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)

Successful peripheral nerve regeneration and functional recovery require the reestablishment of the neuron-Schwann cell relationship in the regenerating rat sciatic nerve, neurons differentially regulate Schwann cell genes. The message for the low-affinity NGF receptor, p75NGFR, is induced in Schwann cells distal to the injury and is repressed as regenerating axons make contact with these cells. The inverse is true for mRNA of the myelin gene P0; expression decreases distal to injury and increases as new axons contact Schwann cells and a program of myelination is initiated. Using an in vitro co-culture paradigm in which primary neurons and adult Schwann cells are separated by a microporous membrane, we show that axon contact is not an absolute requirement for neuronal regulation of Schwann cell genes. In this system neurons but not other cell types, repress the expression of Schwann cell p75NGFR while inducing the expression of the POU domain transcription factor, suppressed cAMP inducible POU, and myelin P0. These results demonstrate that regenerating axons can direct the Schwann cell genetic program from a distance through diffusible molecules.
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PMID:Neurons regulate Schwann cell genes by diffusible molecules. 840 2

Although central neurons do not naturally recover following injury, damaged adult septal neurons can regenerate when nerve growth factor (NGF) is provided along with a suitable cellular substrate. This study investigates the outgrowth of axotomized septal neurons grafted with primary fibroblasts genetically modified to produce NGF. Confocal microscope images of double staining for neuritic markers (neurofilament or low-affinity NGF receptor) and the astrocytic marker glial fibrillary acidic protein (GFAP) demonstrated that regenerating neurites crossed dense buildups of astrocytic processes at the edges of NGF-producing grafts and were in apposition with astrocytic processes within NGF-producing grafts. Immunoreactivity for acetylcholinesterase and low-(p75) and high-affinity (TrkA) NGF receptors was dense in NGF-producing grafts but absent in control grafts. NGF-grafted rats exhibited significantly increased hippocampal density of p75-immunoreactive fibers and significantly decreased ectopic hippocampal sympathetic ingrowth as compared to control-grafted rats. Rats with unilateral fimbria-fornix lesions and NGF-producing grafts exhibited ameliorated performance on a simple memory task. These findings demonstrate that implantation of NGF-producing grafts to the lesion cavity allows axotomized septal cholinergic neurons to reinnervate the hippocampus, and that rats receiving these grafts show a partial recovery of function.
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PMID:Axonal regeneration and limited functional recovery following hippocampal deafferentation. 884 6

Schwann cells in the distal stump of injured peripheral nerves synthesize the low affinity nerve growth factor receptor (p75). In this study we used short-term (1 week) and long-term (1-12 months) transected distal sciatic nerves of rats to determine the variations of p75 expression by using immunocytochemistry and in situ hybridization. Semi-quantitative analysis revealed that the synthesis of the protein product of the p75 gene is rapidly enhanced to reach a peak within the 1 month after denervation. After that it gradually decreased and was barely detectable 6 months following denervation. Double immunocytochemistry for p75 and the S100 protein revealed that p75 immunoreactivity is confined to the Schwann cells. Quantitative analysis of our in situ hybridization experiments revealed that the upregulation of the p75 mRNA parallels the enhanced synthesis of the corresponding protein and reaches a peak within 1 month, which is maintained until the second month after the transection and declines thereafter to reach background levels at 4 months. The electron microscopic observations reveal that the increase in the number of nuclei in the distal stump belong to severely atrophied Schwann cells and fibroblasts. Since the presence of p75 in the Schwann cells is necessary for reinnervation, our results indicate that, based on the expression of p75, the Schwann cells will provide a most suitable environment for the regenerating axons up to the first month. At later stages the ability of the Schwann cells to synthesize p75 and cell adhesion proteins such as N-CAM and GAP 43 decreases which may be one of the factors that contribute to poor functional recovery if the regenerating axons reach the distal stump after long periods of time.
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PMID:The expression of the low affinity nerve growth factor receptor in long-term denervated Schwann cells. 917 94

Apoptosis is an important cause of secondary cell death in spinal cord injury (SCI). SCI induces the expression of the low affinity neurotrophin receptor p75 (p75NTR), that in the absence of the high affinity component, TrkA, can promote cell death by apoptosis. We therefore hypothesized that a reduction of p75NTR expression in SCI may increase tissue sparing and therefore improve recovery of function. As a tool to test our hypothesis we used the synthetic glucocorticoid dexamethasone (DEX) to down-regulate p75NTR expression. A standardized thoracic spinal cord contusion injury was produced in female rats. Laminectomized and SCI rats received various doses of DEX immediately after injury and the treatment was continued daily for 7 days. DEX, given at high doses (20 mg/kg, s.c.) but not at low doses (1 or 8 mg/kg) prevented the increase in p75NTR mRNA and protein in SCI rats, without affecting the expression of TrkA. High doses of DEX also reduced cellular apoptosis both in white and gray matters. This effect correlated with the ability of DEX to accelerate behavioral recovery of function measured by a combined behavioral score. These data suggest that reduction of p75NTR in SCI may be a therapeutic strategy to limit cell and tissue damage and therefore to improve recovery of function in SCI patients.
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PMID:Dexamethasone reduces the expression of p75 neurotrophin receptor and apoptosis in contused spinal cord. 1122 60

Neural-like cells derived from bone marrow stromal cells (BMSC) have potential usefulness in repair of the CNS injuries or diseases. The functional recovery mediated by these cells, however, depends on secretion of specific growth factors and their designated receptors. In the present study, we have investigated the expression profile of neurotrophins NGF, BDNF and NT-3 and their high-affinity (TrkA, TrkB, TrkC) and common low-affinity (p75NTR) receptors before and during neural differentiation of rat BMSCs by RT-PCR. Results indicate that NGF and BDNF but not NT-3 are expressed in both un-differentiated as well as neurally differentiated BMSCs. In contrast, the expression of TrkA and TrkB is restricted to neurally differentiated cells, while TrkC is not expressed in these cells either before or after differentiation. Interestingly, p75NTR expression is absent in un-differentiated cells but is initiated upon the induction of neural differentiation, and then shut off in fully differentiated neuron-like cells.
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PMID:Differential gene expression pattern of neurotrophins and their receptors during neuronal differentiation of rat bone marrow stromal cells. 1638 45

In our previous studies, we demonstrated that intraperitoneal (i.p.) injections with the neurotransmitter/neuromodulatory peptide Cholecystokinin-8 (CCK-8) stimulate the synthesis of the neurotrophin nerve growth factor (NGF) resulting in the structural and functional recovery of neuronal damage. This neurotrophin-mediated neuroprotective action of CCK-8 has opened a new perspective for a better understanding of the CCK neurobiological and pharmacological properties. To explore the possible beneficial effects of the CCK-induced increase of neurotrophin availability in brain, we compared the effects of i.p. CCK-8 in healthy rats and in a chemical kindling model using a subconvulsive dose of pentylenetetrazol (PTZ). Behavioural changes were monitored during treatment and classified according to a six-point scale. After 3 weeks of treatment (12 trials), the PTZ group of rats manifested generalized clonic-tonic seizures (Class 5 behaviour). For this reason, this time point was chosen to compare the effects of CCK-8 treatment on the expression of NGF, the brain derived neurotrophin factor (BDNF) and their receptors in the septum and hippocampus. We found that repeated i.p. injections with CCK-8 in adult rats result in: (1) an increase of NGF and BDNF protein and mRNA levels in the septum and hippocampus; (2) a down-regulation of TrkA and p75NTR and an up-regulation of TrkB; (3) reduced susceptibility to develop chemical kindling; (4) recovery of the PTZ-induced changes in the expression of neurotrophin receptors in the septal and hippocampal tissues. This data clearly indicates that CCK-induced variation of neurotrophin synthesis in brain is able to influence the susceptibility to develop seizures in adult rats most probably by counteracting the progressive neuronal dysfunction and/or damage.
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PMID:CCK-8 induces NGF and BDNF synthesis and modulates TrkA and TrkB expression in the rat hippocampus and septum: Effects on kindling development. 1696 63

Transplantation of neural stem cell (NSC)-derived dopamine (DA) neurons is associated with low survival of cells, which could be due to limited striatal innervations and uneven distribution of graft because of its dense neuronal core, limited host-graft interaction, poor axonal outgrowth, lack of continuous neurotrophic factors supply, and an absence of cell adhesion molecules mediated appropriate developmental cues. Olfactory ensheathing cells (OEC) express a variety of growth factors and cell adhesion molecules and promote axonal regrowth and functional recovery in spinal cord injury in animal models and patients. In the present study, we explored the possibility to increase the survival, function, axonal outgrowth and striatal reinnervation of NSC by co-grafting with OEC in 6-OHDA lesioned parkinsonian rats. In the presence of OEC, significantly enhanced survival of NSC-derived DA neurons and axonal fiber outgrowth was evident in the striatum of NSC+OEC co-grafted rats at 24 weeks post-grafting as compared with NSC alone grafted rats. The increased survival of NSC and their striatal reinnervation was further manifested in the form of significant and substantial restitution of motor function and neurochemical recovery in the co-grafted group. Significant enhanced expression of p75NTR (from OEC) and tyrosine hydroxylase (TH) (from NSC) confirmed the co-localization and survival of both types of cells at the transplantation site in co-grafted rats. Co-grafting results co-related well with our in vitro studies, which suggest that OEC not only significantly increase survival, neurite outgrowth and DA release of NSC-derived DA neuron but also protect against 6-OHDA neurotoxicity in co-culture conditions. These results collectively suggest that OEC increase the survival and function of transplanted NSC in 6-OHDA lesioned parkinsonian rats.
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PMID:Enhanced survival and function of neural stem cells-derived dopaminergic neurons under influence of olfactory ensheathing cells in parkinsonian rats. 1922 7

The central nervous system (CNS) does not regenerate partly due to the slow clearance of debris from the degenerated myelin sheath by Wallerian degeneration. The mechanism underlying the inefficiency in myelin clearance is not clear. Here we showed that endogenous proBDNF may inhibit the infiltration of ED1+ inflammatory cells after spinal cord injury. After injury, proBDNF and its receptors sortilin and p75NTR are expressed in the spinal cord as determined by Western blots and immunocytochemistry. ProBDNF and mature BDNF were released from macrophages in vitro. Macrophages in vivo (ED1+) and isolated in vitro (CD11b+) express moderate levels of proBDNF, sortilin and p75NTR. ProBDNF suppressed the migration of isolated macrophages in vitro and the antibody to proBDNF enhanced the migration. Suppression of proBDNF in vivo by administering the antiserum to the prodomain of BDNF after spinal cord injury (SCI) increased the infiltration of macrophages and increased number of neurons in the injured cord. BBB tests showed that the treatment of the antibody to proBDNF improved the functional recovery after spinal cord injury. Our data suggest that proBDNF is a suppressing factor for macrophage migration and infiltration and may play a detrimental role after SCI.
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PMID:ProBDNF inhibits infiltration of ED1+ macrophages after spinal cord injury. 2008 90

Repair of injured peripheral nerve is thought to play important roles in tissue homeostasis and regeneration. Recent experiments have demonstrated enhanced functional recovery of damaged neurons by some types of somatic stem cells. It remains unclear, however, if periodontal ligament (PDL) stem cells possess such functions. We recently developed a multipotent clonal human PDL cell line, termed cell line 1-17. Here, we investigated the effects of this cell line on neurocytic differentiation, migration, and survival. This cell line expressed the neural crest cell marker genes Slug, SOX10, Nestin, p75NTR, and CD49d and mesenchymal stem cell-related markers CD13, CD29, CD44, CD71, CD90, CD105, and CD166. Rat adrenal pheochromocytoma cells (PC12 cells) underwent neurocytic differentiation when co-cultured with cell line 1-17 or in conditioned medium from cell line 1-17 (1-17CM). ELISA analysis revealed that 1-17CM contained approximately 50 pg/ml nerve growth factor (NGF). Cell line 1-17-induced migration of PC12 cells, which was inhibited by a neutralizing antibody against NGF. Furthermore, 1-17CM exerted antiapoptotic effects on differentiated PC12 cells as evidenced by inhibition of neurite retraction, reduction in annexin V and caspase-3/7 staining, and induction of Bcl-2 and Bcl-xL mRNA expression. Thus, cell line 1-17 promoted neurocytic differentiation, migration, and survival through secretion of NGF and possibly synergistic factors. PDL stem cells may play a role in peripheral nerve reinnervation during PDL regeneration.
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PMID:A multipotent clonal human periodontal ligament cell line with neural crest cell phenotypes promotes neurocytic differentiation, migration, and survival. 2175 Dec 15

Many people infected with the human immunodeficiency virus type-1 (HIV) exhibit mild or severe neurological problems, termed HIV-associated neurocognitive disorder (HAND), even when receiving antiretroviral therapy. Thus, novel adjunctive therapies must be developed to overcome the neurotoxic effect of HIV. New therapies require a better understanding of the molecular and cellular mechanisms of HIV-induced neurotoxicity and the risk factors that, besides inflammation and T-cell depletion and drugs of abuse, render the central nervous system (CNS) a target of HIV-induced neurotoxicity. HIV appears to impair neuronal plasticity, which refers to the innate ability of the CNS respond to injury and promote recovery of function. The availability of brain-derived neurotrophic factor (BDNF), a potent neurotrophic factor that is present in abundance in the adult brain, is essential for neuronal plasticity. BDNF acts through a receptor system composed of Trk and p75NTR. Here, we present experimental evidence that some of the clinical features of HIV-mediated neurological impairment could result from altered BDNF/TrkB/p75NTR regulation and function.
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PMID:Synaptic dysfunction in human immunodeficiency virus type-1-positive subjects: inflammation or impaired neuronal plasticity? 2360 Apr


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