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)

Axonal demyelination is a critical pathological phenomenon associated with spinal cord injury and multiple sclerosis (MS). Previous studies demonstrated that 4-Aminopyridine, a fast potassium channel blocker, enhances impulse conduction on damaged and/or demyelinated axons, allowing for functional recovery in spinal cord injuries and MS, but with severe therapeutic limitations. To continue to explore the therapeutic value of blocking fast potassium channels while circumventing the side effects of 4-AP, we have developed three novel 4-AP derivatives that enhance impulse conduction in spinal cord trauma. In the current study, we have shown that one of these three derivatives, N-(4-pyridyl) methyl carbamates (MC), significantly inhibits a fast, I(A) like potassium current in guinea pig dorsal root ganglion cells in a whole cell patch clamp configuration. This inhibition of I(A) likely plays a critical role in MC's ability to restore conduction in mechanically injured spinal cord axons and may present a viable alternative to 4-AP for individuals with spinal cord injury or MS. From this, compounds with greater efficacy and perhaps less side effects will likely emerge in the near future, which will greatly enhance the functional restoration and lessen the suffering of SCI and MS patients.
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PMID:N-(4-pyridyl) methyl carbamate inhibits fast potassium currents in guinea pig dorsal root ganglion cells. 1904 86

We describe some of our studies on use of neuro-restorative agents for treatment of neural injury. We focus on cell-based therapies and select from a variety of statins. In addition, we show that cell-based and pharmacological-based therapies enhance brain plasticity and promote recovery of function after stroke and intracerebral hemorrhage (ICH). Injured brain recapitulates ontogeny. Cerebral tissue around the infarction expresses developmental genes, many of which are present only during embryonic or neonatal stages of development. Brain response to injury undergoes remodeling with induction of angiogenesis, neurogenesis, and synaptogenesis. The attempt at remodeling, although expressed as a partial improvement in patients with stroke and ICH, is clearly insufficient to promote substantial recovery in many patients. The goal of restorative therapies should be to activate and amplify this endogenous restorative brain plasticity process to potentiate functional recovery. The logic of restorative therapy is to treat intact or marginally compromised tissue and not injured or dying tissue. Thus, these treatments can be made available for all neurological injury. Once demonstrated to be effective for treatment of a large middle cerebral artery occlusion (MCAo), these restorative treatments can be applied to many types of injury, including ICH, traumatic brain injury, and neurodegenerative disease such as experimental autoimmune encephalomyelitis and multiple sclerosis.
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PMID:Treatment of stroke and intracerebral hemorrhage with cellular and pharmacological restorative therapies. 1906 87

Extracts of Chinese herb Tripterygium wilfordii Hook. f. (TWHF) have been found to have potent anti-inflammatory and immunosuppressive functions and widely used in China for treatment of rheumatoid arthritis. Also they have been considered to be the potential drugs in the treatment of tumor and acute graft rejections. With the progress of neuroimmunological research on neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson disease (PD) and multiple sclerosis (MS), the neuroprotective strategies to rescue neurons from immunological injury are currently being explored. Recently, studies have indicated that extracts of TWHF such as triptolide, tripchlorolide and (5R)-5-hydroxytriptolide are able to attenuate progression of these neuroimmunologic disorders in vitro and in vivo. Accumulating evidence has shown that they can promote neuronal survival and neurite growth and facilitate functional recovery of brain injury by invoking distinct mechanisms that are related to their neuroprotective roles as inhibitor of neuroinflammatory toxicity of activated-microglia, antioxidants, calcium channel blockers, neurotrophic actions, modulating T cell functions, inhibitor of transcriptional activation of NF-kappaB on genes and signaling. Significant pharmaceutical strategies against neuroimmunologic disorders will hopefully be discovered by understanding the valuable components of TWHF.
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PMID:[Advances in the study of immunopharmacological effects and mechanisms of extracts of Tripterygium wilfordii Hook. f. in neuroimmunologic disorders]. 1924 46

Human neurological disorders such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, multiple sclerosis (MS), stroke, and spinal cord injury are caused by a loss of neurons and glial cells in the brain or spinal cord. Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. In recent years, neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells, mesenchymal stem cells, and neural stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable experimental and preclinical studies previously published involving stem cell-based cell and gene therapies for Parkinson's disease, Huntington's disease, ALS, Alzheimer's disease, MS, stroke, spinal cord injury, brain tumor, and lysosomal storage diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. There are still many obstacles to be overcome before clinical application of cell therapy in neurological disease patients is adopted: 1) it is still uncertain what kind of stem cells would be an ideal source for cellular grafts, and 2) the mechanism by which transplantation of stem cells leads to an enhanced functional recovery and structural reorganization must to be better understood. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.
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PMID:Stem cell-based cell therapy in neurological diseases: a review. 1930 31

Remyelination of the CNS in multiple sclerosis is thought to be important to restore conduction and protect axons against degeneration. Yet the role that remyelination plays in clinical recovery of function remains unproven. Here, we show that cats fed an irradiated diet during gestation developed a severe neurologic disease resulting from extensive myelin vacuolation and subsequent demyelination. Despite the severe myelin degeneration, axons remained essentially intact. There was a prompt endogenous response by cells of the oligodendrocyte lineage to the demyelination, with remyelination occurring simultaneously. Cats that were returned to a normal diet recovered slowly so that by 3-4 months they were neurologically normal. Histological examination of the CNS at this point showed extensive remyelination that was especially notable in the optic nerve where almost the entire nerve was remyelinated. Biochemical analysis of the diet and tissues from affected cats showed no dietary deficiencies or toxic accumulations. Thus, although the etiology of this remarkable disease remains unknown, it shows unequivocally that where axons are preserved remyelination is the default pathway in the CNS in nonimmune-mediated demyelinating disease. Most importantly, it confirms the clinical relevance of remyelination and its ability to restore function.
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PMID:Extensive remyelination of the CNS leads to functional recovery. 1934 94

Cell therapy appears as an exciting strategy for myelin repair in pathologies where oligodendrocytes are deficient or impaired, such as leucodystrophies and multiple sclerosis. Many studies indicate that several types of rodent cells, including neural stem and progenitor cells, play a beneficial role after grafting and induce functional recovery in animal models of myelin disorders. However, the difficulties to commit human neural stem cells towards the oligodendroglial lineage have long hampered human cell-based therapy for these diseases. In this review, we present recent advances in the field and discuss the various strategies that helped overcome the challenge of human oligodendroglial differentiation.
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PMID:In search of human oligodendroglia for myelin repair. 1942 45

In the present study, we hypothesized that thymosin beta 4 (Tbeta4) is a potential therapy of multiple sclerosis (MS). To test this hypothesis, SJL/J mice (n=21) were subjected to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE mice were treated with saline or Tbeta4 (6 mg/kg, n=10) every 3 days starting on the day of myelin proteolipid protein (PLP) immunization for total five doses. Neurological function, inflammatory infiltration, oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes were measured in the brain of EAE mice. Double immunohistochemical staining was used to detect proliferation and differentiation of OPCs. Tbeta4 was used to treat N20.1 cells (premature oligodendrocyte cell line) in vitro, and proliferation of N20.1 cells was measured by bromodeoxyuridine (BrdU) immunostaining. Tbeta4 treatment improved functional recovery after EAE. Inflammatory infiltrates were significantly reduced in the Tbeta4 treatment group compared to the saline groups (3.6+/-0.3/slide vs 5+/-0.5/slide, P<0.05). NG2(+) OPCs (447.7+/-41.9 vs 195.2+/-31/mm(2) in subventricular zone (SVZ), 75.1+/-4.7 vs 41.7+/-3.2/mm(2) in white matter), CNPase(+) mature oligodendrocytes (267.5+/-10.3 vs 141.4+/-22.9/mm(2)), BrdU(+) with NG2(+) OPCs (32.9+/-3.7 vs 17.9+/-3.6/mm(2)), BrdU(+) with CNPase(+) mature oligodendrocytes (18.2+/-1.7 vs 10.7+/-2.2/mm(2)) were significantly increased in the Tbeta4 treated mice compared to those of saline controls (P<0.05). These data indicate that Tbeta4 treatment improved functional recovery after EAE, possibly, via reducing inflammatory infiltrates, and stimulating oligodendrogenesis.
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PMID:Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis. 1978 21

Axonal dysfunction as a result of persistent demyelination has been increasingly appreciated as a cause of functional deficit in demyelinating diseases such as multiple sclerosis. Therefore, it is crucial to understand the ultimate causes of ongoing axonal dysfunction and find effective measures to prevent axon loss. Our findings related to functional deficit and functional recovery of axons from a demyelinating insult are important preliminary steps towards understanding this issue. Cuprizone diet for 3-6 wks triggered extensive corpus callosum (CC) demyelination, reduced axon conduction, and resulted in loss of axon structural integrity including nodes of Ranvier. Replacing cuprizone diet with normal diet led to regeneration of myelin, but did not fully reverse the conduction and structural deficits. A shorter 1.5 wk cuprizone diet also caused demyelination of the CC, with minimal loss of axon structure and nodal organization. Switching to normal diet led to remyelination and restored callosal axon conduction to normal levels. Our findings suggest the existence of a critical window of time for remyelination, beyond which demyelinated axons become damaged beyond the point of repair and permanent functional loss follows. Moreover, initiating remyelination early within the critical period, before prolonged demyelination-induced axon damage ensues, will improve functional axon recovery and inhibit disease progression.
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PMID:Functional recovery of callosal axons following demyelination: a critical window. 1980 Sep 49

In the CNS oligodendrocytes produce myelin and ensheath individual axons after birth. Demyelination disables saltatory conduction and leads to loss of neural functions. Oligodendrocyte precursor cells (OPCs) are immature and abundant reservoir cells in the adult brain that are capable of differentiating into myelinating oligodendrocytes. Upon demyelination insults, OPCs are spontaneously induced to differentiate in order to remyelinate denuded axons and promote functional recovery. While remyelination is an efficient regenerative process in the CNS, it often fails in the chronic phase of multiple sclerosis (MS). OPCs are nonetheless preserved in many MS lesions, suggesting that arrested OPC differentiation underlies remyelination failure in chronic MS. Understanding the molecular pathology of this arrested differentiation and remyelination failure in chronic MS is critical for developing remyelination medicines that will promote a full functional recovery in these patients. Recently, TIP30 was identified as an inhibitor of OPC differentiation in MS. TIP30 inhibits proper nucleocytoplasmic transport and thus disables nuclear import of transcription factors that are required for differentiation. TIP30 may also increase susceptibility of OPCs to cell death. In this review, we examine the pathophysiological nature of remyelination failure in chronic MS and discuss the role of TIP30 as a novel therapeutic target.
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PMID:Factors that retard remyelination in multiple sclerosis with a focus on TIP30: a novel therapeutic target. 1983 15

Inflammatory response following central nervous system (CNS) injury contributes to progressive neuropathology and reduction in functional recovery. Axons are sensitive to mechanical injury and toxic inflammatory mediators, which may lead to demyelination. Although it is well documented that degenerated myelin triggers undesirable inflammatory responses in autoimmune diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), there has been very little study of the direct inflammatory consequences of damaged myelin in spinal cord injury (SCI), i.e., there is no direct evidence to show that myelin debris from injured spinal cord can trigger undesirable inflammation in vitro and in vivo. Our data showed that myelin can initiate inflammatory responses in vivo, which is complement receptor 3 (CR3)-dependent via stimulating macrophages to express pro-inflammatory molecules and down-regulates expression of anti-inflammatory cytokines. Mechanism study revealed that myelin-increased cytokine expression is through activation of FAK/PI3K/Akt/NF-kappaB signaling pathways and CR3 contributes to myelin-induced PI3K/Akt/NF-kappaB activation and cytokine production. The myelin induced inflammatory response is myelin specific as sphingomyelin (the major lipid of myelin) and myelin basic protein (MBP, one of the major proteins of myelin) are not able to activate NF-kappaB signaling pathway. In conclusion, our results demonstrate a crucial role of myelin as an endogenous inflammatory stimulus that induces pro-inflammatory responses and suggest that blocking myelin-CR3 interaction and enhancing myelin debris clearance may be effective interventions for treating SCI.
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PMID:Myelin activates FAK/Akt/NF-kappaB pathways and provokes CR3-dependent inflammatory response in murine system. 2018 38


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