Brief suppression of Abcc8 prevents autodestruction of spinal cord after trauma.
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ABSTRACT:
SUBMITTER: Simard JM
PROVIDER: S-EPMC2903041 | biostudies-literature | 2010 Apr
REPOSITORIES: biostudies-literature
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Brief suppression of Abcc8 prevents autodestruction of spinal cord after trauma.
Simard J Marc JM Woo S Kyoon SK Norenberg Michael D MD Tosun Cigdem C Chen Zheng Z Ivanova Svetlana S Tsymbalyuk Orest O Bryan Joseph J Landsman Douglas D Gerzanich Volodymyr V
Science translational medicine 20100401 28
Spinal cord injury (SCI) is typically complicated by progressive hemorrhagic necrosis, an autodestructive process of secondary injury characterized by progressive enlargement of a hemorrhagic contusion during the first several hours after trauma. We assessed the role of Abcc8, which encodes sulfonylurea receptor 1 (SUR1), in progressive hemorrhagic necrosis. After SCI, humans and rodents exhibited similar regional and cellular patterns of up-regulation of SUR1 and Abcc8 messenger RNA. Eliminatio ...[more]
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Project description:Summary: Spinal cord injury (SCI) is a damage to the spinal cord induced by trauma or disease resulting in a loss of mobility or feeling. SCI is characterized by a primary mechanical injury followed by a secondary injury in which several molecular events are altered in the spinal cord often resulting in loss of neuronal function. Analysis of the areas directly (spinal cord) and indirectly (raphe and sensorimotor cortex) affected by injury will help understanding mechanisms of SCI. Hypothesis: Areas of the brain primarily affected by spinal cord injury are the Raphe and the Sensorimotor cortex thus gene expression profiling these two areas might contribute understanding the mechanisms of spinal cord injury. Specific Aim: The project aims at finding significantly altered genes in the Raphe and Sensorimotor cortex following an induced moderate spinal cord injury in T9. Keywords: other
2005-02-11 | GSE2270 | GEO
Project description:We review state-of-the-art monitoring techniques for acute, severe traumatic spinal cord injury (TSCI) to facilitate targeted perfusion of the injured cord rather than applying universal mean arterial pressure targets. Key concepts are discussed such as intraspinal pressure and spinal cord perfusion pressure (SCPP) at the injury site, respectively, analogous to intracranial pressure and cerebral perfusion pressure for traumatic brain injury. The concept of spinal cord autoregulation is introduced and quantified using spinal pressure reactivity index (sPRx), which is analogous to pressure reactivity index for traumatic brain injury. The U-shaped relationship between sPRx and SCPP defines the optimum SCPP as the SCPP that minimizes sPRx (i.e., maximizes autoregulation), and suggests that not only ischemia but also hyperemia at the injury site may be detrimental. The observation that optimum SCPP varies between patients and temporally in each patient supports individualized management. We discuss multimodality monitoring, which revealed strong correlations between SCPP and injury site metabolism (tissue glucose, lactate, pyruvate, glutamate, glycerol), monitored by surface microdialysis. Evidence is presented that the dura is a major, but unappreciated, cause of spinal cord compression after TSCI; we thus propose expansion duroplasty as a novel treatment. Monitoring spinal cord blood flow at the injury site has revealed novel phenomena, e.g., 3 distinct blood flow patterns, local steal, and diastolic ischemia. We conclude that monitoring from the injured spinal cord in the intensive care unit is a safe technique that appears to enable optimized and individualized spinal cord perfusion.
| S-EPMC7283409 | biostudies-literature
Project description:Spinal cord injury (SCI) results in rapid and extensive sublesional bone loss. Sclerostin, an osteocyte-derived glycoprotein that negatively regulates intraskeletal Wnt signaling, is elevated after SCI and may represent a mechanism underlying this excessive bone loss. However, it remains unknown whether pharmacologic sclerostin inhibition ameliorates bone loss subsequent to SCI. Our primary purposes were to determine whether a sclerostin antibody (Scl-Ab) prevents hindlimb cancellous bone loss in a rodent SCI model and to compare the effects of a Scl-Ab to that of testosterone-enanthate (TE), an agent that we have previously shown prevents SCI-induced bone loss. Fifty-five (n = 11-19/group) skeletally mature male Sprague-Dawley rats were randomized to receive: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe (250 kilodyne) SCI, (C) 250 kilodyne SCI + TE (7.0 mg/wk, im), or (D) 250 kilodyne SCI + Scl-Ab (25 mg/kg, twice weekly, sc) for 3 weeks. Twenty-one days post-injury, SCI animals exhibited reduced hindlimb cancellous bone volume at the proximal tibia (via μCT and histomorphometry) and distal femur (via μCT), characterized by reduced trabecular number and thickness. SCI also reduced trabecular connectivity and platelike trabecular structures, indicating diminished structural integrity of the remaining cancellous network, and produced deficits in cortical bone (femoral diaphysis) strength. Scl-Ab and TE both prevented SCI-induced cancellous bone loss, albeit via differing mechanisms. Specifically, Scl-Ab increased osteoblast surface and bone formation, indicating direct bone anabolic effects, whereas TE reduced osteoclast surface with minimal effect on bone formation, indicating antiresorptive effects. The deleterious microarchitectural alterations in the trabecular network were also prevented in SCI + Scl-Ab and SCI + TE animals, whereas only Scl-Ab completely prevented the reduction in cortical bone strength. Our findings provide the first evidence indicating that sclerostin inhibition represents a viable treatment to prevent SCI-induced cancellous and cortical bone deficits and provides preliminary rationale for future clinical trials focused on evaluating whether Scl-Ab prevents osteoporosis in the SCI population.
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Project description:Traumatic spinal cord injuries (SCIs) affect 1.3 million North Americans, producing devastating physical, social, and vocational impairment. Pathophysiologically, the initial mechanical trauma is followed by a significant secondary injury which includes local ischemia, pro-apoptotic signaling, release of cytotoxic factors, and inflammatory cell infiltration. Expedient delivery of medical and surgical care during this critical period can improve long-term functional outcomes, engendering the concept of "Time is Spine". We emphasize the importance of expeditious care while outlining the initial clinical and radiographic assessment of patients. Key evidence-based early interventions (surgical decompression, blood pressure augmentation, and methylprednisolone) are also reviewed, including findings of the landmark Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). We then describe other neuroprotective approaches on the edge of translation such as the sodium-channel blocker riluzole, the anti-inflammatory minocycline, and therapeutic hypothermia. We also review promising neuroregenerative therapies that are likely to influence management practices over the next decade including chondroitinase, Rho-ROCK pathway inhibition, and bioengineered strategies. The importance of emerging neural stem cell therapies to remyelinate denuded axons and regenerate neural circuits is also discussed. Finally, we outline future directions for research and patient care.
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Project description:Several clinical, imaging, and therapeutic factors affecting recovery following spinal cord injury (SCI) have been described. A systematic review of the topic is still lacking. Our primary aim was to systematically review clinical factors that may predict neurological and functional recovery following blunt traumatic SCI in adults. Such work would help guide clinical care and direct future research. Both Medline and Embase (to April 2008) were searched using index terms for various forms of SCI, paraplegia, or quadri/tetraplegia, and functional and neurological recovery. The search was limited to published articles that were in English and included human subjects. Article selection included class I and II evidence, blunt traumatic SCI, injury level above L1-2, baseline assessment within 72?h of injury, use of American Spinal Injury Association (ASIA) scoring system for clinical assessment, and functional and neurological outcome. A total of 1526 and 1912 citations were located from Medline and Embase, respectively. Two surgeons reviewed the titles, abstracts, and full text articles for each database. Ten articles were identified, only one of which was level 1 evidence. Age and gender were identified as two patient-related predictors. While motor and functional recovery decreased with advancing age for complete SCI, there was no correlation considering incomplete ones. Therefore, treatment should not be restructured based on age in incomplete SCI. Among injury-related predictors, severity of SCI was the most significant. Complete injuries correlated with increased mortality and worse neurological and functional outcomes. Other predictors included SCI level, energy transmitted by the injury, and baseline electrophysiological testing.
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Project description:IntroductionFirearm-related spinal cord injuries are commonly missed in the initial assessment as they are often obscured by concomitant injuries and emergent trauma management. These injuries, however, have a significant health and financial impact. The objective of this study was to examine firearm-related spinal cord injuries and identify predictors of presence of such injuries in adult trauma patients.MethodsThis retrospective cohort study examined adult trauma patients (≥16 years) with injuries from firearms included in the 2015 United States National Trauma Data Bank. We performed descriptive and bivariate analyses and compared two groups: patients with no spinal cord injury (SCI) or vertebral column injury (VCI); and patients with SCI and/or VCI. Predictors of SCI and/or VCI in patients with firearm-related injuries were identified using a multivariate logistic regression analysis.ResultsThere were 34,898 patients who sustained a firearm-induced injury. SCI and/or VCI were present in 2768 (7.9%) patients. Patients with SCI and/or VCI had more frequently severe injuries, higher Injury Severity Score (ISS), lower mean systolic blood pressure, and lower Glasgow Coma Scale (GCS). The mortality rate was not significantly different between the two groups (14.7%, N = 407 in SCI and/or VCI vs 15.0%, N = 4,811 in no SCI or VCI group). Significant general positive predictors of presence of SCI and/or VCI were as follows: university hospital; assault; public or unspecified location of injury; drug use; air medical transport; and Medicaid coverage. Significant clinical positive predictors included fractures, torso injuries, blood vessel or internal organ injuries, open wounds, mild (13-15) and moderate GCS scores (9 - 12), and ISS ≥ 16.ConclusionFirearm-induced SCI and/or VCI injuries have a high burden on affected victims. The identified predictors for the presence of SCI and/or VCI injuries can help with early detection, avoiding management delays, and improving outcomes. Further studies defining the impact of each predictor are needed.
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Project description:IntroductionPaclitaxel-induced peripheral neuropathy (PIPN) is a common dose-limiting side effect of this cancer treatment drug. Spinal cord stimulation (SCS) has demonstrated efficacy for attenuating some neuropathic pain conditions.ObjectiveWe aim to examine the inhibitory effect of SCS on the development of PIPN pain and changes of gene expression in the spinal cord in male rats after SCS.MethodsWe examined whether traditional SCS (50 Hz, 6-8 h/session daily for 14 consecutive days) administered during paclitaxel treatment (1.5 mg/kg, i.p.) attenuates PIPN-related pain behavior. After SCS treatment, we performed RNA-seq of the lumbar spinal cord to examine which genes are differentially expressed after PIPN with and without SCS.ResultsCompared to rats treated with paclitaxel alone (n = 7) or sham SCS (n = 6), SCS treatment (n = 11) significantly inhibited the development of paclitaxel-induced mechanical and cold hypersensitivity, without altering open-field exploratory behavior. RNA-seq showed that SCS induced upregulation of 836 genes and downregulation of 230 genes in the spinal cord of paclitaxel-treated rats (n = 3) as compared to sham SCS (n = 5). Spinal cord stimulation upregulated immune responses in paclitaxel-treated rats, including transcription of astrocyte- and microglial-related genes, but repressed transcription of multiple gene networks associated with synapse transmission, neuron projection development, ?-aminobutyric acid reuptake, and neuronal plasticity.ConclusionOur findings suggest that traditional SCS may attenuate the development of pain-related behaviors in PIPN rats, possibly by causing aggregate inhibition of synaptic plasticity through upregulation and downregulation of gene networks in the spinal cord.
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Project description:PURPOSE OF REVIEW:This review discusses recent advances in the rehabilitation of motor deficits after traumatic brain injury (TBI) and spinal cord injury (SCI) using neuromodulatory techniques. RECENT FINDINGS:Neurorehabilitation is currently the only treatment option for long-term improvement of motor functions that can be offered to patients with TBI or SCI. Major advances have been made in recent years in both preclinical and clinical rehabilitation. Activity-dependent plasticity of neuronal connections and circuits is considered key for successful recovery of motor functions, and great therapeutic potential is attributed to the combination of high-intensity training with electrical neuromodulation. First clinical case reports have demonstrated that repetitive training enabled or enhanced by electrical spinal cord stimulation can yield substantial improvements in motor function. Described achievements include regaining of overground walking capacity, independent standing and stepping, and improved pinch strength that recovered even years after injury. SUMMARY:Promising treatment options have emerged from research in recent years using neurostimulation to enable or enhance intense training. However, characterizing long-term benefits and side-effects in clinical trials and identifying patient subsets who can benefit are crucial. Regaining lost motor function remains challenging.
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Project description:Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0?mg/week), or (4) SCI+High-dose TE (7.0?mg/week). Twenty-one days post-injury, SCI animals exhibited a 77-85% reduction in hindlimb cancellous bone volume at the distal femur (measured via ?CT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13-27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI.
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Project description:ObjectiveTo test the hypothesis that daily acute intermittent hypoxia (AIH) combined with hand opening practice improves hand dexterity, function, and maximum hand opening in persons with chronic, motor-incomplete, cervical spinal cord injury.MethodsSix participants completed the double-blind, crossover study. Participants received daily (5 consecutive days) AIH (15 episodes per day: 1.5 minutes of fraction of inspired oxygen [FIo2] = 0.09, 1-minute normoxic intervals) followed by 20 repetitions of hand opening practice and normoxia (sham, FIo2 = 0.21) + hand opening practice. Hand dexterity and function were quantified with Box and Block and Jebsen-Taylor hand function tests. We also recorded maximum hand opening using motion analyses and coactivity of extensor digitorum and flexor digitorum superficialis muscles using surface EMG.ResultsDaily AIH + hand opening practice improved hand dexterity, function, and maximum hand opening in all participants. AIH + hand opening practice improved Box and Block Test scores vs baseline in 5 participants (p = 0.057) and vs sham + hand opening practice in all 6 participants (p = 0.016). All participants reduced Jebsen-Taylor Hand Function Test (JTHF) time after daily AIH + hand opening practice (-7.2 ± 1.4 seconds) vs baseline; 4 of 6 reduced JTHF time vs sham + hand opening practice (p = 0.078). AIH + hand opening practice improved maximum hand aperture in 5 of 6 participants (8.1 ± 2.7 mm) vs baseline (p = 0.018) and sham + hand opening practice (p = 0.030). In 5 participants, daily AIH-induced changes in hand opening were accompanied by improved EMG coactivity (p = 0.029).ConclusionsThis report suggests the need for further study of AIH as a plasticity "primer" for task-specific training in spinal cord injury rehabilitation. Important clinical questions remain concerning optimal AIH dosage, patient screening, safety, and effect persistence.Clinicaltrialsgov identifierNCT01272336.
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