1. Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury
- Author
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Scott R. Whittemore, Sujata Saraswat Ohri, and Michal Hetman
- Subjects
Salubrinal ,Apoptosis ,Hindlimb ,Endoplasmic Reticulum ,Nerve Fibers, Myelinated ,Mice ,chemistry.chemical_compound ,Protein Phosphatase 1 ,Homeostasis ,Phosphorylation ,Endoplasmic Reticulum Chaperone BiP ,Spinal cord injury ,Heat-Shock Proteins ,Cerebral Cortex ,Mice, Knockout ,Oligodendrocytes ,Tunicamycin ,Thiourea ,Cell biology ,Oligodendroglia ,medicine.anatomical_structure ,Neurology ,medicine.symptom ,ER stress ,Locomotion ,Inflammation ,Biology ,Article ,lcsh:RC321-571 ,Glutamate-Ammonia Ligase ,medicine ,Animals ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Gait Disorders, Neurologic ,Spinal Cord Injuries ,Endoplasmic reticulum ,Hindlimb locomotor recovery ,Myelin Basic Protein ,Recovery of Function ,medicine.disease ,Activating Transcription Factor 4 ,Oligodendrocyte ,Mice, Inbred C57BL ,Disease Models, Animal ,Animals, Newborn ,Gene Expression Regulation ,chemistry ,Cinnamates ,Unfolded protein response ,Neuroscience - 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 locomoter 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 homoestatic 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 6 hours post-SCI. Hindlimb locomotion showed significant improvement in animals treated with salubrinal. Treadmill-based-gait assessement 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 supports the contention that pharmacological targeting of the ERSR after CNS trauma is a therapeutically viable approach.
- Published
- 2013
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