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)

Amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease are major human neurodegenerative disorders, the etiologies for which remain unknown. Although a unique subset of neurons is particularly affected in each of the three diseases, they have several intriguing overlapping similarities. Evidence is reviewed supporting the hypothesis that these diseases result from an inability to protect against accumulated damage by free radicals due to oxidative stress. If oxidative stress underlies or exacerbates the etiology of these diseases, then agents that effectively attenuate brain tissue lipid peroxidation or otherwise limit free radical damage may hold promise for the treatment of these neurodegenerative diseases. Although antioxidant chemical supplementation may provide effective therapy, the most effective therapy for neurodegenerative diseases may be treatment with specific neurotrophic, survival-promoting proteins. For example, brain-derived neurotrophic factor promotes survival of spinal motor neurons and mesencephalic dopaminergic neurons. One mechanism through which these proteins may exert their protection may be by stimulating endogenous defenses against oxidative stress and damage by free radicals. This hypothesis is being tested in several laboratories and provides exciting direction both for basic neurobiological research and therapeutic drug discovery.
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PMID:Oxidative stress, age-related neurodegeneration, and the potential for neurotrophic treatment. 774 72

The recent molecular cloning of BDNF and CNTF based on traditional protein purification and protein sequencing and the identification and cloning of NT-3 and NT-4 by homology cloning strategies has led to a tremendous flurry of interest in the biology of these proteins and initiation of studies to assess their potential utility in neurological disorders ranging through degenerative disease, stroke and ischemia, trauma and peripheral neuropathies. Tissue culture studies have been very useful in identifying neuronal specificities of the neurotrophins and CNTF and in combination with localization studies of these growth factors and their receptors have provided the basis for in vivo studies. Initial animal studies with BDNF indicate efficacy of BDNF in models of Alzheimer's and Parkinson's disease and small fiber sensory neuropathy. Studies with CNTF have similarly progressed from in vitro findings, especially the discovery that CNTF is a growth factor for motor neurons, to in vivo findings where CNTF has been shown to be effective in slowing symptoms of motor neuron dysfunction in three genetic models. Based on these positive animal data, CNTF is currently in clinical trials for the potential treatment of motor neuron disease or amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.
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PMID:Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor. 783 3

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) act upon populations of neurons that express specific receptors. The present study demonstrates that BDNF rescues motor neurons from degeneration and may also play a role in the normal physiology of these cells. BDNF is expressed in the local environment and in muscle targets of motor neurons; muscle expression is up-regulated by denervation. The alpha motor neurons express the gene encoding p145trkB, a receptor involved in BDNF signal transduction, whereas a subset of motor neurons express p75NGFR. BDNF is transported selectively to alpha motor neurons from skeletal muscles. Finally, BDNF prevents motor neuron death in the axotomized facial nucleus of the neonatal rat. The effects of BDNF on motor neurons raise the possibility that some neurotrophins may be useful in treating patients with motor neuropathies and amyotrophic lateral sclerosis.
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PMID:Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. 808 Apr 64

Current therapeutic efforts to treat chronic and progressive neurodegenerative disease include, for the first time, attempts to regenerate affected nervous tissue using neurotrophic factors. The rationale for using trophic factors includes the understanding that they support neuronal survival and regrowth processes. The potential benefits of trophic factor therapy will be no more realized in the near future than in the treatment of amyotrophic lateral sclerosis (ALS). ALS is pathologically characterized by the selective degeneration of specific populations of cranial and spinal motoneurons. Evidence for the existence of factors that support motoneurons has come from studies demonstrating that motoneurons receive trophic influences from various tissues, both central and peripheral, within their local environment. Although the identity of these putative tissue-derived factors has remained enigmatic, recent studies have demonstrated that several previously characterized trophic factors exhibit trophic influences on motoneurons. Among these are several members of the neurotrophin family, most notably brain-derived neurotrophic factor. These neurotrophins meet most of the criteria to be considered motoneuron trophic factors: they are locally available to motoneurons in vivo; motoneurons express specific receptors for these factors; and exogenous application of these factors mimicks the effects of the uncharacterized endogenous agents. The clinical use of these factors for the treatment of ALS, therefore, appears to be scientifically justified.
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PMID:Experimental rationale for the therapeutic use of neurotrophins in amyotrophic lateral sclerosis. 828 83

The survival and functional maintenance of spinal motoneurones and of peripheral neurones, such as sensory, sympathetic and parasympathetic neurones, has been shown to depend on neurotrophic factors, both during the period of developmental cell death and in adulthood. A variety of such factors has been identified over recent years, among them factors of the NGF gene family, for example BDNF, NT-3, NT-4/5 and NT-6, and factors such as CNTF and LIF acting on neuronal target cells via receptor components shared with cytokines such as IL-6. In addition, pluripotent mitogens, such as IGF-I and IGF-II can support the survival of a variety of neuronal cell types, including spinal motoneurones both in cell culture and in vivo. The establishment of mice in which the genes for these factors and their receptors have been inactivated by homologous recombination has been a major step in the understanding of their physiological function. It is not clear so far whether or not similar gene defects in human are associated with any neurological disease. However, some of these factors have been demonstrated to be effective in animal models of neuropathy and motoneurone disorders, so that first clinical trials using these factors for symptomatic treatment of amyotrophic lateral sclerosis (ALS) and peripheral neuropathies have already been initiated.
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PMID:Molecular biology of neurotrophic factors. 859 25

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

1. During embryonic development, neuronal populations undergo a period of naturally occurring cell death. In the vertebrate, the survival of neurons during this period is dependent upon specific neurotrophic factors. Recent advances in in vitro and in vivo assays have led to the identification of a number of neurotrophic factors for spinal motoneurons, including brain-derived neurotrophic factor, ciliary neurotrophic fibroblast growth factors, insulin-like growth factors and glial-derived neurotrophic factor. 2. The presence of multiple trophic factors promoting motoneuron survival suggests either that there is significant functional redundancy between the factors or that they act in concert to produce their effects. 3. In addition to their physiological role, neurotrophic factors show tremendous clinical potential for the treatment of human neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, because they are poorly absorbed across biological membranes and are unstable in plasma, the recombinant neurotrophic factors themselves are not optimally suited as drugs. One means to circumvent these problems is to use the known three-dimensional structures of these factors as templates to design low molecular weight compounds that retain neurotrophic activity but exhibit better pharmacokinetic properties.
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PMID:Neurotrophic factors and the development of drugs to promote motoneuron survival. 891 42

Neurotrophic factors (NTFs) such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) are currently being explored as novel therapeutics in a range of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. To this end, animal studies and clinical trials have been conducted to assess the toxic effects of recombinant NTFs. It is apparent that both NGF and BDNF induce a range of adverse effects, for example inflammation, hyperalgesia, and disturbances in CNS biogenic amine levels which variously manifest as weight loss/gain, changes in feeding behaviour and general malaise. It has been demonstrated that NGF induces release of biologically active mediators, such as histamine, from rat peritoneal mast cells (RPMC). However, whether other NTFs do likewise or indeed are able to induce secretion from other mast cells types had not been explored. We have developed a novel protocol for dispersing mast cells from rat brain tissue, in particular the thalamus which contains the highest number of mast cells in the adult rat. Rat brain mast cells (RBMC) released histamine in a concentration dependent manner in response to NTFs, with a rank order of BDNF > CNTF > NGF; in contrast RPMC were refractory to the effects of BDNF and CNTF. The ability of NTFs to induce release of histamine (a neurotransmitter and neuromodulator in the CNS) from RBMC may go some way to explain some of the adverse effects apparent in vivo upon dosing with NTFs. Mast cells in vitro, and brain mast cells in particular, offer the potential to screen novel NTFs for their neuroimmunotoxic potential relevant to detecting likely clinical adverse effects in humans.
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PMID:Rat brain mast cells: an in vitro paradigm for assessing the toxic effects of neurotropic therapeutics. 908 8

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motoneurons, and has no effective treatment. Experimental studies in rodents have shown that motoneurons respond to a variety of molecules including brain-derived neurotrophic factor (BDNF). and the glial-cell line-derived neurotrophic factor (GDNF). Here we investigated the neuroprotective effect of these growth factors, encoded by an adenovirus, on the death of axotomized facial motoneurons in newborn rats. We used a new gene therapy strategy that involves gene transfer to motoneurons by intramuscular injection of an adenoviral vector, which is retrogradely transported from injected target muscle (Finiels et al.,: NeuroReport 7:373-378, 1995). A significant increased survival of motoneurons was observed in animals pretreated with adenovirus encoding BDNF (34.5%, P < 0.05) ou GDNF (41.9%, P < 0.05) 1 week after axotomy. These results indicate that pretreatment with BDNF or GDNF, using this therapeutic strategy, is able to prevent the massive death of motoneurons that normally follows axotomy in the neonatal period, opening new perspectives to limit neuronal death in degenerative disorders.
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PMID:Prevention of motoneuron death by adenovirus-mediated neurotrophic factors. 916 Feb 51

To assess the therapeutic potential of brain-derived neurotrophic factor (BDNF) in clinics, we extensively investigated the effects of BDNF on adult motor neurons in a rat spinal root avulsion model. Intrathecal administration of BDNF immediately after the spinal root avulsion greatly protected against the motor neuron cell death. BDNF also showed a protective effect on the atrophy of soma and on the reduction of transmitter-related enzymes such as choline acetyl transferase and acetylcholine esterase. Very interestingly, BDNF induced axonal outgrowth of severely damaged motor neurons at the avulsion site. The BDNF administration following 2-week treatment with phosphate-buffered saline after avulsion prevented further augmentation of cell death and reversed cholinergic transmitter-related enzyme deficiency. BDNF was demonstrated to possess a wide variety of biological effects on survival, soma size, cholinergic enzymes, and axonal outgrowth of adult motor neurons. These results provide a rationale for BDNF treatment in motor neuron diseases such as spinal cord injury and amyotrophic lateral sclerosis.
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PMID:BDNF prevents and reverses adult rat motor neuron degeneration and induces axonal outgrowth. 916 29


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