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

Autor:	Vázquez-Rosa E; Department of Psychiatry and Department of Free Radical, Radiation Biology Program, Holden Comprehensive Cancer Center , University of Iowa Carver College of Medicine , Iowa City , Iowa 52242 , United States.; Department of Psychiatry Case Western Reserve University, Geriatric Research Education and Clinical Centers , Harrington Discovery Institute, University Hospital, Case Medical Center , Louis Stokes Cleveland VAMC , Cleveland , Ohio 44106 , United States., Watson MR; The Miami Project to Cure Paralysis, Department of Neurological Surgery , University of Miami Miller School of Medicine , Miami , Florida 33136 , United States., Sahn JJ; Department of Chemistry , The University of Texas at Austin , Austin , Texas 78712 , United States., Hodges TR; Department of Chemistry , The University of Texas at Austin , Austin , Texas 78712 , United States., Schroeder RE; Department of Psychiatry and Department of Free Radical, Radiation Biology Program, Holden Comprehensive Cancer Center , University of Iowa Carver College of Medicine , Iowa City , Iowa 52242 , United States., Cintrón-Pérez CJ; Department of Psychiatry Case Western Reserve University, Geriatric Research Education and Clinical Centers , Harrington Discovery Institute, University Hospital, Case Medical Center , Louis Stokes Cleveland VAMC , Cleveland , Ohio 44106 , United States., Shin MK; Department of Psychiatry Case Western Reserve University, Geriatric Research Education and Clinical Centers , Harrington Discovery Institute, University Hospital, Case Medical Center , Louis Stokes Cleveland VAMC , Cleveland , Ohio 44106 , United States., Yin TC; Department of Psychiatry and Department of Free Radical, Radiation Biology Program, Holden Comprehensive Cancer Center , University of Iowa Carver College of Medicine , Iowa City , Iowa 52242 , United States., Emery JL; Department of Psychiatry and Department of Free Radical, Radiation Biology Program, Holden Comprehensive Cancer Center , University of Iowa Carver College of Medicine , Iowa City , Iowa 52242 , United States., Martin SF; Department of Chemistry , The University of Texas at Austin , Austin , Texas 78712 , United States., Liebl DJ; The Miami Project to Cure Paralysis, Department of Neurological Surgery , University of Miami Miller School of Medicine , Miami , Florida 33136 , United States., Pieper AA; Department of Psychiatry and Department of Free Radical, Radiation Biology Program, Holden Comprehensive Cancer Center , University of Iowa Carver College of Medicine , Iowa City , Iowa 52242 , United States.; Department of Psychiatry Case Western Reserve University, Geriatric Research Education and Clinical Centers , Harrington Discovery Institute, University Hospital, Case Medical Center , Louis Stokes Cleveland VAMC , Cleveland , Ohio 44106 , United States.
Jazyk:	angličtina
Zdroj:	ACS chemical neuroscience [ACS Chem Neurosci] 2019 Mar 20; Vol. 10 (3), pp. 1595-1602. Date of Electronic Publication: 2018 Dec 03.
DOI:	10.1021/acschemneuro.8b00543
Abstrakt:	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.
Databáze:	MEDLINE
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