Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glial cell line-derived neurotrophic factor (GDNF) has been shown to rescue developing motoneurons in vivo and in vitro from both naturally occurring and axotomy-induced cell death. To test whether GDNF has trophic effects on adult motoneurons, we used a mouse model of injury-induced adult motoneuron degeneration. Injuring adult motoneuron axons at the exit point of the nerve from the spinal cord (avulsion) resulted in a 70% loss of motoneurons by 3 weeks following surgery and a complete loss by 6 weeks. Half of the loss was prevented by GDNF treatment. GDNF also induced an increase (hypertrophy) in the size of surviving motoneurons. These data provide strong evidence that the survival of injured adult mammalian motoneurons can be promoted by a known neurotrophic factor, suggesting the potential use of GDNF in therapeutic approaches to adult-onset motoneuron diseases such as amyotrophic lateral sclerosis.
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PMID:Rescue of adult mouse motoneurons from injury-induced cell death by glial cell line-derived neurotrophic factor. 756 15

Glial cell line-derived neurotrophic factor (GDNF) has been postulated to be a specific dopaminergic neurotrophic factor since it selectively enhances the survival of dopaminergic neurones in vitro. We report here that GDNF can also act as a neurotrophic factor for motoneurones. GDNF released by GDNF-transfected BHK cells increases the activity of choline acetyltransferase (ChAT) in cultures from embryonic rat ventral mesencephalon containing cholinergic neurones from cranial motor nuclei and in cultured spinal motoneurones. Furthermore, local application of polymer-encapsulated BHK cells releasing GDNF to transected facial nerve in newborn rats diminishes the death of motoneurones normally occurring after axotomy in the neonatal period. The present results indicate that GDNF may have a therapeutic potential in human motoneurone diseases such as amyotrophic lateral sclerosis.
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PMID:Glial cell line-derived neurotrophic factor (GDNF), a new neurotrophic factor for motoneurones. 770 97

Glial cell line-derived neurotrophic factor (GDNF), a member of the TG F-beta superfamily, has been shown to be a highly potent neurotrophic factor that enhances survival of various neuronal cell types including motoneurons. To assess its therapeutic potential in treating neurodegenerative diseases such as amyotrophic lateral sclerosis, we treated mutant mice displaying motoneuron degeneration (progressive motor neuropathy; pmn) with encapsulated GDNF-secreting cells. Effects of GDNF treatment on pmn/pmn mice were compared with previous results obtained with ciliary neurotrophic factor (CNTF) [Sagot Y, Tan SA, Baetge E, Schmalbruch H, Kato AC, Aebischer P (1995) Eur J Neurosci 7:1313-1322]. In contrast to CNTF, GDNF did not increase the lifespan of pmn/pmn mice. However, GDNF significantly reduced the loss of facial motoneurons by 50%, a value similar to what was observed when CNTF was administered to the pmn/pmn mice. Surprisingly, myelinated axon counts revealed that GDNF had no effect on nerve degeneration. Therefore, despite its potential in rescuing motoneuron cell bodies, the inability of GDNF to prevent nerve degeneration in pmn/pmn mice suggests that its usefulness in the treatment of motor neuron diseases may be restricted to cotreatment with other factors that act on the nerve process.
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PMID:GDNF slows loss of motoneurons but not axonal degeneration or premature death of pmn/pmn mice. 860 13

We have previously shown that glial cell line-derived neurotrophic factor (GDNF), in addition to promoting the survival of dopaminergic neurons in cultures from embryonic rat ventral mesencephalon,also increases the activity of choline acetyltransferase (ChAT) in the cranial motoneurons present in these cultures (Zurn et al.: Neuroreport 6:113-118, 1994). By using the intermediate filament protein peripherin as a motoneuron marker, we report here that GDNF increases the number of motoneurons as well as the length of their neurites. Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) also promote ChAT activity, motoneuron survival, and neurite outgrowth in these cultures, but to varying degrees. Although these three molecules have similar effects on cultured motoneurons, we provide evidence for a distinct mode of action of GDNF, BDNF, and CNTF, since combinations of GDNF and BDNF, GDNF and CNTF, and BDNF and CNTF have either additive or synergistic effects on ChAT activity and motoneuron number. In addition to the previously described motoneuron-specific neurotrophic factors BDNF and CNTF, GDNF combined with the latter two factors may provide an important tool for the treatment of human motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy, both by increasing efficiency of treatment, and by decreasing the likelihood of deleterious side-effects.
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PMID:Combined effects of GDNF, BDNF, and CNTF on motoneuron differentiation in vitro. 872 21

A rapid and reproducible spinal motor neuron death occurs after sciatic nerve transection in neonatal rats. This neuronal death could be due to lack of retrogradely transported target derived neurotrophic factors, such as ciliary neurotrophic factor, brain-derived neurotrophic factor, leukemia inhibitory factor and glial cell line-derived neurotrophic factor. Another hypothesis suggests that glutamate and its receptors has been implicated as possible mechanism for motor neuron death. In order to investigate the effect of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on axotomy-induced cell death in the spinal motor neurons of neonatal rats, we have studied neuroprotective effects of these receptor antagonists. Newborn rats were anesthetized with hypothermia. Sciatic nerve was transected near the obturator tendon in the left thigh. Animals were then treated daily with MK-801, APV, and CNQX for 14 days with intraperitoneal injections. Control animals received PBS in the same fashion. After the treatment, the number of spinal motor neurons in the L4-6 was counted. MK-801 and APV did not show any significant neuroprotective effect. By contrast, the number of surviving motor neurons was greater in animals that were treated with 1.0, 2.0 and 4.0 mg/kg of CNQX. This neuroprotective effect was not dose-related. We demonstrate that neuroprotective effect of CNQX on axotomized motor neurons, raises a possibility that such a agent may have therapeutic potential in motor neuronopathy and amyotrophic lateral sclerosis.
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PMID:CNQX prevents spinal motor neuron death following sciatic nerve transection in newborn rats. 874 38

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for several neuronal populations involved in motor control. The present study evaluates the trophic actions of GDNF on corticospinal neurons, an important central nervous system motor projection into the spinal cord. Death of spinal motoneurons and corticospinal neurons is observed in the neurodegenerative disease amyotrophic lateral sclerosis. Axotomy of adult rat corticospinal neurons at internal capsule levels induces half of them to die, and the surviving population displays severe atrophy. To examine the trophic effects of GDNF on corticospinal neurons, Fast Blue-labelled corticospinal neurons were stereotaxically axotomized at internal capsule levels and GDNF was infused intracortically to lesioned corticospinal neurons at total doses of 2, 4, 10, 20, 40, 100 and 300 microg for 7 days. GDNF prevented axotomy-induced death of corticospinal neurons at doses between 2 and 40 microg and abolished or attenuated their atrophy at all doses examined. In addition, treatment with 8 microg GDNF for the first 2 weeks after axotomy resulted in the long-term survival of corticospinal neurons for 42 days. With regard to the development of treatment strategies for upper motoneuron degeneration in amyotrophic lateral sclerosis, application of GDNF via the cerebrospinal fluid may be more relevant than intracortical delivery as its diffusion within the brain parenchyma is limited. Intraventricular as well as intracisternal infusion of GDNF (300 microg over 7 days) completely prevented corticospinal neuron death. These results show that GDNF promotes the long-term survival of corticospinal neurons and has a positive effect on their size in vivo. Furthermore, the survival-promoting effect of GDNF on corticospinal neurons after delivery via cerebrospinal fluid has important clinical implications for potential treatment of the upper motoneuron degeneration seen in amyotrophic lateral sclerosis.
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PMID:GDNF is a trophic factor for adult rat corticospinal neurons and promotes their long-term survival after axotomy in vivo. 946 42

Glial cell line-derived neurotrophic factor (GDNF) is the most potent known survival factor for substantia nigra neurons, which degenerate in Parkinson's disease, for spinal motoneurons, which die in Lou Gehrig's disease (ALS), and for Purkinje neurons, the critical outflow cells of the cerebellum. Moreover, targeted deletion of the GDNF gene results in renal dysgenesis and abnormal development of the enteric nervous system. GDNF mRNA is expressed in a complex temporospatial pattern in the central nervous system and the periphery, consistent with these observations. To begin elucidating mechanisms regulating the pattern of expression of GDNF, we have cloned the human gene, and characterized the promoter. The promoter is highly GC rich, and lacks canonical CCAT-box and TATA-box motifs. It contains more than 12 binding sites for known transcription factors. These cis-elements have the potential to interact with factors regulating constitutive expression (Sp1) and developmental expression (bHLH). Moreover, the promoter contains sites for binding transcription factors which respond to environmental signals, including CREB, AP2, Zif/268, NFkB, and MRE-BP. Combinatorial actions of these transcription factors may account for the extraordinarily complex expression patterns of the GDNF gene. Importantly, we demonstrate that the hGDNF gene utilizes a promoter distinct from that identified in the rodent GDNF gene, a finding with ramifications for Parkinson's disease and ALS research.
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PMID:Novel structure of the human GDNF gene. 972 3

Glial cell line-derived neurotrophic factor (GDNF) was identified as a consequence of the hypothesis that glia secrete factors that influence growth and differentiation of specific classes of neurons. Glia are a likely source of additional neurotrophic factors; however, this strategy has not been applied extensively. The discovery of GDNF in 1993 led to an abundance of studies that within only a few years qualified GDNF as a bona fide neurotrophic factor. Of particular interest are studies demonstrating the effectiveness of GDNF protein in ameliorating neurodegeneration in animal models of Parkinson's disease and amyotrophic lateral sclerosis (ALS). It remains to be determined whether GDNF will be an effective therapy in humans with these diseases. However, since these diseases are slowly progressive and the CNS relatively inaccessible, the delivery of GDNF as a therapeutic molecule to the CNS in a chronic manner is problematic. Studies addressing this problem are applying viral vector mediated transfer of the GDNF gene to the CNS in order to deliver biosynthesized GDNF to a specific location in a chronic manner. Recent studies suggest that these GDNF gene therapy approaches are effective in rat models of Parkinson's disease. These studies are reviewed in the context of what developments will be needed in order to apply GDNF gene therapy to the clinic.
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PMID:A commentary on glial cell line-derived neurotrophic factor (GDNF). From a glial secreted molecule to gene therapy. 989 May 61

Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of various neuronal populations within the normal and diseased brain. Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). In addition, other non-neuronal growth factors such as fibroblast growth factor (FGF) have also been identified. This article reviews the trophic anatomy of these factors within the CNS. Intraventricular and intraparenchymal injections of exogenous nerve growth factor result in retrograde labeling mainly within the cholinergic basal forebrain. Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall. In contrast, intraparenchymal injections of BDNF results in widespread retrograde transport throughout the CNS. BDNF has also been shown to be transported anterogradely within the CNS. Infusion of GDNF into the CNS results in retrograde transport limited to the nigrostriatal pathway. Hippocampal injections of NT-3 retrogradely label mainly basal forebrain neurons. Retrograde transport of radiolabeled CNTF has only been observed in sensory neurons of the sciatic nerve. Following intraventricular and intraparenchymal infusion of radiolabeled bFGF, retrograde neuronal labeling was found in the telecephalon, diencephalon, mesencephalon and pons. In contrast retrograde labeling for aFGF was found only in the hypothalamus and midbrain. Since select neurotrophins traffic anterogradely and retrogradely within the nervous system, these proteins could be used to treat neurological diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.
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PMID:Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. 1008 Mar 85

The expression of glial cell line-derived neurotrophic factor (GDNF) mRNA and brain-derived neurotrophic factor (BDNF) mRNA were studied in muscle biopsies from five patients with amyotrophic lateral sclerosis (ALS), six patients with other neuromuscular diseases and eight healthy control persons. All five patients with ALS had higher GDNF mRNA expressions in their biopsies than the healthy control group (almost a three fold increase). Among the other patients only one, who had a rapidly progressing toxic polyneuropathy, showed a GDNF mRNA expression above those of the controls. The BDNF mRNA expressions in the biopsies from the ALS patients were in the same range as those from the healthy controls, although the mean value of the ALS patients was higher. The only biopsy that showed a markedly higher BDNF mRNA expression was taken from one patient with progressive muscular atrophy. These results suggest that increased GDNF mRNA expression in muscle is an unspecific response to ongoing denervation and that this response is maintained in ALS, at least temporarily. If increased GDNF mRNA in muscle proves to be a constant finding in ALS the rationale for the use of GDNF as a therapeutic agent in ALS must be questioned.
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PMID:Increased expression of glial cell line-derived neurotrophic factor mRNA in muscle biopsies from patients with amyotrophic lateral sclerosis. 1020 82


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