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

Developing effective therapies for serious neurological insults remains a major challenge for biomedical research. Despite intense efforts, the ability to promote functional recovery after contusion injuries, ischemic insults, or the onset of neurodegenerative diseases in the brain and spinal cord remains very limited even while the need for such therapies is increasing with an aging population. Recent studies suggest that cellular therapies utilizing mesenchymal stem cells (MSCs) may provide a functional benefit in a wide range of neurological insults. MSCs derived from a variety of tissue sources have been therapeutically evaluated in animal models of stroke, spinal cord injury, and multiple sclerosis. In each situation, treatment with MSCs results in substantial functional benefit and these pre-clinical studies have led to the initiation of a number of clinical trials worldwide in neural repair.
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PMID:The potential of mesenchymal stem cells for neural repair. 2035 Apr 91

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS). Since current treatments are aimed at nonspecifically down-regulating inflammation and natural mechanisms of repair and remyelination within the CNS are inadequate for recovery of function, MS patients presently only have available treatments that delay symptom progression. The complex nature of this disease means that only multifaceted treatments hold the promise of a cure. Recent studies indicate that the ER stress response, a cellular pathway that allows a cell to survive and recover from a stressful event, could be elicited to help the myelin-generating and myelin-support cells of the CNS survive inflammatory insult.
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PMID:Endoplasmic reticulum stress response as a potential therapeutic target in multiple sclerosis. 2035 12

It has been recently shown that systemically injected neural precursor cells (NPCs) could cross brain endothelium and favor functional recovery in animal models of multiple sclerosis (MS). Here we show that human NPCs express receptors of the chemokines IL8 and CXCL13 (CXCR1 and CXCR5, respectively) and migrate across brain endothelial cells in vitro, in response to these chemokines. Considering that these chemokines have been found overexpressed in MS in active, but not inactive areas of demyelination, our data suggest that systemically injected human NPCs may be considered for targeting active areas of demyelination in therapeutic approaches of MS.
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PMID:IL8 and CXCL13 are potent chemokines for the recruitment of human neural precursor cells across brain endothelial cells. 2040 Jan 87

Remyelination, which occurs subsequent to demyelination, contributes to functional recovery and is mediated by oligodendrocyte progenitor cells (OPCs) that have differentiated into myelinating cells. Therapeutics that impact remyelination in the CNS could be critical determinants of long-term functional outcome in multiple sclerosis (MS). Fingolimod is a S1P receptor modulator in MS clinical trials due to systemic anti-inflammatory properties, yet may impact cells within the CNS by crossing the blood-brain barrier. Previous studies using isolated dissociated cultures indicate that neural cells express S1P receptors and respond to receptor engagement. Our objective was to assess the effects of fingolimod on myelin-related processes within a multicellular environment that maintains physiological cell-cell interactions, using organotypic cerebellar slice cultures. Fingolimod treatment had no impact on myelin under basal conditions. Fingolimod treatment subsequent to lysolecithin-induced demyelination enhanced remyelination and process extension by OPCs and mature oligodendrocytes, while increasing microglia numbers and immunoreactivity for the astrocytic marker glial fibrillary acidic protein. The number of phagocytosing microglia was not increased by fingolimod. Using S1P receptor specific agonists and antagonists, we determined that fingolimod-induced effects on remyelination and astrogliosis were mediated primarily through S1P3 and S1P5, whereas enhanced microgliosis was mediated through S1P1 and S1P5. Taken together, these data demonstrate that fingolimod modulates multiple neuroglial cell responses, resulting in enhanced remyelination in organotypic slice cultures that maintain the complex cellular interactions of the mammalian brain.
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PMID:Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. 2039 29

Multiple sclerosis is a neurodegenerative disease characterized by episodes of autoimmune attack of oligodendrocytes leading to demyelination and progressive functional deficits. Because many patients exhibit functional recovery in between demyelinating episodes, understanding mechanisms responsible for repair of damaged myelin is critical for developing therapies that promote remyelination and prevent disease progression. The chemokine CXCL12 is a developmental molecule known to orchestrate the migration, proliferation, and differentiation of neuronal precursor cells within the developing CNS. Although studies suggest a role for CXCL12 in oligodendroglia ontogeny in vitro, no studies have investigated the role of CXCL12 in remyelination in vivo in the adult CNS. Using an experimental murine model of demyelination mediated by the copper chelator cuprizone, we evaluated the expression of CXCL12 and its receptor, CXCR4, within the demyelinating and remyelinating corpus callosum (CC). CXCL12 was significantly up-regulated within activated astrocytes and microglia in the CC during demyelination, as were numbers of CXCR4+NG2+ oligodendrocyte precursor cells (OPCs). Loss of CXCR4 signaling via either pharmacological blockade or in vivo RNA silencing led to decreased OPCs maturation and failure to remyelinate. These data indicate that CXCR4 activation, by promoting the differentiation of OPCs into oligodendrocytes, is critical for remyelination of the injured adult CNS.
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PMID:CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination. 2067 29

Multiple sclerosis (MS) patients may suffer from optic disturbances. Toxin-induced demyelinations have frequently been developed to investigate the cellular and structural aspects of demyelination and remyelination processes, separately. The present study describes functional consequence of lysolecithin (LPC)-induced lesion in the adult rat optic nerves and chiasm by recording the visual evoked potentials (VEPs) from the visual cortex and its correlation with myelin basic protein (MBP) expression in lesion site. Records of VEP were obtained at 2, 7, 14 and 28 days post-injection. We observed that the VEPs generated by light stimuli progressively changed in both amplitude and latency after the lesion as well as in comparison with those generated in control animals. These observations were confirmed through measurement of mRNA expression level for MBP which is one of the important genes expressed in mature oligodendrocytes and Schwann cells. The level of MBP mRNAs in demyelinated chiasm and optic nerves decreased following lysolecithin injection with its least value on day 7, and then it increased to the control level 14 days post-lesion. However, it continued to increase even after that and reached a maximum level 28 days post lesion. Results of the present paper show that, LPC injection in the chiasm share functional and molecular alterations which are found in demyelinating disorders in both the optic nerves and chiasm and also these alterations were coming back to level of control animal on 28 days post lesion, which is typically seen in myelin repair process. The present paper provides new insights into the experimental toxin-induced models that may be useful for evaluating the functional recovery of demyelinated optic nerves and chiasm following various repairing strategies. It also seems to be useful for studying the protective or remyelinating effects of different therapies in e.g. optic apparatus which is more affected by MS.
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PMID:Visual evoked potentials and MBP gene expression imply endogenous myelin repair in adult rat optic nerve and chiasm following local lysolecithin induced demyelination. 2063 45

Multiple sclerosis (MS) is considered an autoimmune-mediated demyelinating disease that targets the central nervous system (CNS). Despite considerable research efforts over multiple decades, our understanding of the basic biological processes that are targeted in the disease and the mechanisms of pathogenesis are poorly understood. Consequently, current therapies directed at controlling the progression of the disease are limited in their effectiveness. Historically, the primary focus of MS research has been to define the cellular and molecular basis of the immunological pathogenic mechanisms. Recently, however, it has become clear that long-term functional recovery in MS will require the development of strategies that facilitate myelin repair in lesion areas. The emerging evidence that the adult vertebrate CNS retains the capacity to regenerate neural cells that have been lost to disease or damage has provoked intensive research focused on defining the mechanisms of myelin repair. Unfortunately, the existing animal models of MS are poorly equipped to assess myelin repair, and new validated strategies to identify therapeutics targeted at promoting myelin repair are badly needed. This Commentary will review established murine models of MS, and discuss emerging technologies that promise to provide insights into the mechanisms of myelin repair.
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PMID:Restoring the balance between disease and repair in multiple sclerosis: insights from mouse models. 2064 13

Myelin is critical in maintaining electrical impulse conduction in the central nervous system. The oligodendrocyte is the cell type responsible for myelin production within this compartment. The mutual supply of trophic support between oligodendrocytes and the underlying axons may indicate why demyelinated axons undergo degeneration more readily; the latter contributes to the neural decline in multiple sclerosis (MS). Myelin repair, termed remyelination, occurs in acute inflammatory lesions in MS and is associated with functional recovery and clinical remittances. Animal models have demonstrated that remyelination is mediated by oligodendrocyte progenitor cells (OPCs) which have responded to chemotactic cues, migrated into the lesion, proliferated, differentiated into mature oligodendrocytes, and ensheathed demyelinated axons. The limited remyelination observed in more chronic MS lesions may reflect intrinsic properties of neural cells or extrinsic deterrents. Therapeutic strategies currently under development include transplantation of exogenous OPCs and promotion of remyelination by endogenous OPCs. All currently approved MS therapies are aimed at dampening the immune response and are not directly targeting neural processes.
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PMID:Cells of the oligodendroglial lineage, myelination, and remyelination. 2088 85

Oligodendrocyte precursor cells (OPCs) are one of the potential treating tools for multiple sclerosis (MS). Therefore, the cell number and differentiation of OPCs in a demyelinated spinal cord are crucial for improvement of reparative process. In the present study, we investigated whether "Governor Vessel (GV)" electro-acupuncture (EA) could efficiently promote increase in cell number and differentiation of OPCs into oligodendrocytes, remyelination and functional recovery in the demyelinated spinal cord. The spinal cord of adult Sprague-Dawley rats was microinjected with ethidium bromide (EB) at T10, to establish a demyelinated model. Six groups of animals were performed for the experiment. After 15 days EA treatment, neurotrophin-3 (NT-3) level and number of NG2-positive OPCs were significantly increased. Compared with the sham group, more NG2-positive OPCs were distributed between neurofilament (NF)-positive nerve fibres or closely associated with them in the lesion site and nearby tissue. In rats given longer EA treatment for 30 days, the number of adenomatous polyposis coli (APC)-positive oligodendrocytes was increased. Concomitantly, the number of newly formed myelins was increased. This was coupled by increase in endogenous oligodendrocyte involved in myelin formation. Furthermore, behavioural test and spinal cord evoked potential detection demonstrated a significant functional recovery in the EA+EB day 30 group. Our results suggest EA treatment can promote NT-3 expression, increase the cell number and differentiation of endogenous OPCs, and remyelination in the demyelinated spinal cord as well as the functional improvement of demyelinated spinal cord.
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PMID:An experimental electro-acupuncture study in treatment of the rat demyelinated spinal cord injury induced by ethidium bromide. 2147 May 65

Myelin-associated inhibition of axonal regrowth after injury is considered one important factor that contributes to regeneration failure in the adult central nervous system (CNS). Blocking strategies targeting this pathway have been successfully applied in several nerve injury models, including experimental autoimmune encephalomyelitis (EAE), suggesting myelin-associated inhibitors (MAIs) and functionally related molecules as targets to enhance regeneration in multiple sclerosis. NgR1 and NgR2 were identified as interaction partners for the myelin proteins Nogo-A, MAG and OMgp and are probably mediating their growth-inhibitory effects on axons, although the in vivo relevance of this pathway is currently under debate. Recently, alternative functions of MAIs and NgRs in the regulation of immune cell migration and T cell differentiation have been described. Whether and to what extent NgR1 and NgR2 are contributing to Nogo and MAG-related inhibition of neuroregeneration or immunomodulation during EAE is currently unknown. Here we show that genetic deletion of both receptors does not promote functional recovery during EAE and that NgR1 and NgR2-mediated signals play a minor role in the development of CNS inflammation. Induction of EAE in Ngr1/2-double mutant mice resulted in indifferent disease course and tissue damage when compared to WT controls. Further, the development of encephalitogenic CD4(+) Th1 and Th17 responses was unchanged. However, we observed a slightly increased leukocyte infiltration into the CNS in the absence of NgR1 and NgR2, indicating that NgRs might be involved in the regulation of immune cell migration in the CNS. Our study demonstrates the urgent need for a more detailed knowledge on the multifunctional roles of ligands and receptors involved in CNS regeneration failure.
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PMID:Nogo-receptors NgR1 and NgR2 do not mediate regulation of CD4 T helper responses and CNS repair in experimental autoimmune encephalomyelitis. 2209 81


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