A03fa Theme A: ß-Amyloid Diseases A03.f. Drug Development, Clinical Trials: Neuroprotective and mitochondrial compounds
31-Mar-2017 08:00 18:00
Abstract: 10915-MONTHS SAFETY AND EXPLORATORY EFFICACY DATA OF ANAVEX 2-73 IN A PHASE 2A STUDY IN MILD-TO-MODERATE ALZHEIMER’S DISEASE PATIENTS--author requestAbstract not available Co-authorsC. Missling 1 1, USA
Abstract: 007 THE DUAL REGULATION OF OXIDATIVE STRESS BY SIGMA1 RECEPTORS IN PHYSIOLOGICAL OR PATHOLOGICAL CONDITIONS Aims Mitochondrial alterations precede the appearance of pathological hallmarks in Alzheimer’s disease (AD) such as accumulation of Aß peptide and hyperphosphorylated tau protein. The sigma1 receptor (s1R) is a chaperone protein residing at mitochondria associated endoplasmic reticulum membranes and its activation by ligands stimulates neuromodulation and neuroprotection, as shown in AD models in vitro and in vivo. The s1R stabilizes Ca2+ crosstalk between ER and mitochondria and regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1-GTP. The s1R effects on mitochondria in physiological and pathological conditions (amyloid toxicity) and its downstream signaling are not fully understood.
Method We here evaluated the impacts of s1R ligands on reactive oxygen species (ROS) production and mitochondrial respiration and complex activities using application of amyloid-ß peptides (Aß1-42).
Results The s1R agonists PRE084, DHEAS, ANAVEX1-41 or ANAVEX3-71 increased total ROS production in physiological condition but decreased it in pathological conditions. The s1R antagonists NE100 and progesterone had no effect. Both s1R agonists and antagonist showed no direct effect on respiration but agonists ameliorated the RCR deficit triggered by Aß1-42. We also observed that the s1R agonists increased complex I activity in physiological conditions. This effect was blocked by chelating Ca2+ with EGTA. s1R Agonists failed to affect complex II or IV activity.
Conclusion These experiments showed that s1R activity results in a dual regulation of the mitochondrial oxidative status: in basal conditions, s1R activity triggers a moderate ROS increase, putatively used as a physiological signal, while in pathological conditions, agonists promoted a marked anti-oxidant effect.
Co-authors T. Maurice 1, N. Goguadze 1,2, N. Natsvlishvili 2, E. Zhuravliova 2, D. Morin 3, D. Mikeladze 2 1Université de Montpellier, INSERM U 1198, Montpellier, France 2Ilia State University, Institute of Chemical Biology, Tbilisi, Georgia 3Université Paris-Est- Faculty of Medicine, UMR S955- UPEC, Creteil, France
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