myelin-basic-protein and Contusions

Autoimmunity is usually considered only as a cause of disease; nevertheless, human T-cell repertoires are filled naturally with autoimmune lymphocytes. Here, we review evidence that autoimmune T cells can help heal damaged tissues, indicating that natural autoimmunity could also be a cause of health.

Topics: Animals; Autoantigens; Autoimmunity; Central Nervous System; Chemotaxis, Leukocyte; Contusions; Encephalomyelitis, Autoimmune, Experimental; Humans; Injections, Intraperitoneal; Lymphocyte Activation; Models, Immunological; Myelin Basic Protein; Myelin Sheath; Neovascularization, Physiologic; Nerve Crush; Nerve Degeneration; Optic Nerve Injuries; Regeneration; Spinal Cord Injuries; T-Lymphocyte Subsets; Wound Healing

Manipulation of various components of the endoplasmic reticulum (ER) stress response (ERSR) has led to functional recovery in diabetes, cancer, and several neurodegenerative diseases, indicating its use as a potential therapeutic intervention. One of the downstream pro-apoptotic transcription factors activated by the ERSR is CCAAT enhancer binding protein (C/EBP) homologous protein (CHOP). Recently, we showed significant recovery in hindlimb locomotion function after moderate contusive spinal cord injury (SCI) in mice null for CHOP. However, more than 40% of human SCI are complete. Thus the present study examined the potential therapeutic modulation of CHOP in a more severe SCI injury. Contused wild-type spinal cords showed a rapid activation of PERK, ATF6, and IRE-1, the three arms of the ERSR signaling pathway, specifically at the injury epicenter. Confocal images of phosphorylated EIF2α, GRP78, CHOP, ATF4, and GADD34 localized the activation of the ERSR in neurons and oligodendrocytes at the injury epicenter. To directly determine the role of CHOP, wild-type and CHOP-null mice with severe contusive SCI were analyzed for improvement in hindlimb locomotion. Despite the loss of CHOP, the other effectors in the ERSR pathway were significantly increased beyond that observed previously with moderate injury. Concomitantly, Basso Mouse Scale (BMS) scores and white matter sparing between the wild-type and CHOP-null mice revealed no significant differences. Given the complex pathophysiology of severe SCI, ablation of CHOP alone is not sufficient to rescue functional deficits. These data raise the caution that injury severity may be a key variable in attempting to translate preclinical therapies to clinical practice.

Topics: Animals; Apoptosis; Behavior, Animal; Blotting, Western; Claudins; Contusions; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Female; Heat-Shock Proteins; Immunohistochemistry; Locomotion; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Nerve Tissue Proteins; Protein Phosphatase 1; Real-Time Polymerase Chain Reaction; RNA; RNA, Messenger; Spinal Cord; Spinal Cord Injuries; Transcription Factor CHOP

The present study assessed the ability of a combined immunomodulatory treatment using (1) selective depletion of peripheral macrophages with liposomal-encapsulated clodronate, and (2) rolipram, a type 4 phosphodiesterase (PDE4) inhibitor, to promote neuroprotection and improve locomotor recovery following experimental contusion SCI. We demonstrate that delivery of either liposomal clodronate or rolipram alone promotes neuroprotection, enhances myelinated tissue sparing, and improves hindlimb functional recovery. Combined treatment with liposomal clodronate and rolipram produced the greatest improvement in locomotor recovery (inter-limb coordination, paw placement, and toe clearance), at 4 weeks post-injury (2.9 points). Retrograde tracing revealed substantial axonal sparing and/or sprouting from several brainstem motor nuclei, and hindlimb motor cortex. The combined treatment with these two drugs promoted the greatest amount of axonal sparing (3- to 4-fold increase compared to controls). Histological assessments revealed that combined treatment with clodronate/ rolipram resulted in a significant reduction in lesion volume (51%) and lesion area at the injury epicenter (45%), and significantly increased the extent of myelinated tissue sparing. Immunohistochemical studies showed a qualitative reduction in the accumulation of ED-1(+) macrophages within the injured spinal cord 5 weeks after injury. Our results demonstrate robust neuroprotection and improved hindlimb locomotor function using a combined immunomodulatory treatment strategy consisting of liposomal clodronate and rolipram. The present data suggest that clinical trials with acute delivery of combination immunomodulatory therapies may be warranted. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."

Topics: Analysis of Variance; Animals; Axons; Brain Stem; Clodronic Acid; Contusions; Disease Models, Animal; Drug Therapy, Combination; Ectodysplasins; Exploratory Behavior; Female; Glial Fibrillary Acidic Protein; Hindlimb; Immunologic Factors; Liposomes; Locomotion; Macrophages; Motor Cortex; Myelin Basic Protein; Myelin Sheath; Neural Pathways; Neurofilament Proteins; Neuroprotective Agents; Phosphodiesterase 4 Inhibitors; Psychomotor Performance; Rats; Recovery of Function; Rolipram; Spinal Cord Injuries; Stilbamidines; Vimentin

Most experimental models of spinal cord injury (SCI) in rodents induce damage in the thoracic cord and subsequently examine hindlimb function as an indicator of recovery. In these models, functional recovery is most attributable to white-matter preservation and is less influenced by grey-matter sparing. In contrast, most clinical cases of SCI occur at the lower cervical levels, a region in which both grey-matter and white-matter sparing contribute to functional motor recovery. Thus experimental cervical SCI models are beginning to be developed and used to assess protective and pharmacological interventions following SCI. The objective of this study was to characterize a model of graded cervical hemicontusion SCI with regard to several histological and behavioral outcome measures, including novel forelimb behavioral tasks. Using a commercially available rodent spinal cord impactor, adult male rats received hemicontusion SCI at vertebral level C5 at 100, 200, or 300 kdyn force, to produce mild, moderate, or severe injury severities. Tests of skilled and unskilled forelimb and locomotor function were employed to assess functional recovery, and spinal cord tissue was collected to assess lesion severity. Deficits in skilled and unskilled forelimb function and locomotion relating to injury severity were observed, as well as decreases in neuronal numbers, white-matter area, and white-matter gliosis. Significant correlations were observed between behavioral and histological data. Taken together, these data suggest that the forelimb functional and locomotor assessments employed here are sensitive enough to measure functional changes, and that this hemicontusion model can be used to evaluate potential protective and regenerative therapeutic strategies.

Topics: Animals; Benzoxazines; Cell Count; Contusions; Disease Models, Animal; Fluorescence; Forelimb; Functional Laterality; Glial Fibrillary Acidic Protein; Gliosis; Health; Immunohistochemistry; Locomotion; Male; Motor Skills; Myelin Basic Protein; Neuroglia; Neurons; Oxazines; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord; Spinal Cord Injuries

This study characterized the Infinite Horizon (IH) Impactor for use in mouse models of contusion spinal cord injury (SCI), and investigated the feasibility and reliability of using magnetic resonance imaging (MRI) as a method to accurately measure lesion volume after mouse contusion SCI. Eight-week-old female C57Bl/6 mice received a mild (30 kilodyne), moderate (50 kilodyne), or severe (70 kilodyne) contusion injury at the T9 vertebral level. Uninjured control mice received a T9 laminectomy only. Functional recovery was assessed using the Basso, Beattie, Bresnahan (BBB) and Basso Mouse Scale (BMS) open-field locomotor rating scales. Next, 4% paraformaldehyde-perfused spinal cords were collected between the T6 and T12 spinal roots, and stored in phosphate-buffered saline (PBS) at 4 degrees C until MRI analysis. MRI lesion volumes were determined using T1-weighted images on a 7-Tesla MRI. Histology was performed on 20-microm polyester wax-embedded sections processed from the same spinal cords for stereological determination of fibronectin lesion volume and myelin basic protein spared white matter volume. Area of spared white matter at the epicenter was also analyzed. The results demonstrated that the IH Impactor produced precise, graded contusion SCI in mice. Lesion volumes were positively correlated with force of impact, and negatively correlated with spared white matter and functional recovery. Additionally, similar lesion volumes were detected using fibronectin staining and MRI analysis, although MRI may be more sensitive for milder injuries. These results give researchers more options in how to analyze spinal cord injuries in animal models.

Topics: Animals; Behavior, Animal; Brain; Contusions; Female; Fibronectins; Image Processing, Computer-Assisted; Locomotion; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Plastic Embedding; Reproducibility of Results; Spinal Cord Injuries

The intraspinal cues that orchestrate T-cell migration and activation after spinal contusion injury were characterized using B10.PL (wild-type) and transgenic (Tg) mice with a T-cell repertoire biased toward recognition of myelin basic protein (MBP). Previously, we showed that these strains exhibit distinct anatomical and behavioral phenotypes. In Tg mice, MBP-reactive T-cells are activated by spinal cord injury (SCI), causing more severe axonal injury, demyelination, and functional impairment than is found in non-Tg wild-type mice (B10.PL). Conversely, despite a robust SCI-induced T-cell response in B10.PL mice, no overt T-cell-mediated pathology was evident. Here, we show that chronic intraspinal T-cell accumulation in B10.PL and Tg mice is associated with a dramatic and sustained increase in CXCL10/IP-10 and CCL5/RANTES mRNA expression. However, in Tg mice, chemokine mRNA were enhanced 2- to 17-fold higher than in B10.PL mice and were associated with accelerated intraspinal T-cell influx and enhanced CNS macrophage activation throughout the spinal cord. These data suggest common molecular pathways for initiating T-cell responses after SCI in mice; however, if T-cell reactions are biased against MBP, molecular and cellular determinants of neuroinflammation are magnified in parallel with exacerbation of neuropathology and functional impairment.

Topics: Animals; Chemokine CCL5; Chemokine CXCL10; Chemokines; Chemokines, CC; Chemokines, CXC; Chemotaxis, Leukocyte; Contusions; Genes, T-Cell Receptor beta; Growth Substances; Insulin-Like Growth Factor I; Interleukin 1 Receptor Antagonist Protein; Lymphocyte Activation; Lymphokines; Macrophages; Mice; Mice, Transgenic; Microglia; Myelin Basic Protein; Myelitis; RNA, Messenger; Sialoglycoproteins; Spinal Cord Injuries; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets; Transforming Growth Factor beta; Transforming Growth Factor beta1

Spinal cord injury results in a massive loss of neurons, and thus of function. We recently reported that passive transfer of autoimmune T cells directed against myelin-associated antigens provides acutely damaged spinal cords with effective neuroprotection. The therapeutic time window for the passive transfer of T cells was found to be at least 1 week. Here we show that posttraumatic T cell-based active vaccination is also neuroprotective. Immunization with myelin-associated antigens such as myelin basic protein (MBP) significantly promoted recovery after spinal cord contusion injury in the rat model. To reduce the risk of autoimmune disease while retaining the benefit of the immunization, we vaccinated the rats immediately after severe incomplete spinal cord injury with MBP-derived altered peptide ligands. Immunization with these peptides resulted in significant protection from neuronal loss and thus in a reduced extent of paralysis, assessed by an open-field behavioral test. Retrograde labeling of the rubrospinal tracts and magnetic resonance imaging supported the behavioral results. Further optimization of nonpathogenic myelin-derived peptides can be expected to lead the way to the development of an effective therapeutic vaccination protocol as a strategy for the prevention of total paralysis after incomplete spinal cord injury.

Topics: Adjuvants, Immunologic; Amino Acid Substitution; Animals; Autoantigens; Autoimmune Diseases; Contusions; Cordotomy; Exploratory Behavior; Female; Guinea Pigs; Immunotherapy, Active; Locomotion; Magnetic Resonance Imaging; Male; Myelin Basic Protein; Paraplegia; Peptide Fragments; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Safety; Single-Blind Method; Spinal Cord Injuries; Time Factors

In order to determine if a specific response is induced after spinal cord injury, we performed a kinetic search for IgG antibodies against various spinal cord antigenic preparations in a rat contusion model. Even though spinal cord injured animals showed two reactive bands, these could be originated by the reaction of natural antibodies, since they were also observed before lesion. Thus, these antibodies would not be of relevance in the pathogenic events of spinal cord injury in this rat model. Our findings do not demonstrate the existence of a specific IgG response against spinal cord constituents after injury.

Topics: Animals; Antibody Formation; Antigens; Autoantibodies; Contusions; Immunoglobulin G; Myelin Basic Protein; Rats; Rats, Long-Evans; Spinal Cord; Spinal Cord Injuries

Myelin basic protein in spinal fluid was measured with a radioimmunoassay method after surgery of brain tumors and posttraumatic brains in thirteen cases. Three cases were studied daily for up to three weeks. Immediately after the operation the values were high but then successively returned to normal. Repeated measurement of the myelin basic protein in spinal fluid seem to be useful for assessing the healing rate of brain tissue after surgery for brain tumors and after other brain damage.

Topics: Adult; Aged; Brain Diseases; Brain Neoplasms; Contusions; Ependymoma; Female; Glioma; Hematoma; Humans; Male; Meningioma; Middle Aged; Myelin Basic Protein; Postoperative Period; Skull Fractures