Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders.

Maurice, Tangui

INTRODUCTION The sigma-1 receptor (S1R) is attracting much attention as a target for disease-modifying therapies in neurodegenerative diseases. It is a highly conserved protein, present in plasma and endoplasmic reticulum (ER) membranes and enriched in mitochondria-associated ER membranes (MAMs). It modulates ER-mitochondria Ca2+ transfer and activation of the ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in pathologies including Alzheimer's disease and Parkinson's disease. Interestingly, the S1R can be activated by small druggable molecules and accumulating preclinical data suggest that S1R agonists are effective protectants in these neurodegenerative diseases. AREA COVERED In this review, the author presents the data showing the high therapeutic potential of S1R drugs for the treatment of neurodegenerative diseases, focusing on pridopidine as a potent and selective S1R agonist under clinical development. Of particular interest is the bi-phasic (bell-shaped) dose-response effect described in numerous preclinical models in vitro, in vivo and in clinical trials. EXPERT OPINION S1R agonists modulate essential inter-organelles communication altered in all neurodegenerative diseases and activate numerous intracellular survival pathways. Research in the field will continue growing in the near future. The particular cellular nature of this unique chaperone protein must be better understood to facilitate the development of promising molecules at the clinical stage.