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

Apoptosis plays an important role in neuronal cell death in both chronic and acute human neurodegenerative diseases, including amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and human immunodeficiency virus (HIV) encephalopathy. We evaluated the ability of the extracellular binding domain of a dimeric tumor necrosis factor receptor (p75TNFR) to prevent neurotoxicity and death of human fetal cerebral neurons that were exposed in vitro to toxic agents known to be implicated in human neurological disorders, including tumor necrosis factor (TNFalpha) and the HIV proteins Tat and gp120. The extracellular domain of p75TNFR is capable of binding and neutralizing both soluble and transmembrane-anchored TNFalpha. We efficiently transduced human neurons using adenoviral vectors expressing p75TNFR (Ad.p75TNFR) or a control gene (lacZ). Treatment of control cultures with the toxic agents TNFalpha, TNFalpha plus actinomycin D, or Tat and gp120, induced neurotoxic alterations and apoptotic death of neurons. By contrast, transduction of neurons with Ad.p75TNFR prevented apoptosis and cell death due to these agents. We conclude that viral vector transfer of the p75TNFR gene efficiently protects human neurons from TNFalpha-, Tat- or gp120-induced apoptosis and cell death. These results suggest that p75TNFR transduction of neurons by viral vectors could be therapeutically useful in the treatment of many human neurodegenerative diseases.
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PMID:Protection of human cerebral neurons from neurodegenerative insults by gene delivery of soluble tumor necrosis factor p75 receptor. 1582 36

Accumulating evidence suggests that inflammation plays a major role in the pathogenesis of motor neuron death in amyotrophic lateral sclerosis (ALS). Important mediators of inflammation such as the cytokine tumor necrosis factor-alpha (TNF-alpha) and its superfamily member fibroblast-associated cell-surface ligand (FasL) have been implicated in apoptosis. We found increased TNF-alpha and FasL immunoreactivity in lumbar spinal cord sections of ALS patients and G93A transgenic mice. Both increased TNF-alpha and FasL immunostaining in the lumbar spinal cord of the G93A SOD1 transgenic mice occurred at 40-60 d, well before the onset of symptoms and loss of motor neurons. We tested the neuroprotective effect of thalidomide and its analog lenalidomide, pharmacological agents that inhibit the expression of TNF-alpha and other cytokines by destabilizing their mRNA. Treatment with either thalidomide or lenalidomide attenuated weight loss, enhanced motor performance, decreased motor neuron cell death, and significantly increased the life span in G93A transgenic mice. Treated G93A mice showed a reduction in TNF-alpha and FasL immunoreactivity as well as their mRNA in the lumbar spinal cord. Both compounds also reduced interleukin (IL)-12p40, IL-1alpha, and IL-1beta and increased IL-RA and TGF-beta1 mRNA. Therefore, both thalidomide and lenalidomide bear promise as therapeutic interventions for the treatment of ALS.
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PMID:Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis. 1651 Jul 25

We found comparable levels of tumor necrosis factor (TNF)-alpha, interferon-gamma, interleukin (IL)-2, IL-4, IL-10, and IL-12 in the sera of 22 patients with multifocal motor neuropathy (MMN), 12 with amyotrophic lateral sclerosis (ALS), 12 multiple sclerosis, seven chronic inflammatory demyelinating polyneuropathy, five myasthenia gravis, and 13 healthy controls (NS). TNF-alpha levels, however, were higher in 15 (68%) MMN patients than in any NS. In all but one MMN patient tested, TNF-alpha levels repeatedly, albeit slightly, increased after each intravenous immunoglobulin infusion in parallel with clinical improvement and decreased 3-4 weeks after therapy, while in both ALS patients tested, they decreased or remained unchanged. The possible pathogenetic relevance of serum TNF-alpha modification in MMN remains to be clarified.
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PMID:Circulating levels of cytokines and their modulation by intravenous immunoglobulin in multifocal motor neuropathy. 1651 84

Minocycline, a clinically used tetracycline for over 40 years, crosses the blood-brain barrier and prevents caspase up-regulation. It reduces apoptosis in mouse models of Huntington's disease and familial amyotrophic lateral sclerosis (ALS) and is in clinical trial for sporadic ALS. Because apoptosis also occurs after brain and spinal cord (SCI) injury, its prevention may be useful in improving recovery. We analyzed minocycline's neuroprotective effects over 28 days following contusion SCI and found significant functional recovery compared to tetracycline. Histology, immunocytochemistry, and image analysis indicated statistically significant tissue sparing, reduced apoptosis and microgliosis, and less activated caspase-3 and substrate cleavage. Since our original report in abstract form, others have published both positive and negative effects of minocycline in various rodent models of SCI and with various routes of administration. We have since found decreased tumor necrosis factor-alpha, as well as caspase-3 mRNA expression, as possible mechanisms of action for minocycline's ameliorative action. These results support reports that modulating apoptosis, caspases, and microglia provide promising therapeutic targets for prevention and/or limiting the degree of functional loss after CNS trauma. Minocycline, and more potent chemically synthesized tetracyclines, may find a place in the therapeutic arsenal to promote recovery early after SCI in humans.
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PMID:Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. 1663 21

Glutamate released by activated microglia induces excitoneurotoxicity and may contribute to neuronal damage in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, tumor necrosis factor-alpha (TNF-alpha) secreted from activated microglia may elicit neurodegeneration through caspase-dependent cascades and silencing cell survival signals. However, direct neurotoxicity of TNF-alpha is relatively weak, because TNF-alpha also increases production of neuroprotective factors. Accordingly, it is still controversial how TNF-alpha exerts neurotoxicity in neurodegenerative diseases. Here we have shown that TNF-alpha is the key cytokine that stimulates extensive microglial glutamate release in an autocrine manner by up-regulating glutaminase to cause excitoneurotoxicity. Further, we have demonstrated that the connexin 32 hemichannel of the gap junction is another main source of glutamate release from microglia besides glutamate transporters. Although pharmacological blockade of glutamate receptors is a promising therapeutic candidate for neurodegenerative diseases, the associated perturbation of physiological glutamate signals has severe adverse side effects. The unique mechanism of microglial glutamate release that we describe here is another potential therapeutic target. We rescued neuronal cell death in vitro by using a glutaminase inhibitor or hemichannel blockers to diminish microglial glutamate release without perturbing the physiological glutamate level. These drugs may give us a new therapeutic strategy against neurodegenerative diseases with minimum adverse side effects.
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PMID:Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. 1672 May 74

To investigate cytokine/chemokine changes in amyotrophic lateral sclerosis (ALS), we simultaneously measured 16 cytokine/chemokines (interleukin [IL]-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony stimulating factor [G-CSF], macrophage chemoattractant protein-1 [MCP-1], and macrophage inflammatory protein-1beta) in cerebrospinal fluid (CSF) and sera from 37 patients with sporadic ALS and 33 controls using a multiplexed fluorescent bead-based immunoassay. We also conducted immunohistochemical analyses from 8 autopsied ALS cases and 6 nonneurologic disease controls as well as cell culture analyses of relevant cytokines and their receptors. We found that concentrations of G-CSF and MCP-1 were significantly increased in ALS CSF compared with controls. In spinal cords, G-CSF was expressed in reactive astrocytes in ALS cases but not controls, whereas G-CSF receptor expression was significantly decreased in motor neurons of spinal cords from ALS cases. Biologically, G-CSF had a protective effect on the NSC34 cell line under conditions of both oxidative and nutritional stress. We suggested that G-CSF has potentially neuroprotective effects on motor neurons in ALS and that downregulation of its receptor might contribute to ALS pathogenesis. On the other hand, MCP-1 correlated with disease severity, which may aggravate motor neuron damage.
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PMID:Intrathecal upregulation of granulocyte colony stimulating factor and its neuroprotective actions on motor neurons in amyotrophic lateral sclerosis. 1689 15

Recent studies suggest that superoxide dismutase (SOD1) may represent a major target of oxidative damage in neurodegenerative diseases. To test the possibility that oxidized species of wild-type (WT) SOD1 might be involved in pathogenic processes, we analyzed the properties of the WT human SOD1 protein after its oxidation in vivo or in vitro by hydrogen peroxide (H2O2) treatment. Using transfected Neuro2a cells expressing WT or amyotrophic lateral sclerosis-linked SOD1 species, we show that exposure to H2O2 modifies the properties of WT SOD1. Western blot analysis of immunoprecipitates from cell lysates revealed that, like mutant SOD1, oxidized WT SOD1 can be conjugated with poly-ubiquitin and can interact with Hsp70. Chromogranin B, a neurosecretory protein that interacts with mutant SOD1 but not with WT SOD1, was co-immunoprecipitated with oxidized WT SOD1 from lysates of Neuro2a cells treated with H2O2. Treatment of microglial cells (line BV2) with either oxidized WT SOD1 or mutant SOD1 recombinant proteins induced tumor necrosis factor-alpha and inducible nitric oxide synthase. Furthermore, exposure of cultured motor neurons to oxidized WT SOD1 caused dose-dependent cell death like mutant SOD1 proteins. These results suggest that WT SOD1 may acquire binding and toxic properties of mutant forms of SOD1 through oxidative damage.
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PMID:Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. 1739 46

Motor neuron (MN) mitochondrial abnormalities and elevation in spinal fluid levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The mechanism of neuron death in ALS remains unclear, along with the contributions of mitochondrial dysfunction and inflammation in the process. Cell cultures enriched for MN derived from embryonic rat spinal cords were established and directly exposed in vitro to recombinant TNF-alpha for varying lengths of time. Although cytokine exposure for up to 4 days failed to induce MN death, mitochondrial changes were observed shortly after initiating treatment. Our results demonstrate that TNF-alpha induced mitochondrial redistribution toward the soma in MN. We postulate that inflammation may precede, and in fact cause, the mitochondrial changes observed in ALS tissue.
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PMID:Tumor necrosis factor-alpha induces changes in mitochondrial cellular distribution in motor neurons. 1741 57

One of the hypotheses for the development of familial amyotrophic lateral sclerosis (ALS) is that mutations in the superoxide dismutase 1 enzyme lead to aberrant properties of the copper within the active site of the enzyme which then causes increased oxidative damage. The lipophilic metal chelators DP-109 and DP-460 which chelate calcium, copper, and zinc were tested in the G93A-transgenic ALS mouse model. Both compounds significantly extended survival, DP-109 (5 mg/kg/day) by 10%, DP-460 (10 mg/kg/day) by 9%. While the effect on survival was relatively small, chelator treatment also improved motor performance, dramatically reduced cell loss in the lumbar spinal cord and decreased reactive astrocytosis and microgliosis. Markers of oxidative damage, tumor necrosis factor (TNF)-alpha and alpha-synuclein were reduced in the lumbar spinal cord of G93A mice treated with DP-109 or DP-460 as compared with vehicle-treated animals. Furthermore, the treatment induced protein expression of the transcription factor hypoxia inducible factor-1alpha and mRNA levels of vascular endothelial growth factor as a corresponding target gene. In line with previous studies using metal chelators in the G93A animal model, our results suggest that these compounds have neuroprotective capacities in ALS.
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PMID:The lipophilic metal chelators DP-109 and DP-460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis. 1763 Sep 88

As the average ages of North Americans and Europeans continue to rise; similarly the incidence of "old age" associated illnesses likewise increases. Most notably among these ailments are conditions linked to dementia-related neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and stroke. While in the early stages, these conditions are associated with cellular dysfunction in distinctly different brain regions, thus affecting different neuronal cell types; it is most likely that the final stages share similar cellular and molecular processes leading to neuronal death and ultimately overt clinical symptoms. In this regard, different environmental and genetic triggers ranging from head trauma to protein mutations and toxicological exposure may instigate a cascade of intracellular events that ultimately lead to neuronal death. One strong candidate trigger protein, and thus a potential target for therapeutic manipulation is the potent pro-inflammatory / pro-apoptotic cytokine, tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is secreted by the brain resident marcophage (the microglial cell) in response to various stimuli. It has been demonstrated to play a major role in central nervous system (CNS) neuroinflammation-mediated cell death in AD, PD and amyotrophic lateral sclerosis (ALS) as well as several other CNS complications. Recently, agents that modulate the levels of circulating peripheral TNF-alpha protein have been shown to be worthwhile therapeutic agents with the use of Enbrel (Etanercept) and Remicade (Infliximab), both of which display beneficial properties against rheumatoid arthritis and other peripheral inflammatory diseases. Unfortunately, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in the setting of neuroinflammation in the CNS. However, thalidomide, a small molecule drug, can inhibit TNF-alpha protein synthesis and, unlike larger molecules, is readily capable of crossing the blood-brain barrier. Thus thalidomide and its analogs are excellent candidate agents for use in determining the potential value of anti-TNF-alpha therapies in a variety of diseases underpinned by inflammation within the nervous system. Consequently, we have chosen to discuss the relevance of unregulated TNF-alpha expression in illnesses of the CNS and, to an extent, the peripheral nervous system. Additionally, we consider the utilization of thalidomide-derived agents as anti-TNF-alpha therapeutics in the setting of neuroinflammation.
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PMID:TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. 1790 40


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