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)

Cell transplantation using bone marrow stromal cells (BMSCs) to alleviate neurological deficits has recently become the focus of research in regenerative medicine. Evidence suggests that secretion of various growth-promoting substances likely plays an important role in functional recovery against neurological diseases. In an attempt to identify a possible mechanism underlying the regenerative potential of BMSCs, this study investigated the production and possible contribution of neurotrophic factors by transected sciatic nerve defect in a rat model with a 15 mm gap. Cultured BMSCs became morphologically homogeneous with fibroblast-like shape after ex vivo expansion. We provided several pieces of evidence for the beneficial effects of implanted fibroblast-like BMSCs on sciatic nerve regeneration. When compared to silicone tube control animals, this treatment led to (i) improved walking behavior as measured by footprint analysis, (ii) reduced loss of gastrocnemius muscle weight and EMG magnitude, and (iii) greater number of regenerating axons within the tube. Cultured fibroblast-like BMSCs constitutively expressed trophic factors and supporting substances, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), collagen, fibronectin, and laminin. The progression of the regenerative process after BMSC implantation was accompanied by elevated expression of neurotrophic factors at both early and later phases. These results taken together, in addition to documented Schwann cell-like differentiation, provide evidence indicating the strong association of neurotrophic factor production and the regenerative potential of implanted BMSCs.
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PMID:Transplantation of bone marrow stromal cells for peripheral nerve repair. 1722 27

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor involved in the survival and proliferation of neurons. However, there have been few reports examining the relationship between GDNF and functional recovery after cerebral infarction. The authors investigated the change in the expression of GDNF proteins during functional recovery in rats following photochemically induced cerebral infarctions. Functional recovery for the first 14 days after the infarction was evaluated using a beam-walking test. The number of GDNF-like immunoreactive cells around the infarction were counted at various times (24 h, 72 h, 7 days, and 14 days) post-infarction. Immunohistochemical analysis of brain sections showed that the expression of GDNF-like immunoreactive cells was significantly increased in the temporal cortex until 7 days on the side ipsilateral to the infarction, and had decreased by 14 days. Likewise, the functional recovery of paralysis was substantial until 7 days post-infarction, after which the improvement was mild. Therefore, the expression of GDNF protein might have some relationship with the functional recovery of paralysis. There are great hopes that GDNF could be used as a therapeutic agent for cerebral infarction.
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PMID:Functional recovery and expression of GDNF seen in photochemically induced cerebral infarction. 1736 17

Accelerating axonal regeneration to shorten the delay of reinnervation and improve functional recovery after a peripheral nerve lesion is a clinical demand and an experimental challenge. We developed a resorbable nerve conduit (NC) for controlled release of glial cell line-derived neurotrophic factor (GDNF) with the aim of assessing motor functional recovery according to the release kinetics of this factor in a short gap model. Different types of resorbable NCs were manufactured from a collagen tube and multiple coating layers of poly(lactide-coglycolide), varying in poly(lactide-coglycolide) type and coating thickness to afford three distinct release kinetics of the neurotrophic factor. GDNF release was quantified in vitro. End-to-end suture and GDNF-free NC served as controls. Thirty-five Wistar rats underwent surgery. Motor recovery was followed from 1 to 12 weeks after surgery by video gait analysis. Morphometrical data were obtained at mid-tube level and distal to the NC. NCs were completely resorbed within 3 months with minimal inflammation. GDNF induced a threefold overgrowth of fibers at mid-tube level. However, the number of fibers was similar in the distal segment of all groups. The speed of recovery was inversely proportional to the number of fibers at the NC level but the level of recovery was similar for all groups at 3 months. The resorbable conduits proved their ability to modulate axonal regrowth through controlled release of GDNF. In relation to the dose delivered, GDNF strikingly multiplied the number of myelinated fibers within the NC but this increase was not positively correlated with the return of motor function in this model.
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PMID:Variations in glial cell line-derived neurotrophic factor release from biodegradable nerve conduits modify the rate of functional motor recovery after rat primary nerve repairs. 1776 90

Traumatic avulsion of spinal nerve roots causes complete paralysis of the affected limb. Reimplantation of avulsed roots results in only limited functional recovery in humans, specifically of distal targets. Therefore, root avulsion causes serious and permanent disability. Here, we show in a rat model that lentiviral vector-mediated overexpression of glial cell line-derived neurotrophic factor (GDNF) in reimplanted nerve roots completely prevents motoneuron atrophy after ventral root avulsion and stimulates regeneration of axons into reimplanted roots. However, over the course of 16 weeks neuroma-like structures are formed in the reimplanted roots, and regenerating axons are trapped at sites with high levels of GDNF expression. A high local concentration of GDNF therefore impairs long distance regeneration. These observations show the feasibility of combining neurosurgical repair of avulsed roots with gene-therapeutic approaches. Our data also point to the importance of developing viral vectors that allow regulated expression of neurotrophic factors.
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PMID:Neuroregenerative effects of lentiviral vector-mediated GDNF expression in reimplanted ventral roots. 1858 64

We investigated the safety and neuroregenerative potential of an adeno-associated virus (AAV2) containing human glial cell line-derived neurotrophic factor (GDNF) in an MPTP primate model of Parkinson's disease. Dopaminergic function was evaluated by positron emission tomography with 6-[(18)F]fluoro-l-m-tyrosine (FMT) before and after AAV2-GDNF or phosphate-buffered saline infusion bilaterally into the putamen. FMT uptake was significantly increased bilaterally in the putamen of AAV2-GDNF but not phosphate-buffered saline-treated animals 6 months after infusion, indicating increased dopaminergic activity in the nigrostriatal pathways. AAV2-GDNF-treated animals also showed clinical improvement without adverse effects. These findings are consistent with our previous report in aged nonhuman primates that showed evidence of enhanced use of striatal dopamine and dopaminergic nigrostriatal innervation. Clinical improvement and evidence of functional recovery in the nigrostriatal pathway, and the absence of adverse effects, support the safety of this approach for the delivery of GDNF over a 6-month period.
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PMID:Functional effects of AAV2-GDNF on the dopaminergic nigrostriatal pathway in parkinsonian rhesus monkeys. 1925 73

There is a clinical need to enhance functional recovery of injured peripheral nerves. Local administration of neurotrophic factors (NTFs) after surgical repair has been proposed for this purpose. Little is known, however, on the optimal local dose and dosing frequency of NTFs in a peripheral nerve defect. For increasing our knowledge on biologically relevant local NTFs concentrations and for making available an in vitro assay for assessing the bioactivity of NTFs in connection with implantable localized delivery systems, we developed in this study a bioassay for NTFs, which is based on dorsal root ganglion (DRG) explants from E9 (9 days old) chicken embryos. Axonal elongation and extent of axonal branching was analyzed microscopically after addition of glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF), each alone and in combination. GDNF significantly promoted axonal elongation, but only little axonal branching, whereas NGF induced extensive axonal branching with modest axonal elongation. The combination of GDNF and NGF exerted a synergistic effect on the axonal elongation, axonal branching and growth kinetics. GDNF and NGF also enhanced the expression of their respective functional receptors Ret and TrkA on the DRG neurons. This information should be relevant for the development of implants containing NTFs and on drug therapy of damaged peripheral nerves.
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PMID:Synergistic effect of GDNF and NGF on axonal branching and elongation in vitro. 1952 96

Reimplantation of avulsed rat lumbar spinal ventral roots results in poor recovery of function of the denervated hind limb muscles. In contrast, reimplantation of cervical or sacral ventral roots is a successful repair strategy that results in a significant degree of regeneration. A possible explanation for this difference could be that following lumbar root avulsion, axons have to travel longer distances towards their target muscles, resulting in prolonged denervation of the distal nerve and a diminished capacity to support regeneration. Here we present a detailed spatio-temporal analysis of motoneuron survival, axonal regeneration and neurotrophic factor expression following unilateral avulsion and implantation of lumbar ventral roots L3, L4, and L5. Reimplantation prolongs the survival of motoneurons up to one month post-lesion. The first regenerating motor axons entered the reimplanted ventral roots during the first week and large numbers of fibers gradually enter the lumbar plexus between 2 and 4 weeks, indicating that axons enter the reimplanted roots and plexus over an extended period of time. However, motor axon counts show that relatively few axons reach the distal sciatic nerve in the 16 week post-lesion period. The observed initial increase and subsequent decline in expression of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor correlate with the apparent spatio-temporal decline in the regenerative capacity of motor axons, indicating that the distal nerve is losing its capacity to support regenerating motor axons following prolonged denervation. These findings have important implications for future strategies to promote long-distance regeneration through distal, chronically denervated peripheral nerves.
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PMID:A spatio-temporal analysis of motoneuron survival, axonal regeneration and neurotrophic factor expression after lumbar ventral root avulsion and implantation. 1964 36

Neural progenitor cells (NPCs) and bone marrow stromal cells (BMSCs), both of which can differentiate into neural phenotypes, are important candidates for transplantation therapy in the central nervous system (CNS). In most cases of BMSC transplantation, functional recovery is recognized even if few transplanted cells survive in the host tissue. A reason for this may be that transplanted cells produce neurotrophic factors (NFs), which enhance neuronal survival and neurite outgrowth after CNS injury. To provide additional insight into cell therapy, we investigated the types of NFs and receptors that are expressed in NPCs and BMSCs in vitro. Both cells expressed the mRNA of nerve growth factor (NGF), cilliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), and their receptors in the proliferative state. Real-time PCR analysis showed that mRNA expression of GDNF was relatively low in NPCs although its receptor was highly expressed. We thus tested if the overexpression of GDNF in NPCs affected neural differentiation without FGF-2. The overexpression of GDNF did not affect mRNA expression of beta-III tubulin and neuron specific enolase (NSE), but both GDNF and GFRalpha1 overexpression increased the expression of neuronal markers. These results suggest that augmentation of both GDNF and GFRalpha1 could have positive effects during neural tissue repair.
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PMID:Co-overexpression of GDNF and GFRalpha1 induces neural differentiation in neural progenitor cells in comparison to bone marrow stromal cells. 1984 57

Incomplete recovery of function and neuropathic pain are common problems after peripheral nerve injury. To develop new treatment strategies for peripheral nerve injuries we investigated whether the neurotrophic factor artemin could improve outcome after sciatic nerve injuries in rats. Artemin is a member of the glial cell line-derived neurotrophic factor (GDNF) family and exerts neuroprotective effects on sensory neurons as well as influencing behavioural thermal sensitivity. We additionally evaluated if fibrin sealant, which is sometimes used as a nerve glue, had any effects on neuropathic pain-related behaviour. After the sciatic nerve had been transected, 30 animals were randomised to one of three groups: treatment with a fibrin sealant that contained artemin in conjunction with sutures; fibrin sealant with no artemin (sham) in conjunction with sutures; or sutures alone (n=10 in each group). Motor function, sensory function, and autotomy were evaluated from 1 to 12 weeks after injury. Retrograde flourogold tracing 12 weeks after injury showed that the addition of artemin increased the number of regenerating motor neurons. However, it did not improve their performance, as measured by the Sciatic Function Index, compared with sham or suture alone. Animals treated with artemin had a non-significant increase in motor nerve conduction velocity compared with sham. However, artemin did not reverse nerve injury-induced pain behaviour such as cold or heat hypersensitivity. Fibrin sealant in itself did not ameliorate motor performance, or regeneration of motor neurons, or give rise to nerve injury-induced pain behaviour. The results indicate that artemin is of value as a treatment for peripheral nerve injuries, although the effects were limited. As the artemin high-affinity receptor GFRalpha-3 is present in Schwann cells and not in motor neurons, the effect on motor neuron axon regeneration may result from an indirect effect through Schwann cells in the injured nerve.
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PMID:Treatment of transected peripheral nerves with artemin improved motor neuron regeneration, but did not reduce nerve injury-induced pain behaviour. 1986 26

Because there currently is no treatment for spinal cord injury, most patients are living with long-standing injuries. Therefore, strategies aimed at promoting restoration of function to the chronically injured spinal cord have high therapeutic value. For successful regeneration, long-injured axons must overcome their poor intrinsic growth potential as well as the inhibitory environment of the glial scar established around the lesion site. Acutely injured axons that regenerate into growth-permissive peripheral nerve grafts (PNGs) reenter host tissue to mediate functional recovery if the distal graft-host interface is treated with chondroitinase ABC (ChABC) to cleave inhibitory chondroitin sulfate proteoglycans in the scar matrix. To determine whether a similar strategy is effective for a chronic injury, we combined grafting of a peripheral nerve into a highly relevant, chronic, cervical contusion site with ChABC treatment of the glial scar and glial cell line-derived neurotrophic factor (GDNF) stimulation of long-injured axons. We tested this combination in two grafting paradigms: (1) a peripheral nerve that was grafted to span a chronic injury site or (2) a PNG that bridged a chronic contusion site with a second, more distal injury site. Unlike GDNF-PBS treatment, GDNF-ChABC treatment facilitated axons to exit the PNG into host tissue and promoted some functional recovery. Electrical stimulation of axons in the peripheral nerve bridge induced c-Fos expression in host neurons, indicative of synaptic contact by regenerating fibers. Thus, our data demonstrate, for the first time, that administering ChABC to a distal graft interface allows for functional axonal regeneration by chronically injured neurons.
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PMID:Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord. 1994 Jan 84


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