Rapid functional recovery after spinal cord injury in young rats

Responses to traumatic injury in the immature spinal cord may be different from those in adults. We modified an adult model of weight-drop injury to characterize the histopathology and functional recovery after spinal cord injury (SCI) in rat pups at postnatal day 14-15. A 10-g weight was dropped from 2.5 or 5.0 cm at T8-T9. Hindlimb function was evaluated at 24 h and 1, 2, 3, and 4 weeks after injury using the Combined Behavioral Score that estimates overall hind limb sensorimotor function, and the BBB scale for open field locomotion. Histopathology was examined at 15 min, 24 h, and 4 weeks after SCI. The initial hemorrhagic lesion was similar to that seen in adults, but the time course of secondary loss of ventral horn motor neurons was extended. By 4 weeks, only a partial rim of white matter surrounding a central cavity was seen. The 5.0 cm injury group exhibited significantly less recovery of function at 4 weeks than the 2.5 cm group. In the latter, the degree of hindlimb deficit at 4 weeks was similar to that previously described for adults with 10 g x 2.5 cm SCI. However, pups in both injury groups exhibited a significantly faster rate of recovery than adults. Recovery was maximal by 1 week after SCI in pups as compared to 3-4 weeks in adults. The more rapid functional recovery observed in the pups suggests that this new model may be useful for studying mechanisms of functional plasticity after SCI.     

Basic fibroblast growth factor (bFGF) enhances tissue sparing and functional recovery following moderate spinal cord injury.

The rapid increase in basic fibroblast growth factor (bFGF) production following spinal cord injury (SCI) in rats is thought to serve a role in the cellular processes responsible for the functional recovery often observed. In this study, bFGF was intrathecally administered continuously for 1 week beginning 30 min after a moderate (12.5 mm) spinal cord contusion in adult rats using the New York University impactor device. Osmotic minipumps were implanted into the lateral ventricle and lumbar thecal sac to deliver bFGF at a rate of 3 microg or 6 microg per day versus control vehicle. Animals were behaviorally tested for 6 weeks using the Basso, Beattie, Bresnahan locomotor rating scale and histologically assessed for both tissue sparing and glial reactivity rostral and caudal to the lesion. Rats treated with bFGF regained coordinated hindlimb movements earlier than controls and demonstrated consistent coordination from 4 to 6 weeks. Vehicle-treated rats showed only modest improvements in hindlimb function. The amount of spared tissue was significantly higher in bFGF-treated rats than in controls. Astrocyte and microglial reactivity was more pronounced in bFGF-treated animals versus controls. In summary, intrathecal infusion of exogenous bFGF following SCI significantly reduces tissue damage and enhances functional recovery. Early pharmacological intervention with bFGF following SCI may serve a neuroprotective role and/or create a proregenerative environment, possibly by modulating the neuroglial response.     

Relation between spinal cord blood flow and functional recovery after blocking weight-induced spinal cord injury in rats

Spinal cord blood flow (SCBF) and motor performance on the inclined plane were measured up to 9 days after a reversible spinal cord compression injury in 49 Sprague-Dawley rats. A load of 35 g on 11 mm2 of the thoracic spinal cord for 5 minutes caused transient paraparesis with a decrease in the capacity angle on the inclined plane from 62 +/- 1 degree (mean +/- SEM) before injury to 33 +/- 1 degree on Day 1, 45 +/- 2 degrees on Day 4, d and 54 +/- 3 degrees on Day 9. SCBF was measured by the [14C]iodoantipyrine method, and in gray matter there was a decrease from 78.4 +/- 2.3 ml/min/100 g of tissue in uninjured animals to 33.7 +/- 1.5 ml/min/100 g of tissue on Day 1 after injury, increasing to 50.1 +/- 2.0 on Day 4 and to 70.5 +/- 2.7 ml/min/100 g of tissue on Day 9. At the corresponding times, the SCBF values in white matter were 14.5 +/- 0.5, 6.7 +/- 0.5, 10.2 +/- 0.6, and 13.4 +/- 0.6 ml/min/100 g of tissue, respectively. The animals in another group were loaded with 25 g for 5 minutes and on Day 1 exhibited a capacity angle of 43 +/- 2 degrees while the SCBF values for gray and white matter were 55.1 +/- 2.0 and 11.1 +/- 0.4 ml/min/100 g of tissue, respectively; thus, the results in this group were similar to the values on Day 4 in the animals loaded with 35 g.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of swimming on functional recovery after incomplete spinal cord injury in rats

One of the most promising rehabilitation strategies for spinal cord injury is weight-supported treadmill training. This strategy seeks to re-train the spinal cord below the level of injury to generate a meaningful pattern of movement. However, the number of step cycles that can be accomplished is limited by the poor weight-bearing capability of the neuromuscular system after injury. We have begun to study swimming as a rehabilitation strategy that allows for high numbers of steps and a high step-cycle frequency in a standard rat model of contusive spinal cord injury. The purpose of the present study was to evaluate the effect of swimming as a rehabilitation strategy in rats with contusion injuries at T9. We used a swimming strategy with or without cutaneous feedback based on original work in the chick by Muir and colleagues. Adult female rats (n=27) received moderately-severe contusion injuries at T9. Walking and swimming performance were evaluated using the Open-Field Locomotor Scale (BBB; Basso et al., 1995) and a novel swimming assessment, the Louisville Swimming Scale (LSS). Rats that underwent swim-training with or without cutaneous feedback showed a significant improvement in hindlimb function during swimming compared to untrained animals. Rats that underwent swim-training without cutaneous feedback showed less improvement than those trained with cutaneous feedback. Rats in the non-swimming group demonstrated little improvement over the course of the study. All three groups showed the expected improvement in over-ground walking and had similar terminal BBB scores. These findings suggest that animals re-acquire the ability to swim only if trained and that cutaneous feedback improves the re-training process. Further, these data suggest that the normal course of recovery of over-ground walking following moderately-severe contusion injuries at T9 is the result of a re-training process.     

神经营养素3对大鼠脊髓损伤后运动功能恢复的影响

目的 探讨神经营养素3(neurotrophin-3,NT-3)对大鼠急性脊髓损伤的治疗作用.方法 实验于2005-01/06在解放军第三军医大学中心实验室完成.选择60只健康SD大鼠,随机分为3组:对照组(生理盐水组),实验组(NT-3组),假手术组(n=5);用改良Allen's法以30gcm致伤SD大鼠制作大鼠T8全瘫模型,实验组经蛛网膜下腔导管于术后即刻,4h,8h,12h,24h,3d,7d注入NT-320μl(含NT-3 200ng),对照组在相同时间点给予等量生理盐水,假手术组只打开椎板后蛛网膜下腔置管,不致伤,不给药.各组动物分别于术后24h,3d,7d、14d行BBB评分和MEP检查.结果 60只大鼠全部进入结果分析,①实验组在24h、3d、7d、14d较对照组BBB评分分值提高[0.22±0.43/0.70±0.48(P＜0.05);3.2 2.39/8.01 2.05;9.30 1.49/14.32 2.11;12.80±0.92/18.40±1.08(P＜0.01)],②实验组MEP的N1波潜伏期在24h、3d、7d、14d均较对照组明显缩短[80.90±7.49/49.9±2.44(P＜0.01);54.05±8.52/40.55±4.72(P＜0.05);43.10±1.53/33.65±2.78(P＜0.01);38.45±3.98/22.25±2.84(P＜0.01)].结论 神经营养素3能明显促进脊髓损伤后运动功能的恢复,对大鼠脊髓损伤有明显治疗作用.     

Neurological and functional recovery after thoracic spinal cord injury

Objective

To describe neurological and functional outcomes after traumatic paraplegia.

Design

Retrospective analysis of longitudinal database.

Setting

Spinal Cord Injury Model Systems.

Participants

Six hundred sixty-one subjects enrolled in the Spinal Cord Injury Model Systems database, injured between 2000 and 2011, with initial neurological level of injury from T2–12. Two hundred sixty-five subjects had second neurological exams and 400 subjects had Functional Independence Measure (FIM) scores ≥6 months after injury.

Outcome Measures

American Spinal Injury Association Impairment Scale (AIS) grade, sensory level (SL), lower extremity motor scores (LEMS), and FIM.

Results

At baseline, 73% of subjects were AIS A, and among them, 15.5% converted to motor incomplete. The mean SL increase for subjects with an AIS A grade was 0.33 ± 0.21; 86% remained within two levels of baseline. Subjects with low thoracic paraplegia (T10–12) demonstrated greater LEMS gain than high paraplegia (T2–9), and also had higher 1-year FIM scores, which had not been noted in earlier reports. Better FIM scores were also correlated with better AIS grades, younger age and increase in AIS grade. Ability to walk at 1 year was associated with low thoracic injury, higher initial LEMS, incomplete injury and increase in AIS grade.

Conclusion

Little neurological recovery is seen in persons with complete thoracic SCI, especially with levels above T10. Persons who are older at the time of injury have poorer functional recovery than younger persons. Conversion to a better AIS grade is associated with improvement in self-care and mobility at 1 year.     

The effect of hypothermia on sensory-motor function and tissue sparing after spinal cord injury

Background contextIn recent years, hypothermia has been described as a therapeutic approach that leads to potential protective effects via minimization of secondary damage consequences, reduction of neurologic deficit, and increase of motor performance after spinal cord injury (SCI) in animal models and humans.PurposeThe objective of this study was to determine the therapeutic efficacy of hypothermia treatment on sensory-motor function and bladder activity outcome correlated with the white and gray matter sparing and neuronal survival after SCI in adult rats.Study designA standardized animal model of compression SCI was used to test the hypothesis that hypothermia could have a neuroprotective effect on neural cell death and loss of white and/or gray matter.MethodsAnimals underwent spinal cord compression injury at the Th8–Th9 level followed by systemic hypothermia of 32.0°C with gradual re-warming to 37.0°C. Motor function of hind limbs (BBB score) and mechanical allodynia (von Frey hair filaments) together with function of urinary bladder was monitored in all experimental animals throughout the whole survival period.ResultsPresent results showed that hypothermia had beneficial effects on urinary bladder activity and on locomotor function recovery at Days 7 and 14 post-injury. Furthermore, significant increase of NeuN-positive neuron survival within dorsal and ventral horns at Days 7, 14, and 21 were documented.ConclusionsOur conclusions suggest that hypothermia treatment may not only promote survival of neurons, which can have a significant impact on the improvement of motor and vegetative functions, but also induce mechanical allodynia.     

Quercetin promotes functional recovery following acute spinal cord injury

We tested the hypothesis that quercetin, a potent Fe(2+)-chelating flavonoid, would decrease secondary damage following spinal cord trauma. MRI studies using the relaxation of the T1 proton signal caused by Fe(2+) ions and the dose-dependent reversal of this effect by addition of quercetin in aqueous solution were used to guide us to the dosage of quercetin to be used in animal experimentations. Forty-four male Wistar rats were used in two experimental series to test the hypothesis that administration of quercetin improves recovery of motor function after acute traumatic spinal cord injury. Animals were subjected to laminectomy and subjected to an extradural 40-g force clip compression for 5 sec at T7. Quercetin or saline was administered intraperitoneally 1 h after injury and then every 12 hr thereafter. Recovery of motor function was assessed using BBB scores at weekly intervals for 4 weeks. A dose of 2.5 micromoles quercetin/kg body weight did not result in significantly better functional outcome, whereas doses ranging from 5 to 100 micromoles quercetin/kg body weight resulted in a significantly better functional outcome with half or more of the animals walking, although with deficit; in contrast, no animals walked in the group of saline-treated animals. No significant differences in behavioral outcome were seen amongst the doses ranging from 5 to 100 micromol/kg, nor was there a difference if animals were treated for 4 or 10 days. Therapeutic outcome was coincident with more efficient iron clearance, suggesting that one possible mechanism whereby quercetin decreases secondary damage is through iron chelation.     

硫酸软骨素酶ABC置管灌注治疗对大鼠脊髓损伤后神经功能恢复的影响

目的探讨硫酸软骨素酶ABC（ehondroitinase ABC,ChABC）置管灌注治疗对大鼠脊髓完全性横断伤后脊髓功能恢复的影响。方法采用大鼠胸段（T7-8）脊髓完全横断损伤模型,将SD大鼠随机分为4组：正常组（n=6）、假手术组（n=6）、单纯脊髓横断组（n=10）、ChABC置管灌注组（n=10）。正常组不进行任何干预处理;假手术组只切除T7-8椎板,不损伤硬脊膜;在横断节段下方蛛网膜下腔放置PE-10导管灌注,单纯脊髓横断组给予生理盐水10μl/d灌注,连续10 d;ChABC置管灌注组给予ChABC 6μl/次灌注,隔日1次,共5次。大鼠脊髓损伤术后1～8周,1周1次,12～24周,2周1次,进行行为学评估;24周时行大脑皮层诱发电位检测。结果（1）行为学评估：损伤后3周内,评分均在8分左右[单纯脊髓损伤组为（6.5±1.14）分,ChABC置管灌注组为（9.0±2.20分）],3周后ChABC置管灌注组的评分有明显提高,并于14～16周达到峰值,然后呈下降趋势,22～24周时稳定在10周时的水平。单纯脊髓横断组的最高评分为（11.0±1.47）分,ChABC置管灌注组的最高评分为（30.0±4.55）分,正常组的评分为53.5分。假手术组术后2周时的评分与正常组无明显差异,4周后ChABC置管灌注组的评分高于单纯脊髓横断组（P〈0.05）。（2）大脑皮层诱发电位检测：术后24周时,所有脊髓横断组中均未记录到体感诱发电位（somatosensory evoked potentia,SEP）波形。结论ChABC置管灌注治疗后,改善脊髓损伤区及两端的神经细胞功能,促进轴突再生,促进双下肢运动功能的恢复,动物行为学评分有明显提高。     

功能训练促进颈脊髓损伤大鼠功能恢复的机制研究

目的：探讨大鼠颈脊髓不完全性损伤后前肢功能训练促进大鼠前肢功能恢复的机制.方法：在立体定位仪的引导下,致伤大鼠双侧红核和皮质脊髓背侧束后,对大鼠行前肢功能训练6周.免疫组化检测损伤脊髓节段脑源性神经生长因子（brain-derived neurotrophic factor,BDNF）的表达,皮质脊髓束投射神经元（corticospinal neurons,CSNs）中生长相关蛋白43（growth-associated protein 43,CAP43）和神经营养素共同受体P75（P75NTR）的表达,荧光金逆行示踪CSNs存活情况.结果：大鼠不完全性颈脊髓损伤后,前肢功能训练可上调脊髓前角神经元BDNF与CSNs中GAP43和P75NTR的表达,减少CSNs死亡.结论：大鼠颈脊髓不完全性损伤后,前肢功能训练通过上调脊髓前角神经元BDNF与CSNs中GAP43和P75NTR的表达以及减少CSNs的死亡等机制增加未损伤皮质脊髓腹侧束（vCST）的出芽,进而促进大鼠前肢功能恢复.     

Acute baclofen administration promotes functional recovery after spinal cord injury

BACKGROUND CONTEXTTraumatic spinal cord injury (SCI) leads to severe motor and sensory functional impairments that affect personal and social behaviors. Medical advancements have improved supportive therapeutic measures for SCI patients, but no effective neuroregenerative therapeutic options exist to date. Deficits in motor function are the most visible consequence of SCI. However, other complications, as spasticity, produce a significant impact on SCI patient's welfare. Baclofen, a GABA agonist, is the most effective drug for spasticity treatment. Interestingly, emerging data reveals that baclofen can also play a role on neuroprotection and regeneration after SCI.PURPOSEThe goal of this study was to understand the potential of baclofen as a treatment to promote recovery after SCI.STUDY DESIGNWe used a pre-clinical SCI mouse model with the administration of baclofen 1 mg/Kg at different time-points after injury.METHODSBehavior analysis (locomotor and bladder function) were performed during nine weeks of the in vivo experiment. Afterwards, spinal cords were collected and processed for histological and molecular analysis.RESULTSOur data showed that baclofen leads to locomotor improvements in mice when its administered acutely after SCI. Moreover, baclofen administration also led to improved bladder function control in all experimental groups. Interestingly, acute baclofen administration modulates microglia activation state and levels of circulating chemokines and cytokines, suggesting a putative role of baclofen in the modulation of the immune response.CONCLUSIONSAlthough further studies must be performed to understand the mechanisms that underlie the functional improvements produced by baclofen, our data shed light into the pharmacological potential of baclofen to promote recovery after SCI.CLINICAL RELEVANCEOur outcomes revealed that baclofen, a well-known drug used for spasticity management, improves the motor performance after SCI in a pre-clinical animal model. Our data opens new avenues for pharmacological strategies design to promote SCI recovery.     

Effects of continuous intravenous infusion of MCI-186 on functional recovery after spinal cord injury in rats

We investigated the effects of a free radical scavenger, MCI-186 (edaravone), on neuroprotection in the rat post-traumatic spinal cord using various doses and routes of administration. The injury was produced with a weight-drop device. Lipid peroxide formation in the spinal cord was measured using the thiobarbituric acid test for malonyldialdehyde (MDA). In the first experiment, MDA production in the untreated post-traumatic spinal cord reached peak values at 1?h post-trauma, and gradually decreased to control levels in 7 days. In the second experiment, rats received twice-daily injections (0, 1, 3, 5, 10, or 20?mg/kg) for 3 days. We found that 3?mg/kg was most effective functionally and histologically. In the third experiment, rats received a 3?mg/kg bolus?+?continuous infusion (0, 1.5, 2.4, or 3.0?mg/kg/h) for 1, 2, 4, and 8?h. We found that a 3?mg/kg bolus?+ infusion of 3.0?mg/kg/h was most effective for the inhibition of MDA production. In the fourth experiment, a 3?mg/kg bolus given once immediately after injury and twice daily for 3 days, a 3?mg/kg bolus?+?3.0?mg/kg/h for 1 day, or a 3?mg/kg bolus?+?3.0?mg/kg/h for 3 days were administered. The continuous infusion for 1 day showed significant improvement functionally and histologically, but continuous infusion at the same rate for another 2 days did not show any further improvement. To effectively reduce secondary neuronal damage, strong inhibition of free radical chain reactions at the early stage, particularly within the first 24?h post-trauma, is important.     

Priorities of desired functional recovery in Indian spinal cord injury patients

BackgroundSpinal cord injuries (SCI) affect various functions and therefore the Quality of life (QOL) of these patients. Regaining even partial function can lead to improved QOL; making it crucial to know which functions are most important for these patients.Material and methodsThis prompted us to conduct a survey in which subjects were asked to rank seven functions in order of importance to improve their quality of life. Survey was administered by personal interview of patients in different spinal injury rehabilitation centers across India.ResultsA total of 112 patients completed the survey. Regaining arm and hand function was ranked as first priority by quadriplegics while bowel/bladder function and walking movements were ranked as 2nd and 3rd priority. Paraplegics ranked return of walking movements as their first priority, bladder/bowel recovery as second and trunk strength/sexual function as 3rd priority.ConclusionThis knowledge empowers us to focus our research on what is most important for their QOL.     

硫酸软骨素酶ABC促进大鼠脊髓损伤后神经功能恢复的实验研究

目的 探讨硫酸软骨素酶ABC(ChABC)对神经脊髓损伤后运动功能恢复的影响.方法 SD大鼠72只,雌雄不限,随机分为假手术组、生理盐水对照组和ChABC治疗组,采用Allen法打击大鼠胸10脊髓损伤模型,分别在伤后即刻和随后每天一次连续一周蛛网膜下注射生理盐水和ChABC.HE染色和尼氏染色观察各时间点脊髓损伤组织形态和尼氏体及神经元的变化,采用BBB功能评分和运动诱发电位(MEP)观察大鼠的运动功能恢复情况.结果 大鼠脊髓损伤后1周时BBB评分和对照组无显著差别,在2、4周,治疗组评分结果明显优于对照组(P＜0.05;P＜0.01);MEP在1、4周的N1波潜伏期与对照组差异显著(P＜0.05;P＜0.01).HE和Nissl染色显示治疗组的形态和神经元数量要优于对照组.结论 ChABC能促进大鼠脊髓损伤后神经运动功能恢复,并对脊髓组织损伤具有保护作用.     

罗西格列酮对脊髓损伤大鼠神经功能恢复的作用及机制

目的:观察罗西格列酮对脊髓损伤(SCI)大鼠后肢运动功能恢复的作用,探讨其作用机制。方法:75只成年SD大鼠,应用Allen改良法制作大鼠T10SCI模型,随机分为A、B、C三组,每组25只,B、C组于损伤后5min、6h、24h腹腔注射罗西格列酮,C组在腹腔注射罗西格列酮前1h给予G3335,A组于相应时间点腹腔注射等体积生理盐水作为对照组。每组取6只大鼠于伤后1d、7d、2w、4w、6w时对后肢运动功能进行BBB评分;伤后3d每组取4只动物脊髓组织行免疫组织化学染色法检测核转录因子κB(nuclear factor kappa-light-chain-enhancer of activated B cells,NF-κB)的表达;伤后1、3、5、7d和2w每组取3只应用Westernblot法检测脊髓组织中凋亡相关蛋白caspase-3和Bcl-2的表达。结果:伤后1d、7d时3组大鼠BBB评分均为0分,伤后2w开始B组BBB评分高于A组和C组,4w和6w时与A、C组比较有显著性差异(P0.05);伤后3d时三组NF-κB表达均为阳性,但B组平均光密度值明显低于A、C组(P0.05),B组与C组比较无显著性差异(P0.05);伤后各时间点B组caspase-3表达量均低于A组和C组(P0.05),而Bcl-2表达均高于A组和C组(P0.05),其差异均在伤后5d达到高峰,A组与C组同时间点比较无显著性差异(P0.05)。结论:罗西格列酮可促进SCI大鼠神经功能恢复,其机制可能与抑制炎症反应及细胞凋亡有关。     

Detection of sacral sparing in acute spinal cord injury

Sacral dermatomal-evoked responses (DEP) and posterior tibial nerve (PTN) somatosensory-evoked potentials (SSEP) were recorded 28 hours after gunshot injury to the 12th thoracic vertebra of a 17-year-old male. Repeatable responses were obtained from stimulation of the fourth sacral dermatome despite absence of repeatable PTN responses. This suggestion of "sacral sparing" was accompanied by clinical improvement of neural function during the hospital course and 10 months after discharge. This case suggests DEP can make valuable contributions in the diagnosis of sacral sparing in acute spinal cord injury. Considerations regarding the unusual ipsilateral scalp recording location for sacral DEP are discussed.