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Journal of neurotrauma
05, 2023;40 (9-10): 1007-1019.

Acute Pharmacological Inhibition of Protein Kinase R-Like Endoplasmic Reticulum Kinase Signaling After Spinal Cord Injury Spares Oligodendrocytes and Improves Locomotor Recovery.

Sujata Saraswat Ohri, Kariena R Andres, Russell M Howard, Brandon L Brown, Michael D Forston, Michal Hetman, Scott R Whittemore
Author Information
  1. Sujata Saraswat Ohri: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
  2. Kariena R Andres: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
  3. Russell M Howard: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
  4. Brandon L Brown: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
  5. Michael D Forston: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
  6. Michal Hetman: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
  7. Scott R Whittemore: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA.
PMID: 36503284 DOI: 10.1089/neu.2022.0177

Abstract

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a major signal transducer of the endoplasmic reticulum stress response (ERSR) pathway. Outcomes of PERK activation range from abrogating ER stress to induction of cell death, dependent on its level, duration, and cellular context. Current data demonstrate that after mouse spinal cord injury (SCI), acute inhibition of PERK (0-72 h) with the small molecule inhibitor GSK2656157 reduced ERSR while improving white matter sparing and hindlimb locomotion recovery. GSK2656157-treated mice showed increased numbers of oligodendrocytes at the injury epicenter. Moreover, GSK2656157 protected cultured primary mouse oligodendrocyte precursor cells from ER stress-induced cytotoxicity. These findings suggest that in the context of SCI, excessive acute activation of PERK contributes to functionally relevant white matter damage. Pharmacological inhibition of PERK is a potential strategy to protect central nervous system (CNS) white matter following acute injuries, including SCI.

Keywords

GSK2656157 endoplasmic reticulum stress response oligodendrocytes protein kinase R (PKR)-like endoplasmic reticulum kinase spinal cord injury

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Grants

  1. R01 NS108529/NINDS NIH HHS

MeSH Term

Animals
Mice
Spinal Cord Injuries
Endoplasmic Reticulum
Cell Death
Endoplasmic Reticulum Stress
Protein Kinases
Oligodendroglia
Apoptosis

Chemicals

Protein Kinases
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Word Cloud

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