Recent progress on the development of fluorescent probes targeting the translocator protein 18 kDa (TSPO).
Analytical biochemistry
The translocator protein 18 kDa (TSPO) was first identified in 1997, and has now become one of the appealing subcellular targets in medicinal chemistry and its related fields. TSPO involves in a variety of diseases, covering neurodegenerative diseases, psychiatric disorders, cancers, and so on. To date, various high-affinity TSPO ligands labelled with single-photon emission computed tomography (SPECT)/positron emission tomography (PET) radionuclides have been reported, with some third-generation radioligands advanced to clinical trials. On the other hand, only a few number of TSPO ligands have been labelled with fluorophores for disease diagnosis. It is noteworthy that the majority of the TSPO fluorescent probes synthesised to date are based on visible fluorophores, suggesting that their applications are limited to in vitro studies, such as in vitro imaging of cancer cells, post-mortem analysis, and tissue biopsies examinations. In this context, the potential application of TSPO ligands can be broadened for in vivo investigations of human diseases by labelling with near-infrared (NIR)-fluorophores or substituting visible fluorophores with NIR-fluorophores on the currently developed fluorescent probes. In this review article, recent progress on fluorescent probes targeting the TSPO are summarised, with an emphasis on development trend in recent years and application prospects in the future.
10.1016/j.ab.2022.114854
The translocator protein (18kDa) and its role in neuropsychiatric disorders.
Barichello Tatiana,Simões Lutiana R,Collodel Allan,Giridharan Vijayasree V,Dal-Pizzol Felipe,Macedo Danielle,Quevedo Joao
Neuroscience and biobehavioral reviews
Translocator protein (TSPO) is an 18kDa translocator membrane protein expressed in the outer mitochondrial membrane of steroid-synthesizing cells in the central and peripheral nervous systems. TSPO is involved in cellular functions, including the regulation of cell proliferation, transport of cholesterol to the inner mitochondrial membranes of glial cells, regulation of mitochondrial quality control, and haem synthesis. In the brain, TSPO has been extensively used as a biomarker of injury and inflammation. Indeed, TSPO was up-regulated in several inflammatory and neurodegenerative diseases. In contrast, the expression of TSPO was decreased in peripheral blood from psychiatric patients. Since TSPO is involved in several mechanisms related to mitochondrial function and inflammatory alterations, therapeutic approaches focusing on the regulation of TSPO may provide a new avenue for the treatment of neuropsychiatric disorders. Based on the involvement of mitochondrial alterations in the neurobiology of neuropsychiatric disorders, this review will focus on the functions and physiological roles of TSPO and the potential of TSPO ligands as therapeutic strategies for the treatment of neuropsychiatric disorders.
10.1016/j.neubiorev.2017.10.010
The mitochondrial translocator protein (TSPO): a key multifunctional molecule in the nervous system.
The Biochemical journal
Translocator protein (TSPO, 18 kDa), formerly known as peripheral benzodiazepine receptor, is an evolutionary well-conserved protein located on the outer mitochondrial membrane. TSPO is involved in a variety of fundamental physiological functions and cellular processes. Its expression levels are regulated under many pathological conditions, therefore, TSPO has been proposed as a tool for diagnostic imaging and an attractive therapeutic drug target in the nervous system. Several synthetic TSPO ligands have thus been explored as agonists and antagonists for innovative treatments as neuroprotective and regenerative agents. In this review, we provide state-of-the-art knowledge of TSPO functions in the brain and peripheral nervous system. Particular emphasis is placed on its contribution to important physiological functions such as mitochondrial homeostasis, energy metabolism and steroidogenesis. We also report how it is involved in neuroinflammation, brain injury and diseases of the nervous system.
10.1042/BCJ20220050
Translocator protein 18 kDa regulates retinal neuron apoptosis and pyroptosis in glaucoma.
Redox biology
Glaucoma is the leading cause of blindness worldwide. However, our insufficient understanding of the pathogenesis of glaucoma has limited the development of effective treatments. Because recent research has highlighted the importance of non-coding RNAs (ncRNAs) in various diseases, we investigated their roles in glaucoma. Specifically, we detected expression changes of ncRNAs in cell and animal models of acute glaucoma. Further analysis revealed that the Ier2/miR-1839/TSPO axis was critical to cell loss and retinal damage. The knockdown of Ier2, the overexpression of miR-1839, and the silencing of TSPO effectively prevented retinal damage and cell loss. Furthermore, we found that the Ier2/miR-1839/TSPO axis regulated the pyroptosis and apoptosis of retinal neurons through the NLRP3/caspase1/GSDMD, cleaved-caspase3 pathways. In addition to high expression in the retina, TSPO expression was found to be significantly higher in the dorsal lateral geniculate nucleus (DLG) of the brain in the pathologically high intraocular pressure (ph-IOP) rat model, as well as in the peripheral blood mononuclear cells (PBMCs) of glaucoma patients with high IOP. These results indicate that TSPO, which is regulated by Ier2/miR-1839, plays an important role in the pathogenesis of glaucoma, and this study provides a theoretical basis and a new target for the diagnosis and treatment of glaucoma.
10.1016/j.redox.2023.102713
18-kDa translocator protein association complexes in the brain: From structure to function.
Costa Barbara,Da Pozzo Eleonora,Martini Claudia
Biochemical pharmacology
The outer mitochondrial membrane 18-kDa translocator protein (TSPO) is highly conserved in organisms of different species and ubiquitously expressed throughout tissues, including the nervous system. In the healthy adult brain, TSPO expression levels are low and promptly modulated under different pathological conditions, such as cancer, inflammatory states, and neurological and psychiatric disorders. Not surprisingly, several endogenous and synthetic molecules capable of binding TSPO have been proposed as drugs or diagnostic tools for brain diseases. The most studied biochemical function of TSPO is cholesterol translocation into mitochondria, which in turn affects the synthesis of steroids in the periphery and neurosteroids in the brain. In the last 30 years, roles for TSPO have also been suggested in other cellular processes, such as heme synthesis, apoptosis, autophagy, calcium signalling and reactive oxygen species production. Herein, we provide an overview of TSPO associations with different proteins, focusing particular attention on their related functions. Furthermore, recent TSPO-targeted therapeutic interventions are explored and discussed as prospect for innovative treatments in mental and brain diseases.
10.1016/j.bcp.2020.114015
A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury.
Li Han-Dong,Li Minshu,Shi Elaine,Jin Wei-Na,Wood Kristofer,Gonzales Rayna,Liu Qiang
Journal of neuroinflammation
BACKGROUND:Cerebral ischemia is a leading cause of death and disability with limited treatment options. Although inflammatory and immune responses participate in ischemic brain injury, the molecular regulators of neuroinflammation after ischemia remain to be defined. Translocator protein 18 kDa (TSPO) mainly localized to the mitochondrial outer membrane is predominantly expressed in glia within the central nervous system during inflammatory conditions. This study investigated the effect of a TSPO agonist, etifoxine, on neuroinflammation and brain injury after ischemia/reperfusion. METHODS:We used a mouse model of middle cerebral artery occlusion (MCAO) to examine the therapeutic potential and mechanisms of neuroprotection by etifoxine. RESULTS:TSPO was upregulated in Iba1 or CD11bCD45 cells from mice subjected to MCAO and reperfusion. Etifoxine significantly attenuated neurodeficits and infarct volume after MCAO and reperfusion. The attenuation was pronounced in mice subjected to 30, 60, or 90 min MCAO. Etifoxine reduced production of pro-inflammatory factors in the ischemic brain. In addition, etifoxine treatment led to decreased expression of interleukin-1β, interleukin-6, tumor necrosis factor-α, and inducible nitric oxide synthase by microglia. Notably, the benefit of etifoxine against brain infarction was ablated in mice depleted of microglia using a colony-stimulating factor 1 receptor inhibitor. CONCLUSIONS:These findings indicate that the TSPO agonist, etifoxine, reduces neuroinflammation and brain injury after ischemia/reperfusion. The therapeutic potential of targeting TSPO requires further investigations in ischemic stroke.
10.1186/s12974-017-0921-7
Neurogenic Potential of the 18-kDa Mitochondrial Translocator Protein (TSPO) in Pluripotent P19 Stem Cells.
González-Blanco Laura,Bermejo-Millo Juan Carlos,Oliveira Gabriela,Potes Yaiza,Antuña Eduardo,Menéndez-Valle Iván,Vega-Naredo Ignacio,Coto-Montes Ana,Caballero Beatriz
Cells
The 18-kDa translocator protein (TSPO) is a key mitochondrial target by which different TSPO ligands exert neuroprotective effects. We assayed the neurogenic potential of TSPO to induce the neuronal differentiation of pluripotent P19 stem cells in vitro. We studied changes in cell morphology, cell proliferation, cell death, the cell cycle, mitochondrial functionality, and the levels of pluripotency and neurogenesis of P19 stem cells treated with the TSPO ligand, PK 11195, in comparison to differentiation induced by retinoid acid (RA) and undifferentiated P19 stem cells. We observed that PK 11195 was able to activate the differentiation of P19 stem cells by promoting the development of embryoid bodies. PK 11195 also induced changes in the cell cycle, decreased cell proliferation, and activated cell death. Mitochondrial metabolism was also enhanced by PK 11195, thus increasing the levels of reactive oxygen species, Ca, and ATP as well as the mitochondrial membrane potential. Markers of pluripotency and neurogenesis were also altered during the cell differentiation process, as PK 11195 induced the differentiation of P19 stem cells with a high predisposition toward a neuronal linage, compared to cell differentiation induced by RA. Thus, we suggest a relevant neurogenic potential of TSPO along with broad therapeutic implications.
10.3390/cells10102784
An Updated View of Translocator Protein (TSPO).
Denora Nunzio,Natile Giovanni
International journal of molecular sciences
Decades of study on the role of mitochondria in living cells have evidenced the importance of the 18 kDa mitochondrial translocator protein (TSPO), first discovered in the 1977 as an alternative binding site for the benzodiazepine diazepam in the kidneys. This protein participates in a variety of cellular functions, including cholesterol transport, steroid hormone synthesis, mitochondrial respiration, permeability transition pore opening, apoptosis, and cell proliferation. Thus, TSPO has become an extremely attractive subcellular target for the early detection of disease states that involve the overexpression of this protein and the selective mitochondrial drug delivery. This special issue was programmed with the aim of summarizing the latest findings about the role of TSPO in eukaryotic cells and as a potential subcellular target of diagnostics or therapeutics. A total of 9 papers have been accepted for publication in this issue, in particular, 2 reviews and 7 primary data manuscripts, overall describing the main advances in this field.
10.3390/ijms18122640
Translocator Protein 18 kDa (TSPO) Deficiency Inhibits Microglial Activation and Impairs Mitochondrial Function.
Yao Rumeng,Pan Ruiyuan,Shang Chao,Li Xiaoheng,Cheng Jinbo,Xu Jiangping,Li Yunfeng
Frontiers in pharmacology
TSPO is mainly expressed in the mitochondrial outer membrane of microglia in the central nervous system, and its expression is greatly increased when microglia are activated. However, the role and mechanism of this protein in microglial activation is not well characterized. In this study, we investigated the role of TSPO in microglial activation by isolating primary microglia from knockout mice and constructing TSPO-knockdown microglial cell line. We found that TSPO deficiency significantly inhibited microglial activation induced by LPS or IL-4. Mechanistically, TSPO deficiency greatly decreased the mitochondrial membrane potential and ATP production. Moreover, an analysis of cellular energy metabolism showed that TSPO deficiency suppressed mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis, resulting in microglial overall metabolic deficits. Together, our results reveal a crucial role of TSPO in microglial activation through the regulation of mitochondrial metabolism, thus providing a potential therapeutic target for neuroinflammation-related diseases of the central nervous system.
10.3389/fphar.2020.00986
Translocator Protein 18-kDa: A Promising Target to Treat Neuroinflammation- related Degenerative Diseases.
Current medicinal chemistry
In the nervous system, inflammatory responses physiologically occur as defense mechanisms triggered by damaging events. If improperly regulated, neuroinflammation can contribute to the development of chronically activated states of glial cells, with the perpetuation of inflammation and neuronal damage, thus leading to neurological and neurodegenerative disorders. Interestingly, neuroinflammation is associated with the overexpression of the mitochondrial translocator protein (TSPO) in activated glia. Despite the precise role of TSPO in the immunomodulatory mechanisms during active disease states is still unclear, it has emerged as a promising target to promote neuroprotection. Indeed, TSPO ligands have been shown to exert beneficial effects in counteracting neuroinflammation and neuronal damage in several in vitro and in vivo models of neurodegenerative diseases. In particular, the regulation of neurosteroids' production, cytokine release, metabolism of radical oxidative species, and cellular bioenergetics appear to be the main cellular events that underlie the observed effects. The present review aims to illustrate and summarize recent findings on the potential effect of TSPO ligands against neuroinflammation and related neurodegenerative mechanisms, taking into consideration some pathologies of the nervous system in which inflammatory events are crucial for the onset and progression of the disease and attempting to shed light onto the immunomodulatory effects of TSPO.
10.2174/0929867329666220415120820
The Ligands of Translocator Protein: Design and Biological Properties.
Mokrov Grigory V,Deeva Olga A,Gudasheva Tatiana A
Current pharmaceutical design
In 2020, it is already 43 years since Braestrup and Squires discovered 18 kDa translocator protein (TSPO), known until 2006 as "peripheral benzodiazepine receptor". During this time, the functions of this receptor, which is located on the outer membrane of mitochondria, were studied in detail. One of the key functions of TSPO is the transfer of cholesterol from the outer to the inner mitochondrial membrane, which is the limiting stage in the synthesis of neurosteroids. TSPO is also involved in the transport of porphyrins, mitochondrial respiration, the opening of mitochondrial pores, apoptosis and cell proliferation. This review presents current information on the structure of TSPO, the mechanism of its participation in neurosteroidogenesis, as well as endogenous and synthetic TSPO ligands. Particular emphasis is placed on the analysis of approaches to the design of synthetic ligands and their neuropsychotropic activity in vitro and in vivo. The presented review demonstrates the promise of constructing new neuropsychotropic drugs in the series of TSPO ligands.
10.2174/1381612826666200903122025
Targeting the Translocator Protein (18 kDa) in Cardiac Diseases: State of the Art and Future Opportunities.
Journal of medicinal chemistry
Mitochondria dysfunctions are typical hallmarks of cardiac disorders (CDs). The multiple tasks of this energy-producing organelle are well documented, but its pathophysiologic involvement in several manifestations of heart diseases, such as altered electromechanical coupling, excitability, and arrhythmias, is still under investigation. The human 18 kDa translocator protein (TSPO) is a protein located on the outer mitochondrial membrane whose expression is altered in different pathological conditions, including CDs, making it an attractive therapeutic and diagnostic target. Currently, only a few TSPO ligands are employed in CDs and cardiac imaging. In this Perspective, we report an overview of the emerging role of TSPO at the heart level, focusing on the recent literature concerning the development of TSPO ligands used for fighting and imaging heart-related disease conditions. Accordingly, targeting TSPO might represent a successful strategy to achieve novel therapeutic and diagnostic strategies to unravel the fundamental mechanisms and to provide solutions to still unanswered questions in CDs.
10.1021/acs.jmedchem.3c01716
Surface translocator protein 18 kDa (TSPO) localization on immune cells upon stimulation with LPS and in ART-treated HIV subjects.
Journal of leukocyte biology
Translocator protein 18 kDa (TSPO) is a well-known outer mitochondrial membrane protein and it is widely used as a biomarker of neuroinflammation and brain injury. Although it is thought that TSPO plays key roles in a multitude of host cell functions, including steroid biosynthesis, apoptosis, generation of reactive oxygen species, and proliferation, some of these functions have recently been questioned. Here, we report the unexpected finding that circulating immune cells differentially express basal levels of TSPO on their cell surface, with a high percentage of monocytes and neutrophils expressing cell surface TSPO. In vitro stimulation of monocytes with LPS significantly increases the frequency of cells with surface TSPO expression in the absence of altered gene expression. Importantly, the LPS increase in TSPO cell surface expression in monocytes appears to be selective for LPS because two other distinct monocyte activators failed to increase the frequency of cells with surface TSPO. Finally, when we quantified immune cell TSPO surface expression in antiretroviral therapy-treated HIV donors, a chronic inflammatory disease, we found significant increases in the frequency of TSPO surface localization, which could be pharmacologically suppressed with ∆ -tetrahydrocannabinol. These findings suggest that cell surface TSPO in circulating leukocytes could serve as a peripheral blood-based biomarker of inflammation.
10.1002/JLB.3A1219-729RR
Translocator protein in the rise and fall of central nervous system neurons.
Frontiers in cellular neuroscience
Translocator protein (TSPO), a 18 kDa protein found in the outer mitochondrial membrane, has historically been associated with the transport of cholesterol in highly steroidogenic tissues though it is found in all cells throughout the mammalian body. TSPO has also been associated with molecular transport, oxidative stress, apoptosis, and energy metabolism. TSPO levels are typically low in the central nervous system (CNS), but a significant upregulation is observed in activated microglia during neuroinflammation. However, there are also a few specific regions that have been reported to have higher TSPO levels than the rest of the brain under normal conditions. These include the dentate gyrus of the hippocampus, the olfactory bulb, the subventricular zone, the choroid plexus, and the cerebellum. These areas are also all associated with adult neurogenesis, yet there is no explanation of TSPO's function in these cells. Current studies have investigated the role of TSPO in microglia during neuron degeneration, but TSPO's role in the rest of the neuron lifecycle remains to be elucidated. This review aims to discuss the known functions of TSPO and its potential role in the lifecycle of neurons within the CNS.
10.3389/fncel.2023.1210205
Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders?
Molecular psychiatry
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) receptors. 3α-reduced neurosteroids such as allopregnanolone also are positive allosteric GABA 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.
10.1038/s41380-022-01561-3