Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Demyelination contributes to the physiological and behavioral deficits after contusive spinal cord injury (SCI). Therefore, remyelination may be an important strategy to facilitate repair after SCI. We show here that rat embryonic day 14 spinal cord-derived glial-restricted precursor cells (GRPs), which differentiate into both oligodendrocytes and astrocytes, formed normal-appearing central myelin around axons of cultured DRG neurons and had enhanced proliferation and survival in the presence of neurotrophin 3 (NT3) and brain-derived neurotrophin factor (BDNF). We infected GRPs with retroviruses expressing the multineurotrophin D15A (with both BDNF and NT3 activities) and then transplanted them into the contused adult thoracic spinal cord at 9 d after injury. Expression of D15A in the injured spinal cord is five times higher in animals receiving D15A-GRP grafts than ones receiving enhanced green fluorescent protein (EGFP)-GRP or DMEM grafts. Six weeks after transplantation, the grafted GRPs differentiated into mature oligodendrocytes expressing both myelin basic protein (MBP) and adenomatus polyposis coli (APC). Ultrastructural analysis showed that the grafted GRPs formed morphologically normal-appearing myelin sheaths around the axons in the ventrolateral funiculus (VLF) of spinal cord. Expression of D15A significantly increased the percentage of APC+ oligodendrocytes of grafted GRPs (15-30%). Most importantly, 8 of 12 rats receiving grafts of D15A-GRPs recovered transcranial magnetic motor-evoked potential responses, indicating that conduction through the demyelinated VLF axons was restored. Such electrophysiological recovery was not observed in rats receiving grafts of EGFP-GRPs, D15A-NIH3T3 cells, or an injection of an adenovirus expressing D15A. Recovery of hindlimb locomotor function was also significantly enhanced only in the D15A-GRP-grafted animals at 4 and 5 weeks after transplantation. Therefore, combined treatment with neurotrophins and GRP grafts can facilitate functional recovery after traumatic SCI and may prove to be a useful therapeutic strategy to repair the injured spinal cord.
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PMID:Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. 1604 70

We report three male patients with aseptic meningoencephalo- radiculitis presenting with acute urinary retention. Viral antibody titers for herpes types I and II and the PCR studies were negative. The cerebrospinal fluid revealed elevated myelin basic protein. The serum antibodies against a panel of gangliosides, some of which are known to be associated with acquired demyelinating neuropathies, were all negative. The magnetic resonance imaging (MRI) studies revealed spotty T2 high intensities in the basal ganglia, thalamus and brainstem in two patients. In one patient,meningeal gadolinium enhancement of the conus and cauda equina of the spinal cord was recognized. On urodynamic studies, all patients showed features of atonic bladder with or without detrusor hyperactivity. They were treated conservatively without using steroids or immunoglobulins, and made a remarkable functional recovery with the disappearance of abnormal MRI findings.However, all three were left with erectile dysfunction, and two continued to use self-intermittent catheterization at more than 3-year follow-up. There was no recurrence of symptoms. The underlying causes remain unclear, though they may represent a variant of acute disseminated encephalomyelitis.
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PMID:Aseptic meningo-radiculo-encephalitis presenting initially with urinary retention: a variant of acute disseminated encephalomyelitis. 1650 19

Murine models of CNS injury show auto-reactive T cell responses directed at myelin antigens, associated with improved neuronal survival and functional recovery. This pilot study shows, for the first time, that similar immune responses against myelin occur in human traumatic brain injury (TBI), with an expansion of lymphocytes recognising myelin basic protein observed in 40% of patients studied. "Reactive" patients did not have greater contusion volume on imaging, but were younger than the "unreactive" subgroup and tended towards a more favorable outcome. These findings are consistent with the concept of "beneficial autoimmunity".
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PMID:An investigation of auto-reactivity after head injury. 1651 51

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.
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PMID:Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. 1657 44

Human umbilical cord blood stem cells (hUCB) hold great promise for therapeutic repair after spinal cord injury (SCI). Here, we present our preliminary investigations on axonal remyelination of injured spinal cord by transplanted hUCB. Adult male rats were subjected to moderate SCI using NYU Impactor, and hUCB were grafted into the site of injury one week after SCI. Immunohistochemical data provides evidence of differentiation of hUCB into several neural phenotypes including neurons, oligodendrocytes and astrocytes. Ultrastructural analysis of axons reveals that hUCB form morphologically normal appearing myelin sheaths around axons in the injured areas of spinal cord. Colocalization studies prove that oligodendrocytes derived from hUCB secrete neurotrophic hormones neurotrophin-3 (NT3) and brain-derived neurotrophic factor (BDNF). Cord blood stem cells aid in the synthesis of myelin basic protein (MBP) and proteolipid protein (PLP) of myelin in the injured areas, thereby facilitating the process of remyelination. Elevated levels of mRNA expression were observed for NT3, BDNF, MBP and PLP in hUCB-treated rats as revealed by fluorescent in situ hybridization (FISH) analysis. Recovery of hind limb locomotor function was also significantly enhanced in the hUCB-treated rats based on Basso-Beattie-Bresnahan (BBB) scores assessed 14 days after transplantation. These findings demonstrate that hUCB, when transplanted into the spinal cord 7 days after weight-drop injury, survive for at least 2 weeks, differentiate into oligodendrocytes and neurons, and enable improved locomotor function. Therefore, hUCB facilitate functional recovery after moderate SCI and may prove to be a useful therapeutic strategy to repair the injured spinal cord.
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PMID:Axonal remyelination by cord blood stem cells after spinal cord injury. 1737 2

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.
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PMID:Behavioral, histological, and ex vivo magnetic resonance imaging assessment of graded contusion spinal cord injury in mice. 1743 50

Nerve injury brings about axonal disconnection, and thus axonal extension is one of the important steps for nerve regeneration. Expression of the pro-inflammatory cytokine interleukin-1 beta (IL-1beta) is increased at the early stage of nervous system injury, and previously IL-1beta has been reported to promote neurite outgrowth by inhibiting RhoA activity in vitro. However, the effect of IL-1beta on axonal extension in vivo has not been obvious. Now we examine whether IL-1beta takes advantages on sciatic nerve regeneration. Sciatic nerves of rats are transected and sutured, and IL-1beta or PBS is locally administered for 2 weeks. Although IL-1beta does not influence on motor functional recovery, it promotes sensory functional recovery, estimated by toe pinch test, and increases the number and the area of neurofilament-positive axons at 12 weeks compared with PBS. Moreover IL-1beta, which promotes Schwann cell proliferation and thus may inhibit myelination, does not impair remyelination, estimated by myelin basic protein. These findings suggest that IL-1beta may contribute to sensory nerve regeneration following sciatic nerve injury by promoting axonal extension.
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PMID:Interleukin-1 beta promotes sensory nerve regeneration after sciatic nerve injury. 1855 21

The central nervous system (CNS) is considered to be an immune-privileged site. For a long time, autoimmunity-induced inflammation has been viewed as an important mediator of secondary damage in the CNS following injury. However, other studies also suggest that autoimmunity is protective and beneficial. To investigate whether protective autoimmunity is present following spinal cord injury (SCI), we employed neonatally thymectomized (Tx) rats which contain few T lymphocytes in their peripheral blood, and passively immunized them with T lymphocytes activated by myelin basic protein (MBP) or spinal cord homogenate (SCH). Here we report that, among Tx, sham-Tx (sTx) and normal rats that received a contusive SCI, no significant histological and behavioral differences were found, suggesting that the endogenous T lymphocytes had no significant influence on the pathogenesis of secondary SCI. In rats passively immunized with MBP- or SCH-activated T cells (MBP-T or SCH-T, respectively), similar numbers of CD4(+) T cells were found to infiltrate into the injured spinal cords. However, only the MBP-T immunization showed neuroprotection, evidenced by the reduction of post-traumatic neuronal losses and improvement of functional recovery. These results collectively suggest that not all T lymphocytes against CNS antigens are neuroprotective and that a subpopulation of them, such as those of MBP-T cells, could be beneficial for SCI repair.
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PMID:Effects of autoimmunity on recovery of function in adult rats following spinal cord injury. 1862 99

Walking track analysis was used to measure global functional recovery following sciatic nerve injury. The correlation of morphologic outcome and different sciatic functional indices (SFIs) depends on different variables. The objective of this study was to compare three different SFIs and their correlation with histomorphometric findings in a sciatic nerve allograft repair model in the rat without (group I, n = 8) or with (group II, n = 8) daily intramuscular administration of 0.1 mg/kg FK 506. The correlation of SFIs with each other and with the myelin basic protein (MBP) density of nerve sections proximal, median, and distal to sciatic nerve grafts (1.5 cm) at 4, 8, 12, and 16 weeks postoperation (p.o.) was calculated, and unoperated animals served as controls (n = 8). Significant differences between SFIs calculated for experimental groups I and II at 12 and 16 weeks p.o. suggested that superior functional nerve recovery occurred in group II. However, there were significant differences between all SFIs at 16 weeks p.o. in group II, whereas only differences between SFI 1 and SFI 2 + 3 occurred in group I. SFIs of group II did not reach the values of the unoperated group. There were significant differences between the histomorphometric outcomes of groups I and II. There was no significant difference of MBP density between group II and the unoperated group, suggesting complete morphologic recovery. In conclusion, we found significant correlation between the MBP densities of groups I and II and all SFIs, suggesting a close relationship between histomorphometric and functional findings. (c) 2009 Wiley-Liss, Inc. Microsurgery, 2009.
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PMID:Correlation of three sciatic functional indices with histomorphometric findings in a rat sciatic nerve allograft repair model. 1937 28

Implantation of allografts or nerve conduits has been used to promote regeneration following peripheral nerve injuries involving substantial axon loss. Both methods provide promising alternatives to autologous grafting and avoid donor site morbidity. We compared the relative efficacies of allografting versus conduit implantation in a rat model of sciatic nerve regeneration. Two rat strains (Lewis and Dark Agouti; n = 30) were employed. Unoperated animals served as controls (group I). Animals in groups II and III underwent left sciatic nerve resection over a distance of 15 mm; group II animals received implants of collagen type I conduits; and group III animals received allografts from the other rat strain and systemic low-dose (0.1 mg/kg/d) administration of FK506. Walking tracks were recorded after 4, 8, 12, and 16 weeks; nerve sections were stained for myelin basic protein after 16 weeks. Functional tests revealed significantly better recovery in group III animals compared with group II even though there was no significant difference in the extent of remyelination. Neither group achieved the functional or histomorphometric values of control animals. Improved functional recovery following allografting plus systemic FK506, in comparison with conduit implantation, underlines the importance of systemic administration of neurotrophic molecules for nerve regeneration.
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PMID:Allografting combined with systemic FK506 produces greater functional recovery than conduit implantation in a rat model of sciatic nerve injury. 2001 91


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