Traumatic and nontraumatic spinal-cord-injured patients in Quebec, Canada. Part 3: pharmacological characteristics.

STUDY DESIGN: Community-based, cross-sectional study. OBJECTIVES: This study aimed at examining and comparing the pharmacological treatments administered to traumatic and nontraumatic spinal-cord-injured patients (TSCI, NTSCI). SETTING: The Interval Rehabilitation Center, Trois-Rivieres, Province of Quebec, Canada. METHODS: Medical records from a cohort of 175 chronic spinal-cord-injured patients (94 TSCI and 81 NTSCI individuals) were thoroughly studied. RESULTS: More than 19 classes and more than 300 drugs were found to be administered to SCI patients. Among them, drugs against bowel and bladder problems, blood clot or deep venous thrombosis, cardiovascular problems, depression or anxiety, stomach acidity, infections, pain, inflammation, sleeping problems and vitamin deficiency were the most commonly used (between 35 and 66% of all SCI patients). Differences between groups were found specifically for antidepressants and anxiolytics used mainly by TSCI patients whereas bisphosphonates, bronchodilators, lipid regulators and anti-inflammatory drugs were used mainly by NTSCI patients. CONCLUSION: The results revealed an unexpectedly large number of drugs that are prescribed to both groups of SCI patients. Given the existence of between-group differences and known risks of drug-drug interactions, it is suggested that recommendations for each group should be made to carefully examine either the necessity or the effectiveness of each treatment as well as the possibility of developing alternative strategies based on physical activity, nutrition and lifestyle to eventually reduce, hopefully, the number of pharmacological treatments administered to these individuals.

Traumatic and non-traumatic spinal cord-injured patients in Quebec, Canada. Part 2: biochemical profile.

STUDY DESIGN: Community-based, cross-sectional study. OBJECTIVES: This study aimed at examining and comparing biochemical profiles (blood and urine) of traumatic and non-traumatic spinal cord-injured patients (TSCIs vs NTSCIs). SETTING: The Interval Rehabilitation Center, Trois-Rivieres, Province of Quebec, Canada. METHODS: Medical records from a cohort of 175 chronic spinal cord-injured patients (94 TSCI and 81 NTSCI individuals) were thoroughly studied. RESULTS: Augmentations over time of red blood cell (erythrocyte), hematocrit and hemoglobin levels were generally found after spinal cord injury (SCI), specifically in NTSCI patients (late vs early chronic). In contrast, although leukocyte levels generally decreased over time after SCI, higher lymphocyte levels were detected only in NTSCI patients (late vs early chronic). Higher total cholesterol, triglyceride, high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C), protein and albumin serum levels were generally found over time after SCI, again, specifically in chronic NTSCI patients (late vs early chronic), whereas increased (twofold) nitrite and decreased (twofold) ubilirogen urine levels were found specifically in TSCI individuals (late vs early chronic). CONCLUSION: Clear differences were reported between subgroups of SCI patients strongly supporting the idea that therapeutic approaches aimed to treat these problems should be specifically designed for each type of patients (that is, NTSCI vs TSCI or early vs late chronic patients).

Non-assisted treadmill training does not improve motor recovery and body composition in spinal cord-transected mice.

STUDY DESIGN: Experiments in a mouse model of complete paraplegia. OBJECTIVES: To evaluate the effect of non-assisted treadmill training on motor recovery and body composition in completely spinal cord-transected mice. SETTINGS: Laval University Medical Center, Neuroscience Unit, Quebec City, Quebec, Canada. METHODS: Following a complete low-thoracic (Th9/10) spinal transection (Tx), mice were divided into two groups that were either untrained or trained with no assistance. Training consisted of placing the mice during 15 min with no further intervention (that is no tail pinching or body weight support) on a motorized treadmill (8-10 cm s(-1)) five times per week for 5 weeks. Locomotor performances were assessed weekly in both groups using two complementary locomotor rating scales. After 5 weeks, all mice were killed and adipose tissue, soleus, and extensor digitorum longus muscles were dissected for analyses. RESULTS: No significant difference in locomotor performances or in muscle fibre type conversion was found between trained and untrained mice. In contrast, body weight, adipose tissue, whole muscle, and individual fibre cross-sectional area (CSA) values were significantly lower in trained compared with untrained animals. CONCLUSIONS: Non-assisted treadmill training in these conditions did not improve motor performances and contributed to further accentuate body composition changes post-Tx, suggesting that assistance provided manually, robotically, or pharmacologically may be key to spinal learning and recovery of locomotor function and body composition.

Preliminary evidence of safety following administration of L-DOPA and buspirone in an incomplete monoplegic patient.

STUDY DESIGN: Case report. OBJECTIVES: To report a case where a monoplegic patient received L-DOPA and/or buspirone. These compounds, normally used in the treatment of Parkinson's disease and anxiety respectively, were recently shown to induce spinal locomotor network activity and reflex stepping-like movements in animal models of spinal cord injury (SCI). However, the safety of these drugs as potential treatments for Central Pattern Generator (CPG) activation in paralyzed individuals remain unclear. SETTING: St-Jean-Chrysostome, Quebec, Canada. METHOD: The acute effects induced by these compounds were qualitatively assessed by the patient, a 38-year-old man who underwent surgery 17 years ago to remove an intracavernous angioma located at the mid-thoracic level (T5-T6) of the spinal cord. RESULTS: Self-administration every 2 days of L-DOPA (200, 400 and 600 mg, p.o.) and buspirone (5, 10 and 15 mg, p.o.) either separately or combined led to no atypical side effects (that is, occasional sleepiness, nervousness, insomnia or mild headaches). No movement was induced ipsilaterally although some sensations referred to by the patient as an increased blood flow in the lower back and upper leg regions were reported shortly after administration of the combined treatment. CONCLUSION: The results show no significant side effects following acute administration of L-DOPA and/or buspirone. This constitutes the first report providing preliminary evidence of safety following administration of these drugs in incompletely paralyzed individuals. The sensations of increased blood flow ipsilaterally with the combined treatment may also suggest that the dose regimen was not optimal or sub-threshold for inducing detectable CPG-mediated leg movements.

Early adaptive changes in chronic paraplegic mice: a model to study rapid health degradation after spinal cord injury.

STUDY DESIGN: Literature review. OBJECTIVE: To describe quantitatively some of most important anatomic, systemic, and metabolic changes occurring soon (one month) after spinal cord trauma in mice. SETTING: University Laval Medical Center. RESULTS: Significant changes in weight, mechanical and contractile muscle properties, bone histomorphometry and biomechanics, deep-vein morphology, complete blood count, immune cell count, lipid metabolism and anabolic hormone levels were found occurring within 1 month in completely spinal cord transected (Th9/10) mice. CONCLUSION: These data reveal that many changes in mice and humans are comparable suggesting, in turn, that this model may be a valuable tool for neuroscientists to investigate the specific mechanisms associated with rapid health degradation post-SCI.

Spontaneous recovery of hindlimb movement in completely spinal cord transected mice: a comparison of assessment methods and conditions.

STUDY DESIGN: To compare results obtained with a variety of locomotor rating scales in Th9/10 spinal cord transected (Tx) mice. OBJECTIVES: To assess spontaneous recovery with a variety of rating scales to find the most sensitive methods for assessing recovery levels in Tx mice and differences associated with gender and condition. SETTING: Laval University Medical Center, Neuroscience Unit & Laval University, Department of Anatomy and Physiology, Quebec City, Quebec, Canada. METHODS: Scales including the Basso, Beattie and Bresnahan (BBB), the Basso Mouse Score (BMS), the Antri, Orsal and Barthe (AOB), the Motor Function Score (MFS) and the Averaged Combined Score (ACOS) were used to assess, in open-field and treadmill conditions, spontaneous locomotor recovery in male and female Tx mice. RESULTS: The ACOS scale revealed a progressive increase of spontaneous recovery during 5-weeks post-Tx. The other methods detected a progressive increase for the first 2-3 weeks post-Tx without any significant progress in weeks 4 and 5. Generally, scores obtained with each method were nonsignificantly different between males and females or between open-field and treadmill conditions. CONCLUSION: These results further confirm the existence of a limited but significant increase of locomotor function recovery, occurring without intervention, in Tx animals. Although each method could detect small levels of recovery, the ACOS method was discriminative enough to detect progressive changes up to 5 weeks post-Tx. In conclusion, the ACOS rating scale was the most discriminative method for assessing the spontaneous return of hindlimb movements found in Tx mice, both in open-field and treadmill conditions.

Profile of immediate early gene expression in the lumbar spinal cord of low-thoracic paraplegic mice.

Induction of immediate early gene (IEG) expression is believed to constitute one of the earliest steps in plasticity and long-term modification of neuronal properties. Although behavioral evidence of neuronal plasticity at the sublesional level after spinal cord injury exists, spatiotemporal changes of IEGs in spinal segments located caudally to such an injury have never been examined. Here, the authors studied spatiotemporal changes of c-fos, nor-1, nur77, nurr1, and retinoid x receptor (rxr) messenger RNA expression in the lumbar segments L1-L2 after low-thoracic spinal transection (Tx). C-fos expression generally increased in the dorsal horn with significant levels reached at 3 days and 14 days post-Tx. Basal nor-1 transcript levels decreased in the intermediate zone and dorsal horn areas at 7 days. Nur77 levels were nonsignificantly depressed throughout that period of time, whereas nurr1 and rxr transcripts were not detected before or after Tx. In conclusion, the results provide evidence of distinct roles for c-fos and nor-1 in reorganization and plasticity of neuronal networks typically involved in sensorimotor integration and locomotor control.

Paraplegic mice are leading to new advances in spinal cord injury research.

STUDY DESIGN: Experimental laboratory investigations with paraplegic mouse models. OBJECTIVES: To review the most recent advances in the field of spinal cord injury research; immune system response, regeneration, and functional recovery. SETTINGS: Laval University and Laval University Medical Center, Quebec, Canada. METHODS: Assessment of regenerative processes and locomotor function recovery induced by a variety of treatments and approaches in wild-type and genetically engineered mice with complete or incomplete lesions of the spinal cord. RESULTS: Recent studies have reported a number of significant observations providing additional insight into the role and mechanism of regeneration, immune system response, and functional recovery after spinal cord injury (SCI) using incomplete paraplegic mice with Nogo-A, NgR, EphA4, GFAP/vimentime, LIF, or Fas gene knock-out. A novel antibody called CXCL10 was also recently found to increase tissue sparing and angiogenesis after SCI. In an attempt to explore the possibilities of reactivating spared neurons below the injury level, researchers have found that pharmacological activation of specific subtypes of serotonin receptors (eg, 5-HT1A/2A/7) can sustain the production of basic locomotor-like movements in complete paraplegic mice. CONCLUSION: The growing availability of genetically engineered and mutant mouse strains along with molecular biology tools has led scientists to increasingly use murine models in SCI research. These new tools and models may assist scientists in understanding further the complex pathological consequences of SCI.

Semiquantitative assessment of hindlimb movement recovery without intervention in adult paraplegic mice.

STUDY DESIGN: Experimental laboratory investigation of hindlimb movement recovery in chronic paraplegic mice. OBJECTIVES: Development of an assessment method to discriminatively quantify motor and locomotor-like movements of paraplegic mice. SETTING: Laval University Medical Center, Quebec, Canada. METHODS: Signs of 'functional recovery' were examined in open-field condition during 1 month in adult mice with a complete spinal cord transection at the low-thoracic level. RESULTS: None of the mice exhibited hindlimb movements after spinalization. At 7 days, 33% of them displayed weak nonbilaterally alternating movements (NBA). At 14 days, increased NBA were observed and the first bilaterally alternating movements (BA) in 10% of the mice. A progressive increase of movement frequency and amplitude was found after 2-3 weeks. By the end of the month, 86% displayed mixed NBA and BA. However, none of them recovered the ability to stand or bear their own weight with the hindlimbs. CONCLUSION: This study reports signs of partial hindlimb movement recovery in chronic paraplegic mice and provides evidence of plasticity in sublesional circuits of neurons occurring in the absence of inputs from the brain, locomotor training or pharmacological treatment. This assessment method can be used to characterize hindlimb movements in complete spinal cord transected mice tested in open-field condition.

Role of NMDA receptor activation in serotonin agonist-induced air-stepping in paraplegic mice.

STUDY DESIGN: Experimental laboratory investigation of the effects of serotonergic and glutamatergic drugs in early paraplegic mice. OBJECTIVES: To examine whether NMDA and 5-HT receptors synergistically participate to generate basic stepping movements in paraplegic mice. SETTING: Laval University Medical Center, Quebec, Canada. METHODS: Adult mice completely spinalized at the low-thoracic level 1 week earlier were suspended in harnesses for experiments. Acute drug-induced effects were examined on hindlimb movements filmed with a digital video camera. Detailed kinematic analyses included stick diagrams reconstructions of hindlimb movements and analysis of bilateral coordination, angular excursion, stepping amplitude and frequency. RESULTS: A single treatment with the 5-HT2 agonist quipazine (>0.7 mg/kg, i.p.) induced episodes of air-stepping movements in the hindlimbs of paraplegic mice. In contrast, injection of the glutamatergic agonist NMDA (1-45 mg/kg i.p.) failed to induce rhythmicity, although nonlocomotor rhythmic movements were observed with higher doses (45-60 mg/kg i.p.). Subthreshold doses of NMDA (22-30 mg/kg) could induce episodes of hindlimb air-stepping if combined with subthreshold doses of quipazine (0.3-0.7 mg/kg). Air-stepping was entirely blocked by administration of the selective NMDA antagonist MK-801. CONCLUSION: A single treatment with quipazine can trigger episodes of locomotor-like movements in early chronic spinal mice. Even though NMDA alone could not generate bilaterally coordinated air-stepping, NMDA receptor activation was nonetheless critical for spinal locomotor rhythmogenesis induced by 5-HT agonists in awake behaving animals.

Non-volatile general anaesthetics reduce spinal activity by suppressing plateau potentials.

Non-volatile general anaesthetics are thought to reduce brain activity by potentiating inhibitory GABA(A) receptor channels but also cause adverse effects by suppress ing L-type calcium channels in the heart. In sections of the spinal cord, the non-volatile anaesthetics pentobarbital, thiopental and propofol reduced excitability of sensorimotor neurons by suppressing plateau potentials mediated by L-type calcium channels. This effect was independent of GABA(A) receptor potentiation but occurred in an overlapping concentration range. Therefore, the suppressive effect of non-volatile anaesthetics on L-type calcium channels can contribute to the reduction of spinal sensorimotor activity during anaesthesia. The results support the idea that general anaesthesia is achieved through several mechanisms and suggest that procedures for anaesthesia may be improved by combining selective agents for each mechanism in optimal concentrations.

L-type calcium channels but not N-methyl-D-aspartate receptor channels mediate rhythmic activity induced by cholinergic agonist in motoneurons from turtle spinal cord slices.

Rhythmic activity induced by different combinations of N-methyl-D-aspartate (NMDA), serotonin (5-HT), muscarine and D-tubocurarine was monitored intracellularly in lumbar motoneurons in a slice preparation from adult turtles. Low concentration of NMDA (7.5-15 microM) combined with 5-HT (10-80 microM) induced rhythmic motoneuron discharge which was underlied by intrinsic voltage oscillations resistant to tetrodotoxin. This oscillatory activity was abolished by 2-amino-5-phosphonopentanoic acid (AP5), a competitive blocker of NMDA receptors and by nifedipine a selective blocker of L-type calcium channels. In contrast, rhythmicity induced by the cholinergic agents muscarine and d-tubocurarine was abolished by nifedipine but not by AP5 nor by high [Mg2+]o. These results show that different receptor agonists induce intrinsic oscillations in mature motoneurons by independent routes. Each oscillatory mechanism depends on L-type calcium channels but only NMDA/5-HT-induced oscillations depend on voltage-sensitive NMDA-activated ionophores.

NMDA-Induced intrinsic voltage oscillations depend on L-type calcium channels in spinal motoneurons of adult turtles.

NMDA-induced intrinsic voltage oscillations depend on L-type calcium channels in spinal motoneurons of adult turtles. J. Neurophysiol. 80: 3380-3382, 1998. In a slice preparation from adult turtles, bath-applied N-methyl-D-aspartate (NMDA) induced rhythmic activity in spinal motoneurons. The underlying intrinsic oscillation in membrane potential was revealed in the presence of tetrodotoxin (TTX). NMDA-induced rhythmicity, in the presence or absence of TTX, was abolished or reduced by NMDA receptor antagonists and by three different classes of antagonists for L-type calcium channels. It is suggested that both NMDA receptor channels and L-type calcium channels contribute to NMDA-induced intrinsic oscillations in mature spinal motoneurons.

Chemical and electrical stimulation induce rhythmic motor activity in an in vitro preparation of the spinal cord from adult turtles.

Bath application of N-Methyl-D-aspartate (NMDA) and serotonin induced rhythmic activity in hindlimb motoneurons in an isolated spinal cord preparation from adult turtles. Subthreshold concentrations of NMDA and serotonin accompanied by stimulation of the dorsal funiculus also induced rhythmic activity. The induced activity in motoneurons and ventral roots displayed characteristics which resemble that of locomotion. This activity could be evoked in as few as three segments (D8-D10) of the lumbar enlargement isolated from the rest of the spinal cord. The existence of intrinsic oscillations in single neurons was revealed in the presence of tetrodotoxin. Our findings introduce a new in vitro preparation in which electrophysiological and pharmacological tools can be used with ease to study mechanisms of central pattern generation in a mature spinal motor network.