Cord Compression Injury In Rats Research Articles

TGN-020 alleviates edema and inhibits astrocyte activation and glial scar formation after spinal cord compression injury in rats

AimsIdentifying drugs that inhibit edema and glial scar formation and increase neuronal survival is crucial to improving outcomes after spinal cord injury (SCI). Here, we used 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a potent selective inhibitor of aquaporin 4 (AQP4), to investigate the effects of TGN-020 on SCI in Sprague-Dawley rats. Main methodsWe compressed the spinal cord at T10 using a sterile impounder (35 g, 5 min), to induce moderate injury. TGN-020 (100 mg/kg) or an equal volume of 10% dimethyl sulfoxide was then administered via intraperitoneal injection. Neurological function was evaluated using the Basso-Beattie-Bresnahan open-field locomotor scale 1, 3, 7, 14, 21, and 28 days after SCI. The degree of edema was assessed via determination of the precise spinal cord water content 3 days after SCI. Expression levels of AQP4, glial fibrillary acidic protein (GFAP), proliferating cell nuclear antigen (PCNA), and growth-associated protein-43 (GAP-43) were determined via western blotting and immunofluorescence staining 3 days after SCI and 4 weeks after SCI. Numbers of surviving neurons and glial scar sizes were determined using Nissl and hematoxylin-eosin staining, respectively. Key findingsOur results showed that TGN-020 promoted functional recovery at days 3, 7, 14, 21, and 28, as well as reduced the degree of edema and inhibited the expression of AQP4, GFAP, PCNA at days 3 after SCI. Furthermore, observations 4 weeks after SCI revealed that TGN-020 inhibited the glial scar formation and upregulated GAP-43 expression. SignificanceTGN-020 can alleviate spinal cord edema, inhibit glial scar formation, and promote axonal regeneration, conferring beneficial effects on recovery in rats.

The effect of myelotomy following low thoracic spinal cord compression injury in rats

Myelotomy is a surgical procedure allowing removal of extravasated blood and necrotic tissue that is thought to attenuate secondary injury as well as promote recovery in experimental spinal cord injury (SCI) models and humans. Here we examined in rat whether myelotomy at 48 h after low-thoracic compressive SCI provided any benefit over a 12 week period. Compared to animals receiving SCI alone, myelotomy worsened BBB scores (p < 0.05) and also did not improve plantar stepping, ladder climbing, urinary bladder voiding or sensory function (thermal latency) during the 12-week period. Quantitative analyses of tissue sections at 12 weeks showed that myelotomy also did not reduce lesion volume nor alter immunohistochemical markers of axons in spared white matter bridges, microglia, astrocytes or serotinergic fibres. However, myelotomy reduced synaptophysin expression, a marker of synaptic plasticity. We conclude that further studies are required to evaluate myelotomy after SCI. (142 words).

An Intensive Locomotor Training Paradigm Improves Neuropathic Pain following Spinal Cord Compression Injury in Rats.

Spinal cord injury (SCI) is often associated with both locomotor deficits and sensory dysfunction, including debilitating neuropathic pain. Unfortunately, current conventional pharmacological, physiological, or psychological treatments provide only marginal relief for more than two-thirds of patients, highlighting the need for improved treatment options. Locomotor training is often prescribed as an adjunct therapy for peripheral neuropathic pain but is rarely used to treat central neuropathic pain. The goal of this study was to evaluate the potential anti-nociceptive benefits of intensive locomotor training (ILT) on neuropathic pain consequent to traumatic SCI. Using a rodent SCI model for central neuropathic pain, ILT was initiated either 5 d after injury prior to development of neuropathic pain symptoms (the "prevention" group) or delayed until pain symptoms fully developed (∼3 weeks post-injury, the "reversal" group). The training protocol consisted of 5 d/week of a ramping protocol that started with 11 m/min for 5 min and increased in speed (+1 m/min/week) and time (1-4 minutes/week) to a maximum of two 20-min sessions/d at 15 m/min by the fourth week of training. ILT prevented and reversed the development of heat hyperalgesia and cold allodynia, as well as reversed developed tactile allodynia, suggesting analgesic benefits not seen with moderate levels of locomotor training. Further, the analgesic benefits of ILT persisted for several weeks once training had been stopped. The unique ability of an ILT protocol to produce robust and sustained anti-nociceptive effects, as assessed by three distinct outcome measures for below-level SCI neuropathic pain, suggests that this adjunct therapeutic approach has great promise in a comprehensive treatment strategy for SCI pain.

Role of new K(+) channel blocker 4-AP-3-MeOH in acute spinal cord compression injury in rats

To evaluate the effects of 4-aminopyridine-3-methyl hydroxide (4-AP-3-MeOH) in rat's acute spinal cord injury. A total of 12 adult male SD rats (250-300 g) were randomly divided into treatment (n = 6) and control (n = 6) groups. After compressing segment T11 of spinal cord for 30 min, the injured segment received 1 ml 4-AP-3-MeOH (100 µmol/ml) by topically application in treatment group while the control group received 1 ml saline.Somatosensory evoked potential (SSEP) was detected in both groups at pre-injury, 30 min post-injury and post-dosing. Then Luxol fast blue (LFB) staining of target spinal segment was performed. In treatment group, the values of SSEP at pre-injury, 30 min post-injury and post-dosing were 1.26 ± 0.35, 0.03 ± 0.05 and 0.45 ± 0.19 µv respectively. Comparing SSEP of 30 min post-injury with post-dosing, the difference was statistically significant (P < 0.01).While in control group, the values of SSEP at pre-injury, 30 min post-injury and post-dosing were 1.05 ± 0.39, 0.01 ± 0.02 and 0.02 ± 0.02 µv respectively. Comparing SSEP of 30 min post-injury with post-dosing, there was no statistical difference (P > 0.05). After 30 min injury, there were swelling and bleeding of spinal cord.LFB staining showed that both gray and white matter had swelling and bleeding and central canal was destroyed with varying degrees of demyelination. After 30 min of acute spinal cord injury, there are bleeding of gray and white matter with varying degrees of demyelination. Topical usage of K(+) blocker 4-AP-3-MeOH can effectively improve the conduction of SSEP after acute spinal cord injury in rats.

The acute administration of eicosapentaenoic acid is neuroprotective after spinal cord compression injury in rats

The aim of the present study was to investigate the effects of treatment with eicosapentaenoic acid (EPA) after spinal cord compression injury in adult rats. Saline or EPA (250nmol/kg) was administered intravenously 30min after compression injury. Locomotor recovery was assessed daily using the BBB open-field locomotor score. One week after injury, animals were sacrificed and the spinal cord tissue containing the compression epicenter, and the adjacent rostral and caudal segments, was immunostained using specific markers for neurons, oligodendrocytes, axonal injury, and macrophages/microglia. Administration of EPA resulted in decreased axonal injury and increased neuronal and oligodendrocyte survival, in the lesion epicenter and adjacent tissue. The behavioural assessment mirrored the neuroprotective effects and showed a significantly improved functional recovery in animals treated with EPA compared to the saline-treated controls over the 7-day period. These observations suggest that EPA has neuroprotective properties when administered after spinal cord trauma.

Early functional outcomes and histological analysis after spinal cord compression injury in rats

Neuroprotective and repair strategies in spinal cord injuries (SCIs) have been so far largely unsuccessful. One of the prerequisites is the use of appropriate preclinical models to decipher pathophysiological mechanisms; another is the identification of optimal time windows for therapeutic interventions. The authors undertook this study to characterize early motor, sensory, autonomic, and histological outcomes after balloon compression of the spinal cord at the T8-9 level in adult rats. A total of 91 rats were used in this study. Spinal cord balloon compression was performed at T8-9 in adult rats by inflation of a 2 Fr Fogarty catheter into the epidural space. The authors first characterized early motor, sensory, and autonomic outcomes of 2 volumes of compression (10 and 15 microl) using behavioral tests and then examined histological outcomes in the spinal cord using Luxol fast blue staining. To further substantiate the characterization of the epidural balloon-compression model, they used a noncompetitive N-methyl-D-aspartate antagonist, GK11, and demonstrated the involvement of excitotoxicity in this model. Proportional and reproducible functional impairment resulted from compression caused by balloon inflation with either 10 or 15 microl of water and corresponded to the extent of the lesion. Indeed, during the early phase following SCI (1 week postinjury), recovery of locomotor function and bladder control correlated with the volume of inflation, whereas outcomes with respect to sensory function and reflexes were independent of compression severity. Treatment with GK11 significantly improved motor function in all groups of rats 1 week after injury and bladder voiding in the 10-microl injured rats compared to the 15-microl injured rats. The results of this study demonstrate that spinal balloon-compression injury in the rat is a well-characterized, reproducible, and predictable model to analyze early events following SCI.

Effect of methylprednisolone on motor function and spinal cord blood flow after spinal cord compression in rats

The effect of methylprednisolone (MP) on neurologic recovery and spinal cord blood flow (SCBF) was investigated up to 4 days after a spinal cord compression injury in rats. The injury was produced at midthoracic level by applying a load of 35 g on a 2.2 x 5.0 mm compression plate for 5 min, which resulted in transient paraparesis. MP was given as a bolus dose of 30 mg/kg i.v. 60 min after injury (n = 20) and controls were given saline (n = 10). The motor performance was assessed daily as the capacity angle on the inclined plane and SCBF was measured by 14C-iodoantipyrine autoradiography on Days 1 or 4. On Day 1 the capacity angle was reduced from about 63 degrees preoperatively to 33 +/- 2 degrees (mean +/- SEM) in the control group and to 50 +/- 1 degrees in the group treated with MP (p less than 0.05). Thereafter there was a slight improvement in both groups, but the difference persisted throughout the observation period. On Day 4 both gray and white matter SCBF was better preserved in MP-treated animals than in the control group (59 +/- 4 versus 49 +/- 3 ml/min/100 g tissue for gray matter and 13.6 +/- 0.6 versus 10.7 +/- 0.8 ml/min/100 g tissue for white matter). Posttraumatic treatment with MP, thus, improved both the neurologic recovery during the first 4 days and SCBF as measured on Day 4. It is speculated that the effect of MP is at least partly exerted on the vascular bed.

NON-activated protein C as post-treatment after spinal cord compression injury in rats

Neuroprotective effects of recombinant human activated Protein C (rhAPC) in models of Spinal Cord Injury (SCI) and ischemic stroke have been reported in rodents. To rule out immunogenicity of rhAPC and to possibly maintain the physiological PC/thrombin balance the use of zymogen PC in SCI might be preferable. Although activation of Protein C (PC) has been demonstrated in rats, the efficacy and drug safety of NON activated PC has not been previously tested in experimental SCI. Twelve rats were subjected to 40 g compression of the spinal cord at TH11 for 20 minutes and randomly allocated to either the NON activated PC (25 IU/kg) or the Placebo group (saline).Results. 25 IU treatment yielded improved recovery from SCI compared to placebo and the triple fold dose of PC (75 IU/kg) was subsequently tested to detect treatment associated complications (TAC). Treatment was administered as a single shot via the right vena jugularis forty minutes after onset of compression. The observation period was 5 weeks in 25 IU treated and 1 week in the 75 IU treated rats. Improvement of motor function recovery was measured with behaviour tests and electrophysiology. Single shot treatment with 25 IU/kg of NON activated PC led to improved recovery in terms of behaviour and electrophysiology. TACs neither occurred in the 25 IU nor in the 75 IU group within one week. NON activated PC is a potent and safe drug in experimental SCI and should be considered for treatment in neurotrauma.

4-Aminopyridine enhances motor evoked potentials following graded spinal cord compression injury in rats

Although several experimental and clinical studies have demonstrated the ability of 4-aminopyridine (4-AP) to restore electrophysiological and/or behavioral function following chronic spinal cord injury, the mechanism by which this occurs remains unclear. Demonstration of efficacy in rat spinal cord injury has not been reported, evidently because even relatively mild spinal cord contusions that produce only minor permanent locomotor disturbances abolish hind limb myoelectric motor evoked potentials (mMEPs). In this study, mMEPs were recorded acutely 25 days following graded thoracic spinal cord compression in rats. mMEP amplitudes were significantly enhanced by a single, 2 mg/kg i.v. dose of 4-AP. mMEPs were increased in all rats showing some evoked responses initially, and also in some animals which had no responses prior to treatment. 4-AP was further found to increase the maximum following frequency of mMEPs in both normal and injured rats from about 0.1 Hz to between 1 and 10 Hz. These data suggest that 4-AP might act by enhancing synaptic efficacy, as well as enhancing conduction in spinal axons whose myelination has been rendered dysfunctional by trauma.

Chronic regenerative changes in the spinal cord after cord compression injury in rats

Long-term regenerative changes and pathological effects after acute compression injury of the spinal cord were studied in rats. Twenty adult female Wistar rats underwent cord injury by the extradural clip compression technique at T6-7. Following injury, extradural electrodes attached to receiver-stimulators that were implanted subcutaneously were placed proximal and distal to the injury site. The animals were maintained in cages with electromagnetic fields created by encircling antennae. The control animals were in a field adjusted to a frequency below the sensitive frequency range of the receiver-stimulators so that they received no spinal cord stimulation. After 15–20 weeks of continuous spinal cord stimulation, histological sections of the cords were assessed and scored blindly for pathological changes including magnitude and extent of cord injury, and cystic cavitation, and for regenerative changes including proliferation of axons, Schwann cells and ependymal cells, and formation of myelin. In all 20 animals, there was a complete absence of normal cord tissue at the injury site, and cystic cavitation was frequently present at the injury site and beyond. Extensive regenerative changes were seen in all animals including regeneration of axons, Schwann cells and ependymal cells, and formation of myelin. Statistical analysis did not show a significant difference between treatment and control groups.

The value of decompression for acute experimental spinal cord compression injury.

A clip compression method was used to produce acute spinal cord compression injury in rats. The force and duration of the spinal cord compression were independently varied, and functional recovery of the cord was assessed using the inclined plane technique. Mathematical modeling produced a curve defining the relationship between force, duration, and functional recovery for each week after injury. The study clearly showed the beneficial effect of decompression and that increasing either the force or duration of compression, or both, caused a reduction in recovery.