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)

Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:AIDS-related dementia and calcium homeostasis. 784 72

The low expression of MHC antigens is believed to be one factor of importance contributing to the immune-privileged status of CNS neurons. We here describe that motoneurons, in contrast to other nerve cells in the lumbar spinal cord of the adult rat, express both MHC class I and beta2-microglobulin mRNA. The motoneurons also display in situ hybridization signal for IFN-gamma receptor mRNA. After a peripheral axotomy, the motoneurons show a clear upregulation of beta2-microglobulin mRNA. IFN-gamma treatment of cultured rat embryonic spinal motoneurons causes a similar upregulation of especially beta2-microglobulin. Based on these facts, we propose that spinal motoneurons can be influenced by IFN-gamma and recognized by cytotoxic CD8+ T-cells. These findings could be of relevance in the search for pathogenetic mechanisms in motoneuron-specific diseases, such as ALS.
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PMID:Expression of MHC class I and beta2-microglobulin in rat spinal motoneurons: regulatory influences by IFN-gamma and axotomy. 952 98

Naturally occurring sexual dimorphism has been implicated in the risk, progression and recovery from numerous neurological disorders. These include head injury, multiple sclerosis (MS), stroke, and neurodegenerative diseases (Parkinson's disease (PD), Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). Accumulating evidence suggests that observed differences between men and women could result from estrogen's wide range of effects within the mammalian central nervous system (CNS), with it's neuroprotective effect being one of the most important. It seems possible that neuroprotective activity of estrogen could be partially a result of it's anti-inflammatory action. It has been well established that inflammation plays an important role in the etiopathogenesis and manifestation of brain pathological changes. In this regard, an important role has been suggested for pro-inflammatory cytokines produced by activated glial cells, neurons and immune cells that invade brain tissue. Within the CNS, cytokines stimulate inflammatory processes that may impair blood-brain barrier permeability as well as promote apoptosis of neurons, oligodendrocytes and induce myelin damage. Given that estrogen may modulate cytokine expression, coupled with the fact that gender differences of cytokine production are apparent in animal models of PD and MS, suggests an important connection between hormonal-cytokine link in neurodegeneration. Indeed, while MS patients and mice subjected to experimental autoimmune encephalomyelitis (EAE) display gender specific alterations of IFN-gamma and IL-12, variations of TNF and IL-6 were associated with PD. Also in case of more acute neurodegenerative conditions, such as stroke, the effect of IL-6 gene G-174C polymorphism was different in males and females. Given that our understanding of the role of estrogen on cytokine production and accompanying CNS pathological conditions is limited, the present reviews aims to present some of our recent findings in this area and further evaluate the evidence that may be relevant to the design of new hormonal anti-inflammatory treatment strategies for neurodegenerative diseases.
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PMID:Estrogen and cytokines production - the possible cause of gender differences in neurological diseases. 1577 51

T -cells are present in the spinal cord from patients with amyotrophic lateral sclerosis (ALS), and could attack neurons or activate microglia through secretion of cytokines. We report that interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-4, IL-5 and IL-10 could not be detected in cerebrospinal fluid (CSF) samples from 15 ALS patients and 23 out of 25 controls with a multiplexed cytometric bead assay. In vivo activated T-cell clones were established from CSF (n = 26) and blood (n = 21) of one ALS patient. The proliferative capacity of CSF T-cell clones was lower than that of T-cell clones from blood (p = 0.0007). All CD4+ CSF T-cell clones produced IFN-gamma, compatible with a predominant T helper (h) 1 phenotype, but several T-cell clones also produced Th2 cytokines. These data suggest that in vivo activated intrathecal T-cells can be induced to secrete cytokines which may play a role in ALS.
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PMID:ALS: cytokine profile in cerebrospinal fluid T-cell clones. 1696 8

Astrocytes and microglia become activated in a broad spectrum of inflammatory neurodegenerative diseases. Activated microglia are widely believed to be the principal source of inflammation-induced neuronal degeneration in these disorders. To investigate the neurotoxic potential of human astrocytes, we exposed them and human astrocytic U-373 MG cells to a variety of inflammatory stimulants. We then assessed the effects of their supernatants on human SH-SY5 cells. When astrocytes and U-373 MG cells were stimulated with interferon (IFN)-gamma (150U/ml), their supernatants significantly reduced SH-SY5Y cell viability. Other powerful inflammatory stimulants such as lipopolysaccharide (0.5mug/ml), tumor necrosis factor-alpha (10ng/ml) and interleukin-1beta (10ng/ml), alone or in combination, were without effect. These combinations were also unable to enhance the IFN-gamma effect. The induced cytotoxicities were reversed by JAK inhibitor I, a potent and specific inhibitor of JAKs. This result indicates that the neurotoxic effect was proceeding through the IFN-gamma receptor (IFNGR)-JAK-STAT intracellular pathway. To establish that the IFNGR is expressed on both cultured astrocytes and U-373 MG cells, we performed RT-PCR on total RNA extracts to identify a specific IFNGR product. We showed the protein product on these cultured cells by immunocytochemistry using an antibody to IFNGR. Finally, using human postmortem material, we showed sharp upregulation of the IFNGR on activated astrocytes in affected areas in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. These findings suggest that activated astrocytes may become neurotoxic when stimulated by IFN-gamma and may therefore exacerbate the pathology in a spectrum of neurodegenerative diseases.
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PMID:Interferon-gamma-dependent cytotoxic activation of human astrocytes and astrocytoma cells. 1837 19

Mesenchymal stem cells (MSCs) obtained from bone marrow (BM) are currently used as an alternative therapy in amyotrophic lateral sclerosis (ALS) patients. Selection of optimal passages of autologous BM-derived MSCs during long-term in vitro expansion is important for clinical trials in patients with ALS. We isolated and expanded MSCs from the BM of eight ALS patients to analyze the growth kinetics, differentiation potential, cellular surface antigen expression, karyotype modifications and secretion of various cytokines during long-term culture. The morphology and size of the cells changed from small and spindle-like cells to large and polygonal types in later passages. The growth rate of the MSCs was highest in the third passage, followed by a gradual decrease. There were no special modifications of cell surface antigens or the karyotype of the MSCs from the first to the tenth passage. MSCs in the fourth passage were differentiated into adipocytes, osteocytes and chondrocytes. When we analyzed the cultured media of MSCs at the third, fifth, seventh and ninth passages, IL-6, VEGF and IL-8 showed high expression, with more than 50pg/10,000 cells at these passages; however, their expression progressively decreased with additional passages. In addition, secretion of IL-15, GM-CSF, IL-10, PDGF-bb, G-CSF, IL-1beta, basic FGF and IFN-gamma gradually decreased over prolonged culture. We suggest that MSCs at earlier passages are more suitable for stem cell therapy in ALS patients because of their stability and more potent anti-inflammatory and neuroprotective properties.
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PMID:Selection of optimal passage of bone marrow-derived mesenchymal stem cells for stem cell therapy in patients with amyotrophic lateral sclerosis. 2011 76

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which leads to death in a median time of 2-3 years. Inflammation has been claimed important to the ALS pathogenesis, but its role is still not well-characterized. In the present study, a panel of five cytokines (IL-2, IL-6, IL-10, IFN-gamma, and TNF-alpha) measured in plasma has been investigated in ALS. These biomarkers of inflammation were measured in a population-based cohort of 79 patients with ALS and 79 age- and sex-matched healthy controls using the Bio-Plex technology (Bio-Rad). All the five cytokines were significantly increased in plasma samples of patients compared with controls (p < 0.0001), with IL-6 having the highest median concentration (10.11 pg/ml) in the ALS group. Furthermore, IL-6 was the plasma cytokine with the highest discrimination ability between patients and controls according to the receiver operating characteristic analysis (area under the curve = 0.93). At a cut-off point of 5.71 pg/ml, it was able to classify patients and controls with 91% of sensitivity and 87% of specificity. In the ALS group, plasma IL-6 concentration correlated with demographic (age: rs = 0.25, p = 0.025) and clinical (revised ALS Functional Rating Scale at evaluation: rs = -0.32, p = 0.007; Manual Muscle Testing: rs = -0.33, p = 0.004; progression: rs = 0.29, p = 0.0395) parameters. In line with previous studies, our results confirm that inflammatory cytokines are elevated in ALS, supporting a possible role of inflammation in disease mechanism and progression. However, the precise role of inflammation in ALS needs to be further investigated on larger samples and with more mechanistic studies.
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PMID:Plasma Inflammatory Cytokines Are Elevated in ALS. 3328