TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis
| Autor: | Lejri, I. (Imane), Grimm, A. (Amandine), Hallé, F. (Francois), Abarghaz, M. (Mustapha), Klein, C. (Christian), Maitre, M. (Michel), Schmitt, M. (Martine), Bourguignon, J. (Jean-Jacques), Mensah-Nyagan, A. (Ayikoé-Guy), Bihel, F. (Frederic), Eckert, A. (Anne), Albensi, B. (Benedict) (editor) |
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| Přispěvatelé: | Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques (BMNST), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie du système nerveux., Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Neurobiology Laboratory for Brain Aging and Mental Health, University of Basel (Unibas), Psychiatric University Clinics [Basel, Switzerland] (PUC), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), BIHEL, Frédéric |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
[CHIM.THER]Chemical Sciences/Medicinal Chemistry Mitochondrion medicine.disease_cause Ligands 0302 clinical medicine ComputingMilieux_MISCELLANEOUS chemistry.chemical_classification pregnenolone biology Cell Death Chemistry General Neuroscience General Medicine 3. Good health Cell biology Mitochondria Psychiatry and Mental health Clinical Psychology bioenergetics phenotype Pregnenolone neuroprotection [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Alzheimer’s disease medicine.drug Research Article Programmed cell death Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC] [CHIM.THER] Chemical Sciences/Medicinal Chemistry Oxidative phosphorylation TSPO ligands Neuroprotection 03 medical and health sciences Receptors GABA Cell Line Tumor Translocator protein medicine Humans [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Quinazolinones Reactive oxygen species Oxidative Stress 030104 developmental biology HEK293 Cells biology.protein Geriatrics and Gerontology Energy Metabolism Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Journal of Alzheimer's Disease Journal of Alzheimer's Disease, IOS Press, In press, pp.1-14. ⟨10.3233/JAD-190127⟩ Journal of Alzheimer's Disease, In press, pp.1-14. ⟨10.3233/JAD-190127⟩ |
| ISSN: | 1387-2877 |
| Popis: | International audience; 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-β (Aβ). 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 stress-induced cell death as well as lowering Aβ 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. |
| Databáze: | OpenAIRE |
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