TSPO PIGA Ligands Promote Neurosteroidogenesis and Human Astrocyte Well-Being

Pozzo, Eleonora Da; Giacomelli, Chiara; Costa, Barbara; Cavallini, Chiara; Taliani, Sabrina; Barresi, Elisabetta; Settimo, Federico Da; Martini, Claudia

doi:10.3390/ijms17071028

Cited by 33 publications

(28 citation statements)

References 84 publications

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“…For example, Ro5‐4864 and PK 11 195 (another TSPO ligand) were shown to attenuate the tamoxifen‐induced apoptosis and decrease of MMP in human breast cancer cell lines (MCF‐7 and BT‐20) at a concentration of 10 nmol L ‐1 . Other TSPO ligands (PIGA) also increased the oxidative metabolism activity/proliferation index in U87MG human glioma cells in the nanomolar range . In line, we observed that TSPO ligands increased MMP and ATP levels at a low (10 nmol L ‐1 ) concentration after 24 hours.…”

Section: Discussionsupporting

confidence: 72%

Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies

Grimm

Lejri

Hallé

et al. 2019

J Neuroendocrinology

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Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up‐regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β‐amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD‐related tauopathy (human neuroblastoma cells SH‐SY5Y stably overexpressing the P301L‐mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR‐180,575 and Ro5‐4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD‐related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD.

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Section: Discussionsupporting

confidence: 72%

Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies

Grimm

Lejri

Hallé

et al. 2019

J Neuroendocrinology

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“…Briefly, the mitochondrial metabolic activity of senescent H9c2 cells that had been treated with Nar or vehicle was determined using the [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenol)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] (MTS) assay according to manufacturer's instructions (Promega, Milano, Italy) [31]. This tetrazolium dye can be reduced by the metabolic reducing agents NADH and NADPH to a water-soluble formazan salt; the amount of formazan produced is considered to be a marker of the oxidative metabolic activity index [32].…”

Section: Methodsmentioning

confidence: 99%

The Citrus Flavanone Naringenin Protects Myocardial Cells against Age-Associated Damage

Pozzo

Costa

Cavallini

et al. 2017

Oxidative Medicine and Cellular Longevity

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In recent years, the health-promoting effects of the citrus flavanone naringenin have been examined. The results have provided evidence for the modulation of some key mechanisms involved in cellular damage by this compound. In particular, naringenin has been revealed to have protective properties such as an antioxidant effect in cardiometabolic disorders. Very recently, beneficial effects of naringenin have been demonstrated in old rats. Because aging has been demonstrated to be directly related to the occurrence of cardiac disorders, in the present study, the ability of naringenin to prevent cardiac cell senescence was investigated. For this purpose, a cellular model of senescent myocardial cells was set up and evaluated using colorimetric, fluorimetric, and immunometric techniques. Relevant cellular senescence markers, such as X-gal staining, cell cycle regulator levels, and the percentage of cell cycle-arrested cells, were found to be reduced in the presence of naringenin. In addition, cardiac markers of aging-induced damage, including radical oxidative species levels, mitochondrial metabolic activity, mitochondrial calcium buffer capacity, and estrogenic signaling functions, were also modulated by the compound. These results suggested that naringenin has antiaging effects on myocardial cells.

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“…It was later found in a glioma cell line that these TSPO ligands can also increase mitochondrial numbers and mitochondrial division, further linking TSPO to mitochondrial dynamics [51]. However, from the earliest studies, the known strong presence of TSPO expression in steroidogenic organs and the ability of cholesterol to bind with high affinity to TSPO led to several years of study into the specific role of TSPO in cholesterol transport and steroidogenesis [39,[52][53][54]. As this function continues to produce conflicting evidence, a role for TSPO in steroid synthesis cannot be ruled out, though further data in a range of experimental models is required.…”

Section: Tspo In Mitochondrial Bioenergeticsmentioning

confidence: 99%

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Betlazar

Middleton

Bánati

et al. 2020

Cells

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The translocator protein (TSPO) is an outer mitochondrial membrane protein that is widely used as a biomarker of neuroinflammation, being markedly upregulated in activated microglia in a range of brain pathologies. Despite its extensive use as a target in molecular imaging studies, the exact cellular functions of this protein remain in question. The long-held view that TSPO plays a fundamental role in the translocation of cholesterol through the mitochondrial membranes, and thus, steroidogenesis, has been disputed by several groups with the advent of TSPO knockout mouse models. Instead, much evidence is emerging that TSPO plays a fundamental role in cellular bioenergetics and associated mitochondrial functions, also part of a greater role in the innate immune processes of microglia. In this review, we examine the more direct experimental literature surrounding the immunomodulatory effects of TSPO. We also review studies which highlight a more central role for TSPO in mitochondrial processes, from energy metabolism, to the propagation of inflammatory responses through reactive oxygen species (ROS) modulation. In this way, we highlight a paradigm shift in approaches to TSPO functioning.

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TSPO PIGA Ligands Promote Neurosteroidogenesis and Human Astrocyte Well-Being

Cited by 33 publications

References 84 publications

Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies

Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies

The Citrus Flavanone Naringenin Protects Myocardial Cells against Age-Associated Damage

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

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