected predominantly in microglia and reactive astrocytes [ 9 ], where its expression is upregulated in the context of inflammation, neurodegeneration, and malignant neoplasia [ 10 , 11 ]. Although the role of TSPO in de novo steroidogenesis was questioned in view of various genetic TSPO deletion models [ 12 , 13 , 14 , 15 ], our recent studies support a role of TSPO expression as well as of TSPO ligands in the regulation of pregnenolone synthesis in mouse BV-2 and human C20 microglia cells [ 16 , 17 , 18 ].…”

18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model

“…It was already shown that spatial volumes of TSPO-PET add complementary information to amino acid PET since the spatial agreement of both imaging targets was rather poor ( 3 ). Ultimately, TSPO agonists or antagonists could also act as direct modulators of TSPO expression in gliomas ( 4 ) and such therapies would profit from monitoring of altered target expression by TSPO-PET. The value of TSPO imaging in glioma was already determined in prognostication and detection of tumor heterogeneity ( 5 , 6 ).…”

Meta-analysis of molecular imaging of translocator protein in major depression

“…TSPO may not only serve as a diagnostic marker in combination with other neuroimaging modalities, but it might also exert as a direct target for putative therapeutic effects in stress-related diseases such as MDD ( Rupprecht et al, 2022 ). While the present results may present microglia as a therapeutic target, a treatment trial with minocycline failed to rectify the elevated TSPO-PET binding in a cohort of patients with treatment-resistant depression ( Attwells et al, 2021 ).…”