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PubMed1982

Degradation of cytoskeletal proteins in experimental spinal cord injury.

Spinal cord injury was produced in rats by dropping a 10 g weight from 30 cm upon dura-invested exposed spinal cord. Examination of the fine structure of the traumatic lesion (15 min to 30 min) revealed granular degeneration of axons and occasional loosening of myelin lamellae. Older lesions (4 to 72 hours) showed degeneration of axons and vesiculation of myelin. At 15 minutes there is more loss of neurofilament proteins than of myelin proteins. Substantial decreases in the neurofilament and myelin proteins were observed at 30 minutes and the losses were even greater 2-72 hours after injury. This indicates that degeneration of axons may precede degradation of the myelin sheath and also that increased proteinase(s) activity, possibly activated by calcium, mediates the traumatic axonolysis and myelinolysis in experimental spinal cord trauma.

Animals↗
PubMedDate not supplied

[Olfactory glial cells: hope in the treatment of spinal cord injuries].

Spinal cord injuries (SCI) have been reckoned for many years a serious clinical problem. Current strategies of SCI treatment prevent the occurrence of secondary injury in the spine (neuroprotection methods) as well as induce the anatomical and functional reorganization of intact nerve tracts in the spinal cord due to the plasticity of the central nervous system (neurorehabilitation methods). The observed functional recovery in patients treated for SCI depends on the severity of the injury and not always is satisfying. The elucidation in the last two decades of the mechanisms responsible for the induction of regeneration in the central nervous system enabled new strategies for SCI treatment to be developed. These strategies give an opportunity to obtain clinically-essential recovery of motor, sensor and vegetative functions, even in cases of total lesion of the spinal cord. The milestone in these studies was the usage of intraspinal transplants containing cells with neurotrophic properties, tested on the experimental model of rat SCI. Among the transplanted cells special attention should be paid to the olfactory ensheathing cells (OEC) on account of their unique property to stimulate the central neuroregeneration. In this paper the authors present basic characteristics of rat OEC, discuss their neurotrophic properties after transplantation into the injured animal spinal cord, as well as refer to the first attempts to use human olfactory glial cells in the treatment of SCI in humans.

Humans↗
PubMed2002

Partial return of motor function in paralyzed legs after surgical bypass of the lesion site by nerve autografts three years after spinal cord injury.

Spinal cord injuries often result in irreversible loss of motor and somatosensory functions below the lesion level. Treatment is limited to physiotherapy aimed at compensating disability. We previously showed that re-establishment of tissue continuity can be achieved in animal models through nerve autografts implanted between the rostral spinal ventral horn and the caudal ventral roots. Rostral motor neuron axons could thus reach peripheral targets, leading to some return of motor function. We used a similar approach in a paraplegic patient with stabilized clinical states three years after spinal cord traumatic damage at the T9 level. Three segments from autologous sural nerves were implanted into the right and left antero-lateral quadrant of the cord at T7-8 levels, then connected to homolateral L2-4 lumbar ventral roots, respectively. Eight months after surgery, voluntary contractions of bilateral adductors and of the left quadriceps were observed. Muscular activity was confirmed by motor unit potentials in response to attempted muscle contraction. Motor-evoked potentials from these muscles were recorded by transcranial magnetic stimulation. These data support the hypothesis that muscles have been re-connected to supra-spinal centers through motor neurons located in the rostral stump of the damaged cord. They suggest that delayed surgical reconstruction of motor pathways may contribute to partial functional recovery.

Electromyography↗
PubMed1983

Hyperextension trauma in the elderly: an easily overlooked spinal injury.

The diagnosis of hyperextension injury to the cervical spinal cord after a fall is easily overlooked in the elderly. This is because the pattern of neurologic deficit, usually that of the 'central cord syndrome,' is complex and because no radiologic signs of trauma are present apart from changes of cervical spondylosis. The case history of a patient who had delayed onset of paralysis after a fall and in whom the correct diagnosis was initially overlooked is presented. In older patients hyperextension injuries may result in serious damage to the spinal cord due to preexisting weakness of the intervertebral discs, which are fragmented and fissured as a result of degeneration. In such patients, radiologic evidence of spondylosis and a posterior osteophyte at C4/C5 or C5/C6 often go unnoticed. This injury is usually caused by indirect cervical spine trauma resulting from head or face injury. A lateral X-ray view of the area with the patient supine is safe, quick, and inexpensive.

Cervical Vertebrae↗
PubMed2006

Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury.

Spinal cord injury (SCI) results in loss of oligodendrocytes demyelination of surviving axons and severe functional impairment. Spontaneous remyelination is limited. Thus, cell replacement therapy is an attractive approach for myelin repair. In this study, we transplanted adult brain-derived neural precursor cells (NPCs) isolated from yellow fluorescent protein-expressing transgenic mice into the injured spinal cord of adult rats at 2 and 8 weeks after injury, which represents the subacute and chronic phases of SCI. A combination of growth factors, the anti-inflammatory drug minocycline, and cyclosporine A immunosuppression was used to enhance the survival of transplanted adult NPCs. Our results show the presence of a substantial number of surviving NPCs in the injured spinal cord up to 10 weeks after transplantation at the subacute stage of SCI. In contrast, cell survival was poor after transplantation into chronic lesions. After subacute transplantation, grafted cells migrated >5 mm rostrally and caudally. The surviving NPCs integrated principally along white-matter tracts and displayed close contact with the host axons and glial cells. Approximately 50% of grafted cells formed either oligodendroglial precursor cells or mature oligodendrocytes. NPC-derived oligodendrocytes expressed myelin basic protein and ensheathed the axons. We also observed that injured rats receiving NPC transplants had improved functional recovery as assessed by the Basso, Beattie, and Bresnahan Locomotor Rating Scale and grid-walk and footprint analyses. Our data provide strong evidence in support of the feasibility of adult NPCs for cell-based remyelination after SCI.

Animals↗
PubMed2026

The investigation of human cerebrospinal fluid exosome in spinal cord injury.

Spinal cord injury (SCI) leads to severe neurological and functional impairments, yet reliable biomarkers for assessing injury severity and predicting recovery remain limited. Cerebrospinal fluid (CSF) is in direct contact with the central nervous system and provides a valuable source for detecting molecular changes after SCI. Although exosomal microRNAs (miRNAs) and proteins are increasingly recognized as mediators of intercellular communication, the role of human CSF exosomes in SCI has not been systematically investigated. To identify exosome-based biomarkers and potential therapeutic targets, we analyzed CSF and serum exosomes from patients with acute SCI using RNA sequencing and proteomic profiling. Weighted gene co-expression network analysis identified 6 gene modules significantly associated with injury severity and neurological recovery at 3 months. Proteomic analysis revealed a 5-protein panel that distinguished complete from incomplete SCI and a 4-protein panel that predicted neurological improvement. Additionally, 15 CSF-specific and 9 serum-specific exosomal miRNAs were identified independent of injury severity. Among 10 tested miRNAs associated with neurological recovery, 7 regulated astrocyte proliferation, and 6 promoted neurite extension and synapse formation. Overall, this study provides a comprehensive characterization of CSF exosomal miRNAs and proteins in human SCI and identifies molecular signatures associated with injury severity and recovery.

Humans↗
PubMed1978

The effects of low spinal injury on somatosensory evoked potentials from forelimb stimulation.

Spinal cord transection below C6 in anesthetized cats results in an alteration in the configuration of the SEP following direct or percutaneous stimulation of the median or radial nerves. The most significant alterations were in components occurring at latencies from 40 to 60 msec. The results of these experiments support the general conclusion that the spinal cord and supraspinal structures act as a functional unit and that the SEP is not solely determined by input over segmental pathways In addition, the alteration in the SEP produced by median nerve stimulation following spinal cord injury below C6 may serve clinically as a monitor of events at the site of injury in cases where an SEP from lower limb stimulation is no longer obtainable.

Animals↗
PubMed2006

Antinociceptive effect of cannabinoid agonist WIN 55,212-2 in rats with a spinal cord injury.

Spinal cord injury (SCI) pain exhibits many symptoms associated with peripheral neuropathic pain, including increased tactile hypersensitivity. One novel approach to ameliorate SCI pain is the use of cannabinoid (CB) ligands. The current study evaluated the efficacy of the nonselective CB receptor agonist WIN 55,212-2 on tactile hypersensitivity in rats following a brief compression to the thoracic spinal cord. The withdrawal thresholds of the hind paws following SCI were significantly decreased, indicating tactile hypersensitivity. Systemic injection of WIN 55,212-2 increased withdrawal thresholds in a dose-dependent manner. Pretreatment with the CB(1) receptor subtype-selective antagonist AM 251 completely abolished the antinociceptive effect of WIN 55,212-2 whereas pretreatment with the CB(2) receptor subtype-selective antagonist AM 630 did not alter the antinociceptive effect of WIN 55,212-2. These data indicate that a CB(1)-selective agonist may be novel therapeutic treatment for clinical SCI pain.

Analgesics↗
PubMed2000

Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury.

Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and thermal allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of thermal allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the thermal allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.

Animals↗
PubMed1997

Chronic central pain after spinal cord injury.

Spinal cord injury (SCI) frequently results in dysesthesias that have remained refractory to clinical treatments despite a variety of interventions. The failure of therapeutic strategies to treat dysesthesias after SCI is due to the lack of attention given to mechanisms that elicit chronic pain following SCI. An overview of the literature with respect to the development of chronic pain in the SCI patient population will be given. In addition, a mammalian model of chronic central pain following spinal cord trauma will be presented. The model is characterized by the development of mechanical and thermal allodynia, as demonstrated by measuring the thresholds of accepted nociceptive tests, the paw withdrawal responses accompanied by changes in behavior consistent with the experience of noxious stimuli. In addition, vocalization responses that are accompanied by postural and behavioral changes consistent with the receipt of a noxious stimulus and involving supraspinal pathways are measured. Locomotor function was also tested and scored using the Basso, Beattie, and Bresnahan (BBB) open field test scale. Our data indicate that somatosensory thresholds for both mechanical and thermal stimuli that elicit paw withdrawal (flexor reflex) or vocalizations, accompanied by complex changes in behavior, are significantly different following SCI. These changes represent the development of mechanical and thermal allodynia. To determine the underlying mechanism for the altered sensory responses, we used electrophysiological techniques to determine if nociceptive dorsal horn neurons demonstrated increased excitability to peripheral stimulation as evidenced by increased responses to natural somatosensory stimuli. The data presented support the development of central sensitization of dorsal horn neurons after spinal cord hemisection. This provides a mechanism for the development of mechanical and thermal allodynia after SCI. Hypotheses that account for the development of the central pain state after SCI, as well as therapeutic interventions to ameliorate the pain state, are discussed.

Animals↗
PubMed1997

Blood-brain barrier permeability to ebiratide and TNF in acute spinal cord injury.

Spinal cord injury (SCI) in mammals has a poor outcome because of a lack of regeneration. Alteration of the local environment after injury may induce regeneration. However, the passage of blood-borne or exogenous neurotrophic substances through the blood-brain barrier (BBB) is not well characterized in either normal or injured states. We investigated the permeability of the BBB in normal and injured states to two markers of permeability (albumin and sucrose), to a peptide (ebiratide), and to a cytokine [tumor necrosis factor-alpha(TNF)]. We found that in normal mice the cervical and lumbar areas of the spinal cord were more permeable than the thoracic area and the brain to all four substances. The penetration of the alpha-MSH/ACTH analogue ebiratide and of TNF, substances that have saturable transport systems across the BBB and may be involved in regenerative processes in the CNS, followed a regional pattern of differential permeability comparable to that of albumin and sucrose. Complete transection at the lumbar level induced a temporal change in the permeability of the BBB. The increased permeability, as measured by the radioactively labeled tracers albumin and sucrose, was most apparent in the lumbar region proximal to the transection. After SCI, the permeability to ebiratide remained unchanged, suggesting that disruption of the BBB did not affect the transport system for ebiratide. By contrast, the increase of permeability to TNF exceeded that detected by the markers albumin and sucrose. This enhanced permeability was inhibited by excess unlabeled TNF in the blood, showing saturability. This suggests that the transport system for TNF may be activated in SCI.

Acute Disease↗
PubMed2005

Exogenous Bcl-xL fusion protein spares neurons after spinal cord injury.

Spinal cord injury (SCI) induces neuronal death, including apoptosis, which is completed within 24 hr at and around the impact site. We identified early proapoptotic transcriptional changes, including upregulation of proapoptotic Bax and downregulation of antiapoptotic Bcl-xL, Bcl-2, and Bcl-w, using Affymetrix DNA microarrays. Because Bcl-xL is the most robustly expressed antiapoptotic Bcl-2 molecule in adult central nervous system, we decided to characterize better the effect of SCI on Bcl-xL expression. We found Bcl-xL expressed robustly throughout uninjured spinal cord in both neurons and glia cells. We also found Bcl-xL localized in different cellular compartments: cytoplasmic, mitochondrial, and nuclear. Bcl-xL protein levels decreased in the cytoplasm and mitochondria 2 hr after SCI and persisted for 24 hr. To test the contribution of proapoptotic decreases in Bcl-xL to neuronal death, we augmented endogenous Bcl-xL levels by administering Bcl-xL fusion protein (Bcl-xL FP) into injured spinal cords. Bcl-xL FP significantly increased neuronal survival, suggesting that SCI-induced changes in Bcl-xL contribute considerably to neuronal death. Because Bcl-xL FP increases survival of dorsal horn neurons and ventral horn motoneurons, it could become clinically relevant in preserving sensory and motor functions after SCI.

Animals↗
PubMed1986

Posterolateral approach and anterior spinal canal recalibration in severe spinal injury affecting T-12, L-1: a study of seven cases.

The authors present seven cases of spinal trauma at the T-12--L-1 level with severe spinal canal stenosis secondary to compressive, anterior discocorporeal lesions. Associated neurological disorders were of varying severity. Six cases were investigated by computed tomography, which enabled the degree of thoracolumbar spinal canal stenosis to be determined. In all cases, the surgical procedure involved rectification of spinal deformity, with an initial unilateral posterolateral approach permitting anterior spinal canal recalibration, either by impaction of protrusive fragments or ablation of ejected disc fragments. The stabilization was in all cases achieved by complimentary bilateral plates using Roy-Camille material, associated with posterolateral arthrodesis by grafting with reconstruction of the articulopedicular structure. The functional spinal result was excellent in all cases, and recalibration was verified by tomography. In those cases showing neurological deficiency, good and early recovery was attributable to the suppression of spinal canal stenosis. The application of this posterolateral approach for severe lesions of the thoracolumbar junction seems to represent, in all cases of recent lesions, an alternative to the anterior or combined methods, which present widely recognized difficulties at the thoracoabdominal junction.

Adult↗
PubMed2005

[Pathophysiology and treatment of spinal cord injury].

Spinal cord injury can lead to devastating functional disability. Pathophysiological studies show that, very early after the initial trauma, secondary damage is caused by toxic phenomena involving excitatory amino acids (excitotoxicity). The use of specific antagonists can attenuate this secondary damage in murine models. However, the kinetics of this phenomenon must be precisely documented before launching clinical trials of multidrug therapy. Axonal regeneration, previously considered impossible within the mammalian central nervous system, depends on appropriate control of glial reactivity. This may be achieved through gene therapy (si RNA) targeting glial obstacles. Finally, the existence in the spinal cord of autonomous centers such as the locomotor CPG suggests that cell therapy-based approaches may also be effective.

Animals↗