Pathophysiology and pharmacologic treatment of acute spinal cord injury.

BACKGROUND CONTEXT: The past three decades have witnessed increasing interest in strategies to improve neurologic function after spinal cord injury. As progress is made in our understanding of the pathophysiologic events that occur after acute spinal cord injury, neuroprotective agents are being developed. PURPOSE: Clinicians who treat acute spinal cord injuries should have a basic understanding of the pathophysiologic processes that are initiated after the spinal cord has been injured. A familiarity with the literature on which the current use of methylprednisolone is based is also essential. STUDY DESIGN/SETTING: Literature review. METHODS: Literature review of animal data on pathophysiologic mechanisms, and of both animal and human trials of neuroprotective agents. RESULTS: The mechanical forces imparted to the spinal cord cause primary damage to the neural tissue, but a complex cascade of pathophysiologic processes that imperil adjacent, initially spared tissue to secondary damage rapidly follows this. Attenuating this secondary damage with neuroprotective strategies requires an understanding of these pathophysiologic processes. Many researchers are investigating the role of such processes as ischemia, inflammation, ionic homeostasis and apoptotic cell death in the secondary injury cascade, with hopes of developing specific therapies to diminish their injurious effects. Beyond methylprednisolone, a number of other pharmacologic treatments have been investigated for the acute treatment of spinal cord injury, and even more are on the horizon as potential therapies. CONCLUSIONS: This review summarizes some of the important pathophysiologic processes involved in secondary damage after spinal cord injury and discusses a number of pharmacologic therapies that have either been studied or have future potential for this devastating injury.     

The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration

Following an initial impact after spinal cord injury (SCI), there is a cascade of downstream events termed 'secondary injury', which culminate in progressive degenerative events in the spinal cord. These secondary injury mechanisms include, but are not limited to, ischemia, inflammation, free radical-induced cell death, glutamate excitotoxicity, cytoskeletal degradation and induction of extrinsic and intrinsic apoptotic pathways. There is emerging evidence that glutamate excitotoxicity plays a key role not only in neuronal cell death but also in delayed posttraumatic spinal cord white matter degeneration. Importantly however, the differences in cellular composition and expression of specific types of glutamate receptors in grey versus white matter require a compartmentalized approach to understand the mechanisms of secondary injury after SCI. This review examines mechanisms of secondary white matter injury with particular emphasis on glutamate excitotoxicity and the potential link of this mechanism to apoptosis. Recent studies have provided new insights into the mechanisms of glutamate release and its potential targets, as well as the downstream pathways associated with glutamate receptor activation in specific types of cells. Evidence from molecular and functional expression of glutamatergic AMPA receptors in white matter glia (and possibly axons), the protective effects of AMPA/kainate antagonists in posttraumatic white matter axonal function, and the vulnerability of oligodendrocytes to excitotoxic cell death suggest that glutamate excitotoxicity is associated with oligodendrocyte apoptosis. The latter mechanism appears key to glutamatergic white matter degeneration after SCI and may represent an attractive therapeutic target.     

高位脊髓损伤后心血管系统改变的病理生理学机制

背景高位脊髓损伤（spinal cord injury,SCI）是临床上一种较为凶险的创伤性疾病,损伤之后会出现各种器官系统的并发症,其中以心血管系统尤为突出。目的拟对高位SCI后心血管系统改变的临床表现及病理生理机制进行综述。内容损伤即刻即出现脊髓休克的症状,伴随各种类型心律失常,许多患者急性期即失去代偿能力,严重的会引起死亡;随着病情的发展,体位性低血压、自主神经反射异常是慢性期最常见的并发症,静息时血压较低而受到恶性刺激时血压急剧升高,严重影响患者的生命安全及生活质量。趋向研究高位SCI后心血管系统并发症的病理生理学机制,可以为临床高位SCI患者的诊断治疗及相关的基础研究起到指导作用。     

Pharmacological approaches to repair the injured spinal cord

Acute traumatic spinal cord injury (SCI) results in a devastating loss of neurological function below the level of injury and adversely affects multiple systems within the body. The pathobiology of SCI involves a primary mechanical insult to the spinal cord and activation of a delayed secondary cascade of events, which ultimately causes progressive degeneration of the spinal cord. Whereas cell death from the mechanical injury is predominated by necrosis, secondary injury events trigger a continuum of necrotic and apoptotic cell death mechanisms. These secondary events include vascular abnormalities, ischemia-reperfusion, glutamate excitotoxicity and disturbances in ionic homeostasis, oxidative cell injury, and a robust inflammatory response. No gold standard therapy for SCI has been established, although clinical trials with methylprednisolone (NASCIS II and III) and GM-1 ganglioside (Maryland and Sygen) have demonstrated modest, albeit potentially important therapeutic benefits. In light of the overwhelming impact of SCI on the individual, other therapeutic interventions are urgently needed. A number of promising pharmacological therapies are currently under investigation for neuroprotective abilities in animal models of SCI. These include the sodium (Na+) channel blocker riluzole, the tetracycline derivative minocycline, the fusogen copolymer polyethylene glycol (PEG), and the tissue-protective hormone erythropoietin (EPO). Moreover, clinical trials investigating the putative neuroprotective and neuroregenerative properties ascribed to the Rho pathway antagonist, Cethrin (BioAxone Therapeutic, Inc.), and implantation of activated autologous macrophages (ProCord; Proneuron Biotechnologies) in patients with thoracic and cervical SCI are now underway. We anticipate that these studies will harken an era of renewed interest in translational clinical trials. Ultimately, due to the multi-factorial pathophysiology of traumatic SCI, effective therapies will require combined approaches.     

大鼠脊髓损伤中的细胞凋亡及甲基强的松龙的干预作用

目的：探讨脊髓损伤（SCI）继发损伤机制,研究损伤脊髓细胞的凋亡及其意义,观察甲基强的松龙（MP）对细胞凋亡的影响。方法：使用改良Allen法制作大鼠急性SCI模型,实验分3组,假损伤（脊髓未受打击）,损伤组及MP治疗组,采用HE,荧光Hoechst 33342,TUNEL(末端脱氧核苷转移酶介导的脱氧尿苷三磷酸生物素缺口末端标记技术）等技术观察SCI后4h,8h,3d,7d,14d,21d及28d时损伤中心及邻近节段脊髓细胞的凋亡,治疗组损伤后30min给予大剂量MP,比较MP治疗组与损伤组脊髓细胞凋亡的变化,同时平行观察大鼠神经学和组织学恢复情况及两组神经丝蛋白（NF）含量的变化。结果：假损伤组各检测方法未见脊髓细胞凋亡,损伤组大鼠急性SCI后1d开始出现脊髓细胞凋亡,3d达高峰,自损伤中心向头尾端递减分布,持续21d,MP治疗组在伤后3d及7d凋亡脊髓细胞较损伤组显著减少,神经学恢复及组织学评分较损伤组有显著性提高,结论：凋亡是SCI后脊髓神经元死亡的一种重要方式,在继发性损伤中起极为重要的作用。MP的治疗作用可能与其干预SCI后细胞凋亡有关。     

Audit of early bladder management complications after spinal cord injury in first-treating hospitals

OBJECTIVE: The incidence of spinal cord injury is on the increase. It has been observed since World War II that proper initial management of the paralyzed bladder is a key factor in the prevention of complications of the urinary tract and renal function. METHODS: All traumatic spinal cord-injured patients admitted to the Thuringian Spinal Cord Rehabilitation Center, Sülzhayn, Germany, between January 1994 and December 1995 were reviewed for the method of initial bladder management, and all complications and events related to the urinary tract during the period from the date of injury/initial treatment in community-based hospitals to the date of transfer to our center were analyzed. RESULTS: The cohort included 170 spinal cord-injured patients (40 females, 130 males; mean age 35. 6 years). At the time of transfer to the rehabilitation center 48.8% of the patients still had an indwelling urethral catheter, 29.4% had a suprapubic catheter, and only 16.5% of the patients were on intermittent catheterization. The urine cultures were positive in 100, 44 and 28.6%, respectively. Severe complications due to an indwelling urethral catheter were seen in 15 patients. CONCLUSION: In contrast to early intermittent catheterization, indwelling urethral catheters are associated with a high complication rate. At the end of this century, the results of this study are most disappointing. There seems to be a lack of knowledge regarding sufficient bladder management in many hospitals and departments initially treating acute spinal cord-injured patients.     

Recovery from a spinal cord injury: significance of compensation, neural plasticity, and repair

Clinical recovery after a lesion of the central nervous system (CNS) can be attributed to mechanisms of functional compensation, neural plasticity, and/or repair. The relative impact of each of these mechanisms after a human spinal cord injury (SCI) has been explored in a prospective European multi-center study in 460 acute traumatic SCI subjects. Functional (activities of daily living and ambulatory capacity), neurological (sensory-motor deficits), and spinal conductivity (motor- and somato-sensory evoked potentials) measures were repeatedly followed over 12 months. In accordance with previous studies, complete SCI subjects (cSCI; n = 217) improved in activities of daily living unrelated to changes of the neurological condition, while incomplete SCI subjects (iSCI; n = 243) showed a greater functional and neurological recovery. The functional recovery in iSCI subjects was not related to an improvement of spinal conductivity, as reflected in unchanged latencies of the evoked potentials. This is in line with animal studies, where spinal conductivity of damaged spinal tracts has been reported to remain unchanged. These findings support the assumption that functional recovery occurs by compensation, especially in cSCI and by neural plasticity leading to a greater improvement in iSCI. Relevant repair of damaged spinal pathways does not take place.     

低剂量他克莫司治疗大鼠急性脊髓损伤的实验研究

目的：探讨低剂量他克莫司（tacrolimus，又名FK506）对大鼠急性脊髓损伤是否具有神经保护作用。方法：雄性Wistar大鼠72只，随机分为假手术组（12只）、损伤组（30只）和FK506治疗组（30只）。采用Allen’s打击法致伤大鼠T10脊髓，假手术组仅做椎板切除术。FK506治疗组在脊髓损伤后5min一次性经尾静脉注射FK5060．3mg／kg，其余两组以相同方法给予等量生理盐水。致伤后30min、6h、24h、48h、72h取伤段脊髓组织行病理观察及原位末端标记法（TUNEL）检测神经细胞凋亡，伤后1、3、7、14、21d行脊髓功能BBB评分和斜板实验。结果：伤后3、7、14、21d，FK506治疗组斜板实验和BBB评分明显优于损伤组，两组间比较差异有显著性（P〈0．05）；伤后各时间点FK506治疗组脊髓损伤区出血坏死较损伤组轻；伤后6、24、48、72h神经细胞凋亡FK506治疗组较损伤组明显减少，两组间比较差异有显著性（P〈0．05）。结论：在大鼠急性脊髓损伤后早期应用低剂量他克莫司（0．3mg/kg）治疗对神经具有保护作用，可减少神经细胞凋亡，减轻脊髓继发性损伤，促进脊髓功能恢复。     

Diffusion tensor imaging predicts hyperacute spinal cord injury severity

Experimental strategies that focus on ventral white matter (VWM) preservation during the hyperacute phase hold great potential for our improved understanding of functional recovery following traumatic spinal cord injury (SCI). Critical comparisons of human SCI to rapidly accumulating data derived from rodent models are limited by a basic lack of in vivo measures of subclinical pathophysiologic changes and white matter damage in the spinal cord. Spinal cord edema and intraparenchymal hemorrhage demonstrated with routine MR sequences have limited value for predicting functional outcomes in SCI animal models and in human patients. We recently demonstrated that in vivo derived diffusion tensor imaging (DTI) parameters are sensitive and specific biomarkers for spinal cord white matter damage. In this study, non-invasive in vivo DTI was utilized to evaluate the white matter of C57BL/6 mice 3 h after mild (0.3 mm), moderate (0.6 mm), or severe (0.9 mm) contusive SCI. In the hyperacute phase, relative anisotropy maps provided excellent gray-white matter contrast in all degrees of injury. In vivo DTI-derived measurements of axial diffusion differentiated between mild, moderate, and severe contusive SCI with good histological correlation. Cross-sectional regional measurements of white matter injury severity between dorsal columns and VWM varied with increasing cord displacement in a pattern consistent with spinal cord viscoelastic properties.     

Methylprednisolone reduces spinal cord injury in rats without affecting tumor necrosis factor-alpha production

Methylprednisolone (MPS) is the only therapeutic agent currently available for traumatic spinal cord injury (SCI). However, little is known about its therapeutic mechanisms. We have demonstrated that tumor necrosis factor-alpha (TNF-alpha) plays a critical role in posttraumatic SCI in rats. Since MPS has been shown to inhibit TNF-alpha production in vitro, it is possible that MPS can reduce SCI by inhibiting TNF-alpha production. To examine this possibility, we investigated the effect of MPS on TNF-alpha production in injured segments of rat spinal cord. Leukocytopenia and high-dose intravenous administration of MPS markedly reduced the motor disturbances observed following spinal cord trauma. Both treatments also reduced the intramedullary hemorrhages observed histologically 24 hr posttrauma. Leukocytopenia significantly reduced tissue levels of both TNF-alpha mRNA and TNF-alpha, 1 and 4 hr posttrauma, respectively, and it also inhibited the accumulation of leukocytes in the injured segments 3 hr posttrauma, while MPS had no effects. Lipid peroxidation and vascular permeability at the site of spinal cord lesion were both significantly increased over time after the induction of SCI, peaking 3 hr posttrauma. These events were significantly reduced in animals with leukocytopenia and in those given anti-P-selectin monoclonal antibody compared to sham-operated animals. Administration of MPS significantly inhibited both the increase in lipid peroxidation and the vascular permeability. These findings suggested that MPS reduces the severity of SCI, not by inhibiting the production of TNF-alpha at the site of spinal cord trauma, but by inhibiting activated leukocyte induced lipid peroxidation of the endothelial cell membrane. This suggests that MPS may attenuate spinal cord ischemia by inhibiting the increase in endothelial permeability at the site of spinal cord injury.     

Magnetic resonance imaging in acute spinal cord trauma

Magnetic resonance imaging (MRI) has proven to be an invaluable tool for evaluating neoplastic, congenital, and degenerative conditions of the spine and spinal cord. Because of various technical limitations, however, the use of MRI in acutely spinal cord-injured patients has not been fully explored. Sixty-two spinal cord-injured patients underwent MRI within the first 36 hours of injury. A variety of pathological findings were detected on the MRI scans: anatomical cord transection (7 cases), spinal cord deformity secondary to extrinsic compression (28), focal cord enlargement/swelling (21), hyperintense intramedullary lesions (17), and disc herniations (2). MRI may be a useful adjunct in the evaluation of acute spinal cord injury.     

Sequential changes of hypoxia—inducible factor 1 alpha in experimental spinal cord injury and its significance

Ｔｈｅｈｏｍｅｏｓｔａｓｉｓｏｆｏｘｙｇｅｎｉｓｉｍｐａｉｒｅｄｕｎｄｅｒｔｈｅｃｏｎｄｉｔｉｏｎｓｏｆｃａｒｃｉｎｏｇｅｎｅｓｉｓａｎｄｔｒａｕｍａ.Ｗｈｅｎｈｙｐｏｘｉａｏｃｃｕｒｓ ,ｔｈｅｉｎｔｒｉｎｓｉｃｍａｎｉｐｕｌａｔｉｎｇｍｅｃｈａｎｉｓｍｓａｒｅｉｎｉｔｉａｔｅｄ .Ｈｙｐｏｘｉａｉｎｄｕｃｉｂｌｅｆａｃｔｏｒ(ＨＩＦ)ｌｉｅｓｉｎｔｈｅｋｅｙｐｏｓｉｔｉｏｎｏｆａｄａｐｔａｔｉｏｎｔｏｈｙｐｏｘｉｃｓｔｒｅｓｓ.Ｉｔｓｅｆｆｅｃｔｓｏｎｃａｒｃｉｎｏｇｅｎｅｓｉｓａｎｄｃａｒｄｉｏ …     

A mouse model of acute ischemic spinal cord injury

Mice models of spinal cord injury (SCI) should improve our knowledge of the mechanisms of injury and repair of the nervous tissue. They represent a powerful tool for the development of therapeutic strategies in the fields of pharmacological, cellular, and genetic approaches of neurotrauma. We demonstrate here that the photochemical graded ischemic spinal cord injury model, described in rats, can be successfully adapted in mice, in a reliable and reproducible manner. Following the intravenous injection of Rose Bengal, the translucent dorsal surface of the T9 vertebral laminae of C57BL/6 female mice was irradiated with a 560-nm wavelength-light (3-8 min depending on the experimental group). Animals were sacrificed at 1 day or 7 days after injury. Functional tests were performed daily for motor, sensory, autonomic, and reflex responses. Lesion histopathology was assessed for lesion length, percentage of residual white matter, and astrocytic reactivity. Experimental groups demonstrated a functional deficit, which was correlated to the increase of the irradiation time and, therefore, to the severity of the injury. Histopathological and immunocytochemical data were reliable morphological measurements characterizing the degree of injury, which were strongly correlated to the severity of the functional impairment. Despite differences in the mechanism of injury, the wound healing response described in other traumatic SCI mice models was confirmed (no cavitation and, conversely, the formation of a dense connective tissue matrix). In this context, the precise understanding of the mechanisms of healing response after SCI in mice and of neurochemical kinetics appear to be crucial in the development of therapeutic strategies of CNS repair. Thus, the possible use of an increasing collection of transgenic mice offers a new dimension for experimental research in this area. The ischemic photochemical model of SCI in mice represents a relevant model that can play a key role in this new era of neurotrauma research.     

Maximum principal strain correlates with spinal cord tissue damage in contusion and dislocation injuries in the rat cervical spine

The heterogeneity of the primary mechanical mechanism of spinal cord injury (SCI) is not currently used to tailor treatment strategies because the effects of these distinct patterns of acute mechanical damage on long-term neuropathology have not been fully investigated. A computational model of SCI enables the dynamic analysis of mechanical forces and deformations within the spinal cord tissue that would otherwise not be visible from histological tissue sections. We created a dynamic, three-dimensional finite element (FE) model of the rat cervical spine and simulated contusion and dislocation SCI mechanisms. We investigated the relationship between maximum principal strain and tissue damage, and compared primary injury patterns between mechanisms. The model incorporated the spinal cord white and gray matter, the dura mater, cerebrospinal fluid, spinal ligaments, intervertebral discs, a rigid indenter and vertebrae, and failure criteria for ligaments and vertebral endplates. High-speed (～ 1 m/sec) contusion and dislocation injuries were simulated between vertebral levels C3 and C6 to match previous animal experiments, and average peak maximum principal strains were calculated for several regions at the injury epicenter and at 1-mm intervals from +5 mm rostral to -5 mm caudal to the lesion. Average peak principal strains were compared to tissue damage measured previously in the same regions via axonal permeability to 10-kD fluorescein-dextran. Linear regression of tissue damage against peak maximum principal strain for pooled data within all white matter regions yielded similar and significant (p<0.0001) correlations for both contusion (R(2)=0.86) and dislocation (R(2)=0.52). The model enhances our understanding of the differences in injury patterns between SCI mechanisms, and provides further evidence for the link between principal strain and tissue damage.     

对急性创伤性无骨折脱位型颈髓损伤的病因探讨

作者报道近年来收治的急性创伤性无骨折脱位型颈髓损伤患者２７例。常规Ｘ线及ＣＴ扫描均不能确切了解脊髓损伤的真正原因和致伤机理。１６例经ＭＲＩ检查表明两种机制造成了脊髓损伤：（１）脊髓的一过性挫伤。由伤时椎间瞬间的小位移造成，原先存在的颈椎退变因素也参与了损伤。（２）脊髓的持续性压迫。主要由急性外伤性椎间盘突出造成。作者强调对本病的诊断应提高警惕，对Ｘ线等检查无骨折脱位而临床表现有脊髓损伤者应首选ＭＲＩ检查。     

Review of experimental spinal cord injury with emphasis on the local and systemic circulatory effects.

Studies of experimental spinal cord injury began approximately 100 years ago, and since then many useful models of acute experimental spinal cord injury have been developed which stimulate many of the common types injuries in man. This review will describe some of these models and the information they have provided about the acute pathophysiological mechanisms in the injured spinal cord. There is good experimental evidence that the spinal cord suffers both a primary or mechanical injury and then a secondary injury which may worsen the prognosis for recovery. This review will emphasize the concept of the secondary injury, especially with respect to the vascular mechanisms. There is evidence from our laboratory and others to support the concept of the secondary injury and that the chief mechanism of the secondary injury is posttraumatic ischemia and infarction of the spinal cord. We have found evidence for the role of vascular mechanisms in three different injury models of acute spinal cord injury (A.S.C.I.) in three species of experimental animals. This review will describe the microangiographic and blood flow methods for assessing the microcirculation of the spinal cord after trauma. In addition, to these local vascular effects, this review will also describe the systemic vascular effects of A.S.C.I. which cause the neurogenic shock in this condition. It is our hypothesis that these local and systemic vascular effects are principal causes of the secondary injury leading to posttraumatic ischemia and infarction of the spinal cord after A.S.C.I. Furthermore, it is our hypothesis that early treatment of these microcirculatory changes and neurogenic shock can lead to improved recovery after A.S.C.I.     

Beneficial effects of vitamin E in sperm functions in the rat after spinal cord injury

Male infertility as a result of spinal cord injury (SCI) is associated with abnormal semen qualities including low sperm counts and poor sperm motility and morphology. Clinical studies suggest that reactive oxygen species (ROS)-related events might contribute to abnormal sperm functions after SCI. The current study examined whether impaired sperm functions after SCI can be ameliorated by an antioxidant, vitamin E. Vitamin E feeding of spinal cord transected (SCX) rats during the acute (maintenance) and chronic (restoration) phases of the injury partially preserved sperm viability and mitochondrial potential; similar effects were only seen in spinal cord contused (SCC) rats during the chronic phase. A beneficial effect of vitamin E on sperm motility, however, was only observed in SCX rats during the chronic phase of the injury. These results suggest that ROS-related events might account for some of the effects of cord injury on sperm functions, depending on the extent of injury and time postinjury. Furthermore, we found that sperm heads from SCC and SCX rats were less condensed compared to those from sham control rats. Such effects were attenuated by vitamin E, suggesting that ROS-related events may also contribute to abnormal sperm morphology after SCI. Partial restoration of male accessory gland weights in those rats fed vitamin E further suggests its beneficial effects on the functions of these glands. Conclusion: Vitamin E feeding attenuated some of the effects of spinal cord injury on sperm functions and male accessory glands in the rat. These results support a role of ROS-related events in deterioration of semen quality after cord injury. Further understanding of the underlying mechanisms for effects of vitamin E on sperm functions and male accessory glands will provide scientific rationale for the use of vitamin E or other antioxidant as therapeutic means to preserve sperm functions and semen quality in SCI men.     

Comparison of medical complications following nontraumatic and traumatic spinal cord injury

BACKGROUND: Nontraumatic spinal cord injury (NT/SCI) has been shown to represent a significant proportion of individuals admitted for SCI rehabilitation. Although medical complications of patients with traumatic SCI (T/SCI) have been well studied, there is a paucity of literature regarding those with nontraumatic SCI. Our objective was to compare the incidence of secondary SCI medical complications in patients with nontraumatic and traumatic SCI. DESIGN: A 2-year prospective data comparison of 117 patients with SCI admitted to a regional SCI rehabilitation unit and tertiary university medical center was undertaken. NT/SCI was defined as spinal stenosis, tumorous compression, vascular ischemia, and infectious etiologies. METHODS: Outcome measures included secondary SCI medical complications, injury characteristics, demographics, and rehabilitation outcomes. Statistical analyses were conducted between the 38 NT/SCI and 79 T/SCI who met admission criteria for acute inpatient rehabilitation. RESULTS: Statistically significant differences (P<.05) between nontraumatic and traumatic SCI were noted for deep venous thrombosis (7.9% vs 22.8%), pressure ulcers (21.1% vs 41.8%), autonomic dysreflexia (0% vs 24.1%), pneumonia (2.6% vs 26.6%), orthostatic hypotension (5.3% vs 36.7%), spasticity (21.1% vs 44.3%), and wound infections (16% vs 3%). Similar incidences were found for depression (23.7% vs 26.6%), urinary tract infections (52.6% vs 67.1%), heterotopic ossification (2.6% vs 7.6%), pain at admission (55.3% vs 62.0%), and gastrointestinal bleed (2.6% vs 2.5%). In addition, significant differences were noted between NT/SCI and T/SCI for age (55 years vs 39 years), rehabilitation length of stay (26.4 days vs 43.0 days), and neurologically complete injury (5.3% vs 45.6%). CONCLUSION: This study indicates that patients with NT/SCI present with different incidences of secondary SCI medical complications when compared with individuals with T/SCI. These data, along with differences in demographics, clinical presentation, and rehabilitation outcomes, have important implications for the medical, rehabilitation management, and long-term outcome of individuals with NT/SCI.     

NBQX treatment improves mitochondrial function and reduces oxidative events after spinal cord injury

The purpose of this study was to examine the effects of inhibiting ionotropic glutamate receptor subtypes on measures of oxidative stress events at acute times following traumatic spinal cord injury (SCI). Rats received a moderate contusion injury and 15 min later were treated with one of two doses of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzol[f]quinoxaline-7-sulfonamide disodium (NBQX), MK-801, or the appropriate vehicle. At 4 h following injury, spinal cords were removed and a crude synaptosomal preparation obtained to examine mitochondrial function using the MTT assay, as well as measures of reactive oxygen species (ROS), lipid peroxidation, and glutamate and glucose uptake. We report here that intraspinal treatment with either 15 or 30 nmol of NBQX improves mitochondrial function and reduces the levels of ROS and lipid peroxidation products. In contrast, MK-801, given intravenously at doses of 1.0 or 5.0 mg/kg, was without effect on these same measures. Neither drug treatment had an effect on glutamate or glucose uptake, both of which are reduced at acute times following SCI. Previous studies have documented that drugs acting on non-N-methyl-D-aspartate (NMDA) receptors exhibit greater efficacy compared to NMDA receptor antagonists on recovery of function and tissue sparing following traumatic spinal cord injury. The results of this study provide a potential mechanism by which blockade of the non-NMDA ionotropic receptors exhibit positive effects following traumatic SCI.