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Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

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Sigma Receptors: Their Role in Disease and as Therapeutic Targets

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 964))

Abstract

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.

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Authors and Affiliations

  1. Department of Behavioral Medicine and Psychiatry, School of Medicine, West Virginia University, 930 Chestnut Ridge Road, Morgantown, WV, 26506, USA

    Linda Nguyen & Rae R. Matsumoto

  2. Department of Pharmaceutical Sciences, School of Pharmacy, One Medical Center, West Virginia University, Morgantown, WV, 26506, USA

    Linda Nguyen

  3. Graduate Program in Neuroscience, School of Medicine, West Virginia University, One Medical Center Drive, Morgantown, WV, 26506, USA

    Brandon P. Lucke-Wold

  4. College of Pharmacy, Touro University California, 1310 Club Drive, Vallejo, CA, 94592, USA

    Shona Mookerjee & Rae R. Matsumoto

  5. Takeda California, Inc., San Diego, CA, 92121, USA

    Nidhi Kaushal

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  1. Linda Nguyen
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  2. Brandon P. Lucke-Wold
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  3. Shona Mookerjee
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  4. Nidhi Kaushal
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  5. Rae R. Matsumoto
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Correspondence to Rae R. Matsumoto .

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Editors and Affiliations

  1. Departments of Cellular Biology and Anatomy and Ophthalmology and the James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

    Sylvia B. Smith

  2. Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland, USA

    Tsung-Ping Su

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Nguyen, L., Lucke-Wold, B.P., Mookerjee, S., Kaushal, N., Matsumoto, R.R. (2017). Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection. In: Smith, S., Su, TP. (eds) Sigma Receptors: Their Role in Disease and as Therapeutic Targets. Advances in Experimental Medicine and Biology, vol 964. Springer, Cham. https://doi.org/10.1007/978-3-319-50174-1_10

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