Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection.
Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.
Department of Behavioral Medicine and Psychiatry, School of Medicine, West Virginia University, 930 Chestnut Ridge Road, Morgantown, WV, 26506, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, One Medical Center, West Virginia University, Morgantown, WV, 26506, USA.
Linda
L
Nguyen
Graduate Program in Neuroscience, School of Medicine, West Virginia University, One Medical Center Drive, Morgantown, WV, 26506, USA.
Brandon P
BP
Lucke-Wold
College of Pharmacy, Touro University California, 1310 Club Drive, Vallejo, CA, 94592, USA.
Shona
S
Mookerjee
Takeda California, Inc., San Diego, CA, 92121, USA.
Nidhi
N
Kaushal
Department of Behavioral Medicine and Psychiatry, School of Medicine, West Virginia University, 930 Chestnut Ridge Road, Morgantown, WV, 26506, USA. rae.matsumoto@tu.edu.|College of Pharmacy, Touro University California, 1310 Club Drive, Vallejo, CA, 94592, USA. rae.matsumoto@tu.edu.
Rae R
RR
Matsumoto
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D018832:Molecular Chaperones / Q000494:pharmacology*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism*; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D008024:Ligands; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
Alzheimer’s disease; Amyotrophic lateral sclerosis; Neurorestoration; Parkinson’s disease; Stroke