Differential effects of TSPO ligands on mitochondrial function in mouse microglia cells

Bader, Stefanie; Wolf, Luisa; Milenkovic, Vladimir M.; Gruber, Michael; Nothdurfter, Caroline; Rupprecht, Rainer; Wetzel, Christian H.

doi:10.1016/j.psyneuen.2019.03.029

Cited by 64 publications

(62 citation statements)

References 47 publications

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“…Recently, Bader and colleagues demonstrated that pregnenolone biosynthesis is dependent on TSPO expression in mouse BV-2 microglia cells [39]. In fact, they showed that XBD173 and Ro5-4864 were able to stimulate pregnenolone biosynthesis in a TSPO-dependent way and that mitochondrial function is differentially modulated by TSPO ligands [39]. The ligand-specific effects could be in a TSPO-dependent or independent manner on different cellular functions [39].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, they showed that XBD173 and Ro5-4864 were able to stimulate pregnenolone biosynthesis in a TSPO-dependent way and that mitochondrial function is differentially modulated by TSPO ligands [39]. The ligand-specific effects could be in a TSPO-dependent or independent manner on different cellular functions [39]. Further investigations are needed on the effect of our TSPO ligands on TSPO expression providing evidence for both specific TSPO-mediated, as well as off-target effects.…”

Section: Discussionmentioning

confidence: 99%

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TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis

Lejri

Grimm

Hallé

et al. 2019

JAD

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Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro. In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-␤ (A␤). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stressinduced cell death as well as lowering A␤ levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis

Lejri

Grimm

Hallé

et al. 2019

JAD

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“…In another recent study, using the rodent microglial cell line BV2, TSPO knockdown cells had altered mitochondrial membrane potential compared to scrambled controls. Furthermore, scramble BV2 cells treated with Ro5-4864 and PK11195 had increased basal respiration and ATP-related respiration [58], demonstrating the ability of TSPO-specific ligands to alter mitochondrial processes of microglia. A very recent and comprehensive study of the role of TSPO in several key mitochondrial functions has demonstrated similar results.…”

Section: Tspo In Mitochondrial Bioenergeticsmentioning

confidence: 93%

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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“…Furthermore, radioligand-labeled research revealed the protective effects of moderate-affinity TSPO ligands, such as Etifoxine, against brain injury and brain disorders [168,169]. Thus, TSPO has become the target of research into high-affinity as well as low-affinity therapeutic ligands against various pathologies of the CNS, leading to a plethora of patents [14,65,170,171]. Interestingly, although counterintuitive, from the results of various studies, it can be assumed that low-and moderate-affinity TSPO ligands are at least as efficacious as high-affinity ligands, while showing far fewer risks of side effects [28,47,66,172,173].…”

Section: Tspo and Traumatic Brain Injuries (Tbis)mentioning

confidence: 99%

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

Dimitrova-Shumkovska

Krstanoski

Veenman

2020

Cells

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Neuroinflammation and cell death are among the common symptoms of many central nervous system diseases and injuries. Neuroinflammation and programmed cell death of the various cell types in the brain appear to be part of these disorders, and characteristic for each cell type, including neurons and glia cells. Concerning the effects of 18-kDa translocator protein (TSPO) on glial activation, as well as being associated with neuronal cell death, as a response mechanism to oxidative stress, the changes of its expression assayed with the aid of TSPO-specific positron emission tomography (PET) tracers’ uptake could also offer evidence for following the pathogenesis of these disorders. This could potentially increase the number of diagnostic tests to accurately establish the stadium and development of the disease in question. Nonetheless, the differences in results regarding TSPO PET signals of first and second generations of tracers measured in patients with neurological disorders versus healthy controls indicate that we still have to understand more regarding TSPO characteristics. Expanding on investigations regarding the neuroprotective and healing effects of TSPO ligands could also contribute to a better understanding of the therapeutic potential of TSPO activity for brain damage due to brain injury and disease. Studies so far have directed attention to the effects on neurons and glia, and processes, such as death, inflammation, and regeneration. It is definitely worthwhile to drive such studies forward. From recent research it also appears that TSPO ligands, such as PK11195, Etifoxine, Emapunil, and 2-Cl-MGV-1, demonstrate the potential of targeting TSPO for treatments of brain diseases and disorders.

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Differential effects of TSPO ligands on mitochondrial function in mouse microglia cells

Cited by 64 publications

References 47 publications

TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis

TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis

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

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

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