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 in mitochondria, abundantly expressed in a variety of organs and tissues. TSPO contributes to a wide range of biological processes, including cholesterol transportation, mitochondrial membrane potential and respiratory chain regulation, apoptosis, and oxidative stress. Recent studies have demonstrated that TSPO might also be involved in the physiological regulation of cardiac chronotropy and inotropy. Accordingly, TSPO ligands play significant roles in protecting the cardiovascular systems under pathological conditions through cardiac electrical activity retention, intracellular calcium maintenance, mitochondrial energy provision, mitochondrial membrane potential equilibrium, and reactive oxygen species inhibition. This paper focuses on the physiological and pathological characteristics of TSPO in the cardiovascular systems and also summarizes the properties of TSPO ligands. TSPO represents a potential therapeutic target and diagnostic tool for cardiovascular diseases including arrhythmia, myocardial infarction, cardiac hypertrophy, atherosclerosis, myocarditis, and large vessel vasculitis.

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Therapeutic actions of translocator protein (18 kDa) ligands in experimental models of psychiatric disorders and neurodegenerative diseases

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2015.07.007 ◽

2015 ◽

Vol 154 ◽

pp. 68-74 ◽

Cited By ~ 23

Author(s):

B.D. Arbo ◽

F. Benetti ◽

L.M. Garcia-Segura ◽

M.F. Ribeiro

Keyword(s):

Neurodegenerative Diseases ◽

Psychiatric Disorders ◽

Experimental Models ◽

Translocator Protein ◽

Translocator Protein 18 Kda

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Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain

Frontiers in Pharmacology ◽

10.3389/fphar.2021.692917 ◽

2021 ◽

Vol 12 ◽

Author(s):

Bojun Xiong ◽

Guilin Jin ◽

Ying Xu ◽

Wenbing You ◽

Yufei Luo ◽

...

Keyword(s):

Neuropathic Pain ◽

Therapeutic Target ◽

Pain Treatment ◽

Translocator Protein ◽

Allosteric Modulator ◽

Positive Allosteric Modulator ◽

Pharmacological Characterization ◽

Competitive Binding Assay ◽

Translocator Protein 18 Kda

Koumine is an alkaloid that displays notable activity against inflammatory and neuropathic pain, but its therapeutic target and molecular mechanism still need further study. Translocator protein 18 kDa (TSPO) is a vital therapeutic target for pain treatment, and recent research implies that there may be allostery in TSPO. Our previous competitive binding assay hint that koumine may function as a TSPO positive allosteric modulator (PAM). Here, for the first time, we report the pharmacological characterization of koumine as a TSPO PAM. The results imply that koumine might be a high-affinity ligand of TSPO and that it likely acts as a PAM since it could delay the dissociation of 3H-PK11195 from TSPO. Importantly, the allostery was retained in vivo, as koumine augmented Ro5-4864-mediated analgesic and anti-inflammatory effects in several acute and chronic inflammatory and neuropathic pain models. Moreover, the positive allosteric modulatory effect of koumine on TSPO was further demonstrated in cell proliferation assays in T98G human glioblastoma cells. In summary, we have identified and characterized koumine as a TSPO PAM for the treatment of inflammatory and neuropathic pain. Our data lay a solid foundation for the use of the clinical candidate koumine to treat inflammatory and neuropathic pain, further demonstrate the allostery in TSPO, and provide the first proof of principle that TSPO PAM may be a novel avenue for the discovery of analgesics.

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