Journal
ACS CHEMICAL NEUROSCIENCE
Volume 10, Issue 3, Pages 1595-1602Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00543
Keywords
Neuroprotection; traumatic brain injury; blast injury; controlled cortical impact injury; sigma 2R/TMEM97
Funding
- Brockman Medical Research Foundation
- Titan Neurology Research Fund
- Department of Veterans Affairs Merit Review [1IO1BX002444]
- Robert A. Welch Foundation [F-0652]
- Dell Medical School's Texas Health Catalyst program
- NIH/NINDS [NS098740]
- Miami Project to Cure Paralysis
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Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (sigma 2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimers disease and schizophrenia. These promising applications coupled with our previous observation that the sigma 2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild-type mice suggests that modulating sigma 2R/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 sigma 2R/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 sigma 2R/Tmem97 modulation in neuroprotection and suggest a new approach for treating patients suffering from TBI.
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