title: Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury.
abstract: The endoplasmic reticulum (ER) stress response (ERSR) is activated to maintain protein homeostasis or induce apoptosis in the ER in response to distinct cellular insults including hypoxia, inflammation, and oxidative damage. Recently, we showed ERSR activation in a mouse model of a contusive spinal cord injury (SCI) and an improved hindlimb locomotor function following SCI when the pro-apoptotic arm of ERSR was genetically inhibited. The objective of the current study was to explore if the pharmacological enhancement of the homeostatic arm of the ERSR pathway can improve the functional outcome after SCI. Salubrinal enhances the homeostatic arm of the ERSR by increasing phosphorylation of eIF2α. Salubrinal significantly enhanced the levels of phosphorylated eIF2α protein and modulated the downstream ERSR effectors assessed at the lesion epicenter 6h post-SCI. Hindlimb locomotion showed significant improvement in animals treated with salubrinal. Treadmill-based-gait assessment showed a significant increase in maximum speed of coordinated walking and a decrease in rear stance time and stride length in salubrinal-treated animals. This improved functional recovery corresponded with increased white matter sparing and decreased oligodendrocyte apoptosis. In addition, salubrinal protected cultured mouse oligodendrocyte progenitor cells against the ER stress-inducing toxin tunicamycin. These data suggest that boosting the homeostatic arm of the ERSR reduces oligodendrocyte loss after traumatic SCI and support the contention that pharmacological targeting of the ERSR after CNS trauma is a therapeutically viable approach.
authors: University of Louisville, School of Medicine, Louisville, KY 40292, USA. s0sara03@louisville.edu
authors: Sujata Saraswat
authors: SS
authors: Ohri
authors: Michal
authors: M
authors: Hetman
authors: Scott R
authors: SR
authors: Whittemore
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000166:cytology; D002934:Cinnamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005974:Glutamate-Ammonia Ligase / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009836:Oligodendroglia / Q000502:physiology* / Q000637:transplantation; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000172:deficiency / Q000235:genetics; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: C081452:Atf4 protein, mouse; D002934:Cinnamates; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D004676:Myelin Basic Protein; C496827:salubrinal; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1; D005974:Glutamate-Ammonia Ligase; D013890:Thiourea
keywords: Apoptosis; ER stress; Hindlimb locomotor recovery; Oligodendrocytes; Salubrinal; Spinal cord injury
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