Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury

Edwin Vázquez-Rosa, Michael R. Watson, James J. Sahn, Timothy R. Hodges, Rachel E. Schroeder, Coral J. Cintrón-Pérez, Min Kyoo Shin, Terry C. Yin, Josie L. Emery, Stephen F. Martin, Daniel J. Liebl, Andrew A. Pieper

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (σ2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimer's disease and schizophrenia. These promising applications coupled with our previous observation that the σ2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild-type mice suggests that modulating σ2R/TMEM97 may also have therapeutic benefits in other neurodegenerative conditions such as traumatic brain injury (TBI). Herein, we report that DKR-1677, a novel derivative of SAS-0132 with increased affinity and selectivity for σ2R/Tmem97 (K i = 5.1 nM), is neuroprotective after blast-induced and controlled cortical impact (CCI) TBI in mice. Specifically, we discovered that treatment with DKR-1677 decreases axonal degeneration after blast-induced TBI and enhances survival of cortical neurons and oligodendrocytes after CCI injury. Furthermore, treatment with DKR-1677 preserves cognition in the Morris water maze after blast TBI. Our results support an increasingly broad role for σ2R/Tmem97 modulation in neuroprotection and suggest a new approach for treating patients suffering from TBI.

Original languageEnglish (US)
Pages (from-to)1595-1602
Number of pages8
JournalACS Chemical Neuroscience
Volume10
Issue number3
DOIs
StatePublished - Mar 20 2019

Keywords

  • Neuroprotection
  • blast injury
  • controlled cortical impact injury
  • traumatic brain injury
  • σ2R/TMEM97

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Vázquez-Rosa, E., Watson, M. R., Sahn, J. J., Hodges, T. R., Schroeder, R. E., Cintrón-Pérez, C. J., Shin, M. K., Yin, T. C., Emery, J. L., Martin, S. F., Liebl, D. J., & Pieper, A. A. (2019). Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury. ACS Chemical Neuroscience, 10(3), 1595-1602. https://doi.org/10.1021/acschemneuro.8b00543