Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury
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...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-10-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996113001423 |
| _version_ | 1818734063237726208 |
|---|---|
| author | Sujata Saraswat Ohri Michal Hetman Scott R. Whittemore |
| author_facet | Sujata Saraswat Ohri Michal Hetman Scott R. Whittemore |
| author_sort | Sujata Saraswat Ohri |
| collection | DOAJ |
| description | 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 6 h 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. |
| first_indexed | 2024-12-17T23:59:24Z |
| format | Article |
| id | doaj.art-e83e2c004fc14a32a34606cc99b8cfc4 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T23:59:24Z |
| publishDate | 2013-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-e83e2c004fc14a32a34606cc99b8cfc42022-12-21T21:28:00ZengElsevierNeurobiology of Disease1095-953X2013-10-01582937Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injurySujata Saraswat Ohri0Michal Hetman1Scott R. Whittemore2Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, USAKentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, USA; Department of Pharmacology & Toxicology, University of Louisville, School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, USA; Anatomical Sciences & Neurobiology, University of Louisville, School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, USAKentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, USA; Department of Neurological Surgery, University of Louisville, School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, USA; Anatomical Sciences & Neurobiology, University of Louisville, School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, USA; Corresponding author at: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40292, USA. Fax: +1 502 852 5148.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 6 h 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.http://www.sciencedirect.com/science/article/pii/S0969996113001423ApoptosisER stressHindlimb locomotor recoveryOligodendrocytesSalubrinalSpinal cord injury |
| spellingShingle | Sujata Saraswat Ohri Michal Hetman Scott R. Whittemore Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury Neurobiology of Disease Apoptosis ER stress Hindlimb locomotor recovery Oligodendrocytes Salubrinal Spinal cord injury |
| title | Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury |
| title_full | Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury |
| title_fullStr | Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury |
| title_full_unstemmed | Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury |
| title_short | Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury |
| title_sort | restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury |
| topic | Apoptosis ER stress Hindlimb locomotor recovery Oligodendrocytes Salubrinal Spinal cord injury |
| url | http://www.sciencedirect.com/science/article/pii/S0969996113001423 |
| work_keys_str_mv | AT sujatasaraswatohri restoringendoplasmicreticulumhomeostasisimprovesfunctionalrecoveryafterspinalcordinjury AT michalhetman restoringendoplasmicreticulumhomeostasisimprovesfunctionalrecoveryafterspinalcordinjury AT scottrwhittemore restoringendoplasmicreticulumhomeostasisimprovesfunctionalrecoveryafterspinalcordinjury |