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)

In recent years, the investigation of erroneous regulation of apoptotic mechanisms during acute and chronic injury of neuronal cells has gained increasing attention. Besides acute neuronal trauma and ischemia, chronic neurodegenerative diseases like Alzheimer's, Huntington's, Parkinson's and Lou-Gehrig's disease (amyotrophic lateral sclerosis) are of particular interest. The present article will provide an overview of basic apoptotic mechanisms, the contribution of neuronal apoptosis to the above-mentioned disorders, potential clinical applications and their limitations and the possible implications for future studies regarding these neurodegenerative diseases.
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PMID:Neuronal apoptosis in neurodegenerative diseases: from basic research to clinical application. 1690 69

Pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear transcription factor kappa-B (NF-kappaB) and an antioxidant, has beneficial effects in animal models of various diseases, including arthritis, brain ischemia, spinal cord injury, Alzheimer's disease, and Duchenne muscular dystrophy. Because inflammation and oxidative damage are also hallmarks of amyotrophic lateral sclerosis (ALS), we studied the effect of oral PDTC treatment on G93A-superoxide dismutase 1 (SOD1) transgenic (TG) rat model of human ALS and observed that PDTC treatment significantly decreases the survival. PDTC treatment evoked the end stage of the disease at 121 +/- 21 days, whereas untreated TG animals reached the end stage at 141 +/- 13 days (p < 0.01). The DNA binding activity of NF-kappaB was not altered in G93A-SOD1 TG rats by PDTC treatment. The copper concentration in the spinal cord was increased after PDTC treatment both in G93A-SOD1 TG and wild-type rats, suggesting that increased copper may enhance the neurotoxicity of mutant SOD1. The amount of ubiquitinated proteins were significantly higher and proteasomal activity was decreased in the spinal cords of PDTC-treated TG rats compared with other groups, suggesting that PDTC treatment decreases proteasome function. Immunoblotting and immunocytochemistry showed that the level of immunoproteasome but not constitutive proteasome was increased in glia of G93A-SOD1 TG rats along with disease development. PDTC treatment completely blocked the induction of immunoproteasome expression without affecting constitutive proteasome. These results suggest that PDTC acts as an immunoproteasome inhibitor in mutant SOD1 rats and that immunoproteasome may help the nervous system to cope with deleterious effects of SOD1-G93A mutation.
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PMID:Pyrrolidine dithiocarbamate inhibits induction of immunoproteasome and decreases survival in a rat model of amyotrophic lateral sclerosis. 1700 87

In mouse models of familial amyotrophic lateral sclerosis (fALS), motor neurons are especially vulnerable to oxidative stresses in vitro. To determine whether this increased vulnerability also extends to motor nerve terminals in vivo, we assayed the effect of tourniquet-induced ischemia/reperfusion (I/R) injury on motor terminals innervating fast and slow hindlimb muscles in male G93A-SOD1 mice and their wild-type littermates. These mice also expressed yellow fluorescent protein (YFP) in motor neurons. We report that in SOD1-G93A/YFP mice the motor terminals innervating two predominantly fast muscles, extensor digitorum longus (EDL) and plantaris, were more vulnerable to I/R injury than motor terminals innervating the predominantly slow soleus muscle. The mean duration of EDL ischemia required to produce a 50% reduction in endplate innervation in SOD1-G93A/YFP mice was 26 min, compared to 45 min in YFP-only mice. The post-I/R destruction of EDL terminals in SOD1-G93A mice was rapid (<2 h) and was not duplicated by cutting the sciatic nerve at the tourniquet site. The increased sensitivity to I/R injury was evident in EDL muscles of SOD1-G93A/YFP mice as young as 31 days, well before the onset of motor neuron death at approximately 90 days. This early vulnerability to I/R injury may correlate with the finding (confirmed here) that in fALS mice motor nerve terminals innervating fast hindlimb muscles degenerate before those innervating slow muscles, at ages that precede motor neuron death. Early vulnerability of fast motor terminals to I/R injury thus may signal, and possibly contribute to, early events involved in motor neuron death.
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PMID:Early vulnerability to ischemia/reperfusion injury in motor terminals innervating fast muscles of SOD1-G93A mice. 1729 57

One major pathogenesis in degenerative disorders of the central nervous system (CNS), including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemia, is the oxidative stress induced by reactive oxygen species (ROS). The present study investigated the protective effect of colloidal silver, which is widely marketed as a dietary supplement for diseases like diabetes, AIDS, cancer, and various infections, upon the oxidative brain damage induced by H(2)O(2) or naphthazarin treatment. LDH release from primary cultured astrocytes was enhanced by naphthazarin treatment, and this elevation of the LDH concentration in medium was blocked by colloidal silver treatment. However, hydrogen peroxide was little affected by the colloidal silver. Fluorescence of DCF (peroxides) increased in astrocytes incubated with hydrogen peroxide or naphthazarin compared to the control. When exposed to naphthazarin-induced cells, ROS formation appeared to be reduced by colloidal silver. However, intracellular ROS formation in hydrogen peroxide-treated cells slightly reduced by colloidal silver. These results suggest that colloidal silver has a protective activity against the oxidative stress induced by naphthazarin, but not by hydrogen peroxide.
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PMID:Effect of colloidal silver against the cytotoxicity of hydrogen peroxide and naphthazarin on primary cultured cortical astrocytes. 1736 22

Mitochondria, being the principal source of cellular energy, are vital for cell life. Yet, ironically, they are also major mediators of cell death, either by necrosis or apoptosis. One means by which these adverse effects occur is through the mitochondrial permeability transition (mPT) whereby the inner mitochondrial membrane suddenly becomes excessively permeable to ions and other solutes, resulting in a collapse of the inner membrane potential, ultimately leading to energy failure and cell necrosis. The mPT may also bring about the release of various factors known to cause apoptotic cell death. The principal factors leading to the mPT are elevated levels of intracellular Ca2+ and oxidative stress. Characteristically, the mPT is inhibited by cyclosporin A. This article will briefly discuss the concept of the mPT, its molecular composition, its inducers and regulators, agents that influence its activity and describe the consequences of its induction. Lastly, we will review its potential contribution to acute neurological disorders, including ischemia, trauma, and toxic-metabolic conditions, as well as its role in chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.
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PMID:The mitochondrial permeability transition in neurologic disease. 1739 69

Hypoxia-ischemia (HI) may play a significant role in motor neuron death associated with the pathology of spinal cord injury and, perhaps, amyotrophic lateral sclerosis. The present study employs an in vitro model of HI to investigate the role of a stress kinase pathway, i.e., p38 MAP kinase, in cell death signaling in a motor neuron cell line, i.e., NSC34, subjected to oxygen-glucose deprivation (OGD). Although the neurons were essentially tolerant to either hypoxia (0.2% O(2)) or low glucose (1 mM) alone, more than 60% of them died in response to combined low oxygen and low-glucose exposure. Minocycline, a semi-synthetic tetracycline known for its neuroprotective effects in models of neurodegeneration, afforded substantial (approximately 50%) protection against hypoxic cell death, assessed by lactate dehydrogenase release and flow cytometry, while suppressing OGD-induced p38 MAP kinase activation. An inhibitor of p38 kinase, SB203580, as well as siRNA-mediated down-regulation of p38 kinase elicited an almost complete blockade of OGD-induced cell death. The use of p38 isoform-specific siRNAs further revealed preferential involvement of the alpha over the beta isoform of p38 MAP kinase in hypoxic neuronal cell death in our model.
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PMID:p38alpha MAP kinase mediates hypoxia-induced motor neuron cell death: a potential target of minocycline's neuroprotective action. 1759 16

Manipulation of the cellular stress response offers strategies to protect brain cells from damage induced by ischemia and neurodegenerative diseases. Overexpression of Hsp70 reduced ischemic injury in the mammalian brain. Investigation of the domains within Hsp70 that confers ischemic neuroprotection revealed the importance of the carboxyl-terminal domain. Arimoclomol, a coinducer of heat shock proteins, delayed progression of amyotrophic lateral sclerosis (ALS) in a mouse model in which motor neurons in the spinal cord and motor cortex degenerate. Celastrol, a promising candidate as an agent to counter neurodegenerative diseases, induced expression of a set of Hsps in differentiated neurons grown in tissue culture. Heat shock "preconditioning" protected the nervous system at the functional level of the synapse and selective overexpression of Hsp70 enhanced the level of synaptic protection. Following hyperthermia, constitutively expressed Hsc70 increased in synapse-rich areas of the brain where it associates with Hsp40 to form a complex that can refold denatured proteins. Stress tolerance in neurons is not solely dependent on their own Hsps but can be supplemented by Hsps from adjacent glial cells. Hence, application of exogenous Hsps at neural injury sites is an effective strategy to maintain neuronal viability.
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PMID:Heat shock proteins and protection of the nervous system. 1765 67

This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the most common neurodegenerative disorders and their related animal models. We discuss recent literature in relation to Alzheimer's disease and dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, alcoholism, ischemia, epilepsy and major depression.
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PMID:Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence? 1818 68

Melatonin and its metabolites are potent antioxidants by virtue of their ability to scavenge both oxygen-based and nitrogen-based radicals and intermediates but also as a consequence of their ability to stimulate the activity of antioxidative enzymes. Melatonin also prevents electron leakage from the mitochondrial electron transport chain thereby diminishing free radical generation; this process is referred to as radical avoidance. The fact that melatonin and its metabolites are all efficient radical scavengers indicates that melatonin is a precursor molecule for a variety of intracellular reducing agents. In specific reference to the brain, melatonin also has an advantage over some other antioxidants given that it readily passes through the blood-brain-barrier. This, coupled with the fact that it and its by-products are particularly efficient detoxifiers of reactive species, make these molecules of major importance in protecting the brain from oxidative/nitrosative abuse. This review summarizes the literature on two brain-related situations, i.e., traumatic brain and spinal cord injury and ischemia/reperfusion, and the neurodegenerative disease, amyotrophic lateral sclerosis, where melatonin has been shown to have efficacy in abating neural damage. These, however, are not the only age-associated neurodegenerative states where melatonin has been found to be protective.
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PMID:Melatonin defeats neurally-derived free radicals and reduces the associated neuromorphological and neurobehavioral damage. 1821 98

Glutamate is an essential neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters primarily expressed in astroglial cells. Dysfunction of EAAT2 is implicated in acute and chronic neurological disorders, including stroke/ischemia, temporal lobe epilepsy, amyotrophic lateral sclerosis, Alzheimer disease, human immunodeficiency virus 1-associated dementia, and growth of malignant gliomas. Ceftriaxone, one of the beta-lactam antibiotics, is a stimulator of EAAT2 expression with neuroprotective effects in both in vitro and in vivo models based in part on its ability to inhibit neuronal cell death by glutamate excitotoxicity. Based on this consideration and its lack of toxicity, ceftriaxone has potential to manipulate glutamate transmission and ameliorate neurotoxicity. We investigated the mechanism by which ceftriaxone enhances EAAT2 expression in primary human fetal astrocytes (PHFA). Ceftriaxone elevated EAAT2 transcription in PHFA through the nuclear factor-kappaB (NF-kappaB) signaling pathway. The antibiotic promoted nuclear translocation of p65 and activation of NF-kappaB. The specific NF-kappaB binding site at the -272 position of the EAAT2 promoter was responsible for ceftriaxone-mediated EAAT2 induction. In addition, ceftriaxone increased glutamate uptake, a primary function of EAAT2, and EAAT2 small interference RNA completely inhibited ceftriaxone-induced glutamate uptake activity in PHFA. Taken together, our data indicate that ceftriaxone is a potent modulator of glutamate transport in PHFA through NF-kappaB-mediated EAAT2 promoter activation. These findings suggest a mechanism for ceftriaxone modulation of glutamate transport and for its potential effects on ameliorating specific neurodegenerative diseases through modulation of extracellular glutamate.
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PMID:Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. 1832 97


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