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Inflammatory Response after Spinal Cord Injury in Rats is Modified by Etanercept (Enbrel®)
Proceedings of the NASS 28th Annual Meeting / The Spine Journal 13 (2013) 1S–168S of cervical and thoracolumbar deformities. PJK was prevalent, developing in 37.3% of ASD patients undergoing 3CO. PJK patients with long fusions to the upper thoracic spine (UT) developed cervical sagittal deformities with an increase in their CPL and CTPA. These patients had to compensate for increases in their T1S by creating more CL. Cervical sagittal deformity results from PJK in the upper thoracic spine following thoracolumbar 3CO. FDA DEVICE/DRUG STATUS: This abstract does not discuss or include any applicable devices or drugs. http://dx.doi.org/10.1016/j.spinee.2013.07.054
Wednesday, October 9, 2013 4:05 – 5:05 PM Concurrent Session: Spinal Trauma & Cord Injury
11S
(Spp1), was similarly up-regulated in injury-only and injuryþetanercept at 7 days relative to control (pO0.05 between test groups, p!0.05 against control), but significantly down regulated at 7 days in injuryþetanercept relative to other groups (p!0.05 for both comparisons). Chemokine Ligand 21(Ccl21), for neuron-glia communication, was down-regulated at 24h in all groups (pO0.05 between test groups, p!0.05 for each comparison against control) but up-regulated at 7 days with injuryþetanercept (p!0.05 for comparison with injury-only and control). CONCLUSIONS: This is the first study to combine gene array techniques to evaluate SCI after treatment with etanercept. Etanercept had an influence in modifying inflammation by up-regulating anti-inflammatory cytokine (Adipoq) and lowering expression of pro-inflammatory cytokines and chemokines (Ccl20, Spp1). Also, etanercept up-regulated Ccl21, an important factor during neuron-glia communication. Further analysis will be completed to understand if cascades induced by etanercept can modulate down-stream regeneration pathways and if any of these data correlate with functional locomotor recovery (Basso, Beattie and Bresnahan scale). FDA DEVICE/DRUG STATUS: EnbrelÒ (Not approved for this indication) http://dx.doi.org/10.1016/j.spinee.2013.07.056
22. Inflammatory Response after Spinal Cord Injury in Rats is Modified by Etanercept (EnbrelÒ) Alexandre Rasouli, MD1, Zorica Buser, PhD1, Li Zhao2, Yalda Safai3, LEA Kanim, MA4, Marshall L. Grode, MD1, Rick B. Delamarter, MD1; 1 Los Angeles, CA, US; 2Spine Research Foundation, Los Angeles, CA, US; 3 Cedars Sinai Medical Center, Los Angeles, CA, US; 4Spine Center, Cedars-Sinai Medical Center, Los Angeles, CA, US BACKGROUND CONTEXT: Spinal cord injury (SCI) elicits an immune-mediated inflammatory response that results in secondary damage to surrounding tissues and inhibits regeneration of the central nervous system. Insight into this process of secondary injury at the genetic level under conditions of an anti-inflammatory drug, etanercept, may reveal new mechanisms of injury and thus therapeutic targets for intervention. The identification of genes that suppress inflammation and/or apoptosis at early stages after SCI will elucidate the molecular pathways that may be targeted to limit the secondary damage cascade that prevents recovery. PURPOSE: To evaluate the anti-inflammatory properties of etanercept and its modulatory effects on pro- and anti-inflammatory markers using novel application of gene arrays. STUDY DESIGN/SETTING: Assay after randomized and experimentally administered etanercept in traumatic spinal cord contusion injury in vivo rat model. PATIENT SAMPLE: Twenty adult female Sprague-Dawley rats (200 – 220 g) OUTCOME MEASURES: Cytokine and chemokine PCR array. METHODS: Under general anesthesia and after T10 laminectomy, a moderate traumatic spinal cord contusion injury was delivered to adult Sprague-Dawley rats. All injured rats (n520) were randomly divided into three treatments: (1) injury only (n54), (2) injury þ in situ injection of mouse etanercept (0.09mg) (n54) and compared (3) to laminectomy-only control (n54 rats). Etanercept was intrathecally injected in sit immediately after the injury. Rats were sacrificed at 24h and 7days post injury. The spinal cords from the site of injury (or analogous region in uninjured controls) were harvested, RNA was extracted, reverse transcribed into cDNA and loaded on the cytokine and chemokine PCR array; data were analyzed based on cycle threshold (Ct) values provided by SABiosciences. RESULTS: The anti-inflammatory Adiponectin (Adipoq) gene was up-regulated in injuryþetanercept treated rats at 24h compared to control (p! 0.05), whereas in injury-only treated rats it was down-regulated (p! 0.001). At 7 days, anti-adipoq was down-regulated in both treatment groups relative to control (pO0.05 between groups, p!0.01 for comparisons with control). Chemokine Ligand 20 (Ccl20), a pro-inflammatory gene, was up-regulated significantly in the injury-only group relative to control (p! 0.05), but less upregulated in injuryþetanercept treated rats at 24h (p! 0.05 against injury-only and control) and the trend was maintained up to 7days. Another potent pro-inflammatory gene, Secreted Phosphoprotein 1
23. Critical Events Before Spinal Cord Injury in a Porcine Compression Model Vishal Sarwahi, MD1, Abhijit Y. Pawar, MD1, Aviva Dworkin2, Etan P. Sugarman, MD3, Marina Moguilevitch, MD2, Terry D. Amaral, MD4, Beverly Thornhill, MD5, Adam L. Wollowick, MD4, Alan D. Legatt, MD, PhD2; 1New York, NY, US; 2Montefiore Medical Center, Bronx, NY, US; 3 Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, US; 4Bronx, NY, US; 5Albert Einstein College of Medicine, Bronx, NY, US BACKGROUND CONTEXT: Iatrogenic spinal cord injury is a devastating complication of spinal deformity surgery. Currently, multimodal neuromonitoring is the preferred method of spinal cord monitoring. However, it cannot detect spinal cord perturbation pre-injury. Identification of critical events before spinal cord injury occurs utilizing real time laser Doppler flowmetry (LDF) measurements of spinal cord blood flow will allow surgical and pharmacological interventions at a much earlier stage, when the threat is still avertable. This changes the entire paradigmdfrom diagnosis to prevention. In the case of an injury, LDF can also determine spinal cord vascularity post injury (hyperemia or persistent ischemia) which has prognostic value for recovery, something that is not feasible at present. Laser Doppler monitoring can thus elevate the safety standards in deformity surgery, decreasing neurological complications, and costs of the family and the health care system. PURPOSE: To identify the critical events pre-injury to spinal cord and loss of MEP signals. STUDY DESIGN/SETTING: Porcine study. PATIENT SAMPLE: In this pilot study, 9 farm-bred pigs were used. OUTCOME MEASURES: Mean and correlation METHODS: After prone positioning and induction, multilevel laminectomies were performed in the mid thoracic region. LDF electrodes were placed on the exposed dura in multiple areas to measure spinal cord blood flow and to assess real-time microcirculatory changes in the spinal cord. Spinal cord injury via compression was induced cephalad to laminectomy by inflating the balloon incrementally until MEP signals disappeared. After injury, as detected by a loss of MEP signals, several interventions were carried out: raising the systolic blood pressure, expanding the intravascular volume with colloids and IV lidocaine. After interventions, a wake-up test was performed and a CT scan was done to measure the thoracic spinal canal volume. RESULTS: The mean reading 3 minutes before motor signals loss was -24.4% from the baseline for 9 pigs. When the pressure of the balloon was on average (avg) less than 7 psi, the blood flow was close to baseline, but on average, as it reached over 7 and until 11 psi, this was considered a gray zone where ischemia was seen. Three minutes before the loss of motor signals was considered critical. Lastly, the critical volume of less than 0.75 cc was on average a safe zone, and greater than 0.75 cc to 1.5 cc was
Refer to onsite Annual Meeting presentations and postmeeting proceedings for possible referenced figures and tables. Authors are responsible for accurately reporting disclosures and FDA device/drug status at time of abstract submission.
Wednesday, October 9, 2013 4:05 – 5:05 PM Concurrent Session: Spinal Trauma & Cord Injury
11S
(Spp1), was similarly up-regulated in injury-only and injuryþetanercept at 7 days relative to control (pO0.05 between test groups, p!0.05 against control), but significantly down regulated at 7 days in injuryþetanercept relative to other groups (p!0.05 for both comparisons). Chemokine Ligand 21(Ccl21), for neuron-glia communication, was down-regulated at 24h in all groups (pO0.05 between test groups, p!0.05 for each comparison against control) but up-regulated at 7 days with injuryþetanercept (p!0.05 for comparison with injury-only and control). CONCLUSIONS: This is the first study to combine gene array techniques to evaluate SCI after treatment with etanercept. Etanercept had an influence in modifying inflammation by up-regulating anti-inflammatory cytokine (Adipoq) and lowering expression of pro-inflammatory cytokines and chemokines (Ccl20, Spp1). Also, etanercept up-regulated Ccl21, an important factor during neuron-glia communication. Further analysis will be completed to understand if cascades induced by etanercept can modulate down-stream regeneration pathways and if any of these data correlate with functional locomotor recovery (Basso, Beattie and Bresnahan scale). FDA DEVICE/DRUG STATUS: EnbrelÒ (Not approved for this indication) http://dx.doi.org/10.1016/j.spinee.2013.07.056
22. Inflammatory Response after Spinal Cord Injury in Rats is Modified by Etanercept (EnbrelÒ) Alexandre Rasouli, MD1, Zorica Buser, PhD1, Li Zhao2, Yalda Safai3, LEA Kanim, MA4, Marshall L. Grode, MD1, Rick B. Delamarter, MD1; 1 Los Angeles, CA, US; 2Spine Research Foundation, Los Angeles, CA, US; 3 Cedars Sinai Medical Center, Los Angeles, CA, US; 4Spine Center, Cedars-Sinai Medical Center, Los Angeles, CA, US BACKGROUND CONTEXT: Spinal cord injury (SCI) elicits an immune-mediated inflammatory response that results in secondary damage to surrounding tissues and inhibits regeneration of the central nervous system. Insight into this process of secondary injury at the genetic level under conditions of an anti-inflammatory drug, etanercept, may reveal new mechanisms of injury and thus therapeutic targets for intervention. The identification of genes that suppress inflammation and/or apoptosis at early stages after SCI will elucidate the molecular pathways that may be targeted to limit the secondary damage cascade that prevents recovery. PURPOSE: To evaluate the anti-inflammatory properties of etanercept and its modulatory effects on pro- and anti-inflammatory markers using novel application of gene arrays. STUDY DESIGN/SETTING: Assay after randomized and experimentally administered etanercept in traumatic spinal cord contusion injury in vivo rat model. PATIENT SAMPLE: Twenty adult female Sprague-Dawley rats (200 – 220 g) OUTCOME MEASURES: Cytokine and chemokine PCR array. METHODS: Under general anesthesia and after T10 laminectomy, a moderate traumatic spinal cord contusion injury was delivered to adult Sprague-Dawley rats. All injured rats (n520) were randomly divided into three treatments: (1) injury only (n54), (2) injury þ in situ injection of mouse etanercept (0.09mg) (n54) and compared (3) to laminectomy-only control (n54 rats). Etanercept was intrathecally injected in sit immediately after the injury. Rats were sacrificed at 24h and 7days post injury. The spinal cords from the site of injury (or analogous region in uninjured controls) were harvested, RNA was extracted, reverse transcribed into cDNA and loaded on the cytokine and chemokine PCR array; data were analyzed based on cycle threshold (Ct) values provided by SABiosciences. RESULTS: The anti-inflammatory Adiponectin (Adipoq) gene was up-regulated in injuryþetanercept treated rats at 24h compared to control (p! 0.05), whereas in injury-only treated rats it was down-regulated (p! 0.001). At 7 days, anti-adipoq was down-regulated in both treatment groups relative to control (pO0.05 between groups, p!0.01 for comparisons with control). Chemokine Ligand 20 (Ccl20), a pro-inflammatory gene, was up-regulated significantly in the injury-only group relative to control (p! 0.05), but less upregulated in injuryþetanercept treated rats at 24h (p! 0.05 against injury-only and control) and the trend was maintained up to 7days. Another potent pro-inflammatory gene, Secreted Phosphoprotein 1
23. Critical Events Before Spinal Cord Injury in a Porcine Compression Model Vishal Sarwahi, MD1, Abhijit Y. Pawar, MD1, Aviva Dworkin2, Etan P. Sugarman, MD3, Marina Moguilevitch, MD2, Terry D. Amaral, MD4, Beverly Thornhill, MD5, Adam L. Wollowick, MD4, Alan D. Legatt, MD, PhD2; 1New York, NY, US; 2Montefiore Medical Center, Bronx, NY, US; 3 Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, US; 4Bronx, NY, US; 5Albert Einstein College of Medicine, Bronx, NY, US BACKGROUND CONTEXT: Iatrogenic spinal cord injury is a devastating complication of spinal deformity surgery. Currently, multimodal neuromonitoring is the preferred method of spinal cord monitoring. However, it cannot detect spinal cord perturbation pre-injury. Identification of critical events before spinal cord injury occurs utilizing real time laser Doppler flowmetry (LDF) measurements of spinal cord blood flow will allow surgical and pharmacological interventions at a much earlier stage, when the threat is still avertable. This changes the entire paradigmdfrom diagnosis to prevention. In the case of an injury, LDF can also determine spinal cord vascularity post injury (hyperemia or persistent ischemia) which has prognostic value for recovery, something that is not feasible at present. Laser Doppler monitoring can thus elevate the safety standards in deformity surgery, decreasing neurological complications, and costs of the family and the health care system. PURPOSE: To identify the critical events pre-injury to spinal cord and loss of MEP signals. STUDY DESIGN/SETTING: Porcine study. PATIENT SAMPLE: In this pilot study, 9 farm-bred pigs were used. OUTCOME MEASURES: Mean and correlation METHODS: After prone positioning and induction, multilevel laminectomies were performed in the mid thoracic region. LDF electrodes were placed on the exposed dura in multiple areas to measure spinal cord blood flow and to assess real-time microcirculatory changes in the spinal cord. Spinal cord injury via compression was induced cephalad to laminectomy by inflating the balloon incrementally until MEP signals disappeared. After injury, as detected by a loss of MEP signals, several interventions were carried out: raising the systolic blood pressure, expanding the intravascular volume with colloids and IV lidocaine. After interventions, a wake-up test was performed and a CT scan was done to measure the thoracic spinal canal volume. RESULTS: The mean reading 3 minutes before motor signals loss was -24.4% from the baseline for 9 pigs. When the pressure of the balloon was on average (avg) less than 7 psi, the blood flow was close to baseline, but on average, as it reached over 7 and until 11 psi, this was considered a gray zone where ischemia was seen. Three minutes before the loss of motor signals was considered critical. Lastly, the critical volume of less than 0.75 cc was on average a safe zone, and greater than 0.75 cc to 1.5 cc was
Refer to onsite Annual Meeting presentations and postmeeting proceedings for possible referenced figures and tables. Authors are responsible for accurately reporting disclosures and FDA device/drug status at time of abstract submission.