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

ABSTRACT

Introduction: The sigma-1 receptor (S1R) is attracting much attention for disease-modifying therapies in neurodegenerative diseases. It is a 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 ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in diseases such as Alzheimer, Parkinson, Huntington or Amyotrophic Lateral Sclerosis. 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, we will present 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, representing a common feature of all S1R agonists and described in numerous preclinical models in vitro, in vivo and in clinical trials.

Expert opinion: S1R agonists modulate inter-organelles communication altered in neurodegenerative diseases and activate intracellular survival pathways. Research will continue growing in the future. The particular cellular nature of this chaperone protein must be better understood to facilitate the clinical developement of promising molecules.

KEYWORDS:

• Sigma-1 receptor
• neurodegerenerative diseases
• bi-phasic dose-response
• pridopidine

Article highlights

- The Sigma-1 receptor (S1R) is an molecular chaperone regulating several cellular pathways in neurons and glial cells.

- S1R agonists are promising neuroprotectants in neurodegenerative diseases.

- Among them, pridopidine is a highly selective S1R agonist and showed efficacy in AD, HD and ALS preclinical models.

- All S1R responses from cellular to in vivo levels display bi-phasic curves, with low doses of ligands showing maximal effects.

- Possible mechanisms for bi-phasic effect rely on S1R dynamics including oligomerization, cellular translocation and BDNF releasing properties.

This box summarizes key points contained in the article.

Acknowledgments

The author warmly thanks Drs Michal Geva (Prilenia, Herzliya, Israel), Michael Hayden (Prilenia, Herzliya, Israel), and Benjamin Delprat (MMDN, Montpellier, France) for their advice, critical reading and input into the manuscript.

Declaration of interest

The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was funded by INSERM.