Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-Methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity may depend, in part, on the generation of nitric oxide (NO.) and superoxide anion (O2.-), which react to form peroxynitrite (OONO-). This form of neurotoxicity is thought to contribute to a final common pathway of injury in a wide variety of acute and chronic neurologic disorders, including focal ischemia, trauma, epilepsy, Huntington disease, Alzheimer disease, amyotrophic lateral scelerosis, AIDS dementia, and other neurodegenerative diseases. Here, we report that exposure of cortical neurons to relatively short durations or low concentrations of NMDA, S-nitrosocysteine, or 3-morpholinosydnonimine, which generate low levels of peroxynitrite, induces a delayed form of neurotoxicity predominated by apoptotic features. Pretreatment with superoxide dismutase and catalase to scavenge O2.- partially prevents the apoptotic process triggered by S-nitrosocysteine or 3-morpholinosydnonimine. In contrast, intense exposure to high concentrations of NMDA or peroxynitrite induces necrotic cell damage characterized by acute swelling and lysis, which cannot be ameliorated by superoxide dismutase and catalase. Thus, depending on the intensity of the initial insult, NMDA or nitric oxide/superoxide can result in either apoptotic or necrotic neuronal cell damage.
 ...
PMID:Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. 763 61

The local redox milieu of a biological system is of critical importance in understanding the actions of the nitrogen monoxide (NO) moiety, as disparate chemical pathways involving distinct redox-related congeners of NO may trigger neurotoxic or neuroprotective pathways. The reactions of nitric oxide (NO.) with superoxide can lead to neurotoxicity through formation of peroxynitrite, whereas NO. alone does not, at least under certain conditions. Reaction (or transfer) of NO+ equivalents to thiol(s) on the NMDA receptor can lead to neuroprotection by inhibiting Ca2+ influx. These findings suggest that cell function can be controlled by, or through, protein S-nitrosylation, and raise the possibility that the NO group may initiate signal transduction in or at the plasma membrane. Neuroprotective effects of NO- suggest that acceleration of disulfide bond formation at the NMDA receptor is of mechanistic importance in the attenuation of Ca2+ influx. Our findings suggest novel therapeutic strategies. For example, downregulation of NMDA receptor activity can be obtained via sulfhydryl oxidation by S-nitros(yl)ation with NO+ donors (to form an RSNO at a cysteine residue on the receptor), or with NO- donors (with intermediate formation of RSNHOH). Pharmacologic intervention with these forms of NO donors could be implemented in the treatment of focal ischemia, neuropathic pain, Huntington's disease, AIDS dementia, and other neurological disorders associated, at least in part, with excessive activation of NMDA receptors.
 ...
PMID:Actions of redox-related congeners of nitric oxide at the NMDA receptor. 787 Feb 83

1. The reactions of nitric oxide with superoxide can lead to neurotoxicity through formation of peroxynitrite, and not by NO. alone, at least under our conditions. 2. Transfer of NO+ groups to thiol(s) on the NMDA receptor can lead to neuroprotection by inhibiting Ca2+ influx. These findings suggest that cell function can be controlled by, or through, protein S-nitrosylation, and raise the possibility that the NO group may initiate signal transduction in or at the plasma membrane. 3. The local redox milieu of a biological system is of critical importance in understanding NO actions as disparate chemical pathways involving distinct redox related congeners of NO may trigger neurotoxic or neuroprotective pathways. These claims are highlighted in the CNS by the recent finding that tissue concentrations of cysteine approach 700 microM in settings of cerebral ischemia (Slivka and Cohen, 1993); these levels of thiol would be expected to influence the redox state of the NO group. 4. Finally, our findings suggest novel therapeutic strategies. For example, downregulation of NMDA receptor activity via S-nitrosylation with NO+ donors could be implemented in the treatment of focal ischemia, AIDS dementia, and other neurological disorders associated, at least in part, with excessive activation of NMDA receptors.
 ...
PMID:Nitric oxide in the central nervous system. 788 18

It has been suggested that microglia, a type of glial cells in the central nervous system, play various important roles in normal and pathologic brains. In this article, we discussed the association or roles of microglia in injury and in brain diseases such as Alzheimer's disease, AIDS dementia complex, multiple sclerosis and ischemia. Furthermore, microglia-derived cytotoxic products and other secretory factors were summarized. In addition to the pathological aspects, secretory factors that showed neurotrophic effects were described with special reference to their physiological significance in the neuronal growth, neuronal function and regeneration processes. Accumulated evidence suggests that microglia are associated with not only brain pathology but also normal physiology in the brain.
 ...
PMID:Functional roles of microglia in the brain. 823 23

Calcium ion (Ca2+) plays a role in several important functions in the central nervous system such as production of action potentials, neurotransmitter release, or neuronal plasticity, etc. However, its excessive influx to neurons due to failure of the mechanisms implicated in the regulation of its intracellular concentration (Ca(2+)-channels, calcium binding proteins), leads to a cascade of events which causes cytotoxicity and neuronal death. Ca2+ mediated toxicity has been implicated in the pathogenesis of neurodegenerative diseases (Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, Huntington's), brain ischemia, epilepsy, cranial trauma, and AIDS-dementia complex. In this article we review the current status of this topic.
 ...
PMID:[Calcium, neuronal death and neurological disease]. 898 15

The Transforming Growth Factor-betas (TGF-beta) are a group of multifunctional proteins whose cellular sites of production and action are widely distributed throughout the body, including the central nervous system (CNS). Within the CNS, various isoforms of TGF-beta are produced by both glial and neural cells. When evaluated in either cell culture or in vivo models, the various isoforms of TGF-beta have been shown to have potent effects on the proliferation, function, or survival of both neurons and all three glial cell types, astrocytes, microglia and oligodendrocytes. TGF-beta has also been shown to play a role in several forms of acute CNS pathology including ischemia, excitotoxicity and several forms of neurodegenerative diseases including multiple sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease.
 ...
PMID:TGF-beta in the central nervous system: potential roles in ischemic injury and neurodegenerative diseases. 962 Jun 42

The bioactive lipid platelet-activating factor (PAF) accumulates in brain during injury, seizures and ischemia and may, in addition, be significant in AIDS dementia and in other neurodegenerative diseases. We have used plasma-type recombinant PAF acetylhydrolase (rPAF-AH) to test the hypothesis that PAF accumulation is involved in early events leading to neuronal apoptosis during excitotoxic neuronal injury. Neuronal cultures were labeled with FITC-12-dUTP (TUNEL technique) and propidium iodide, digitized using fluorescence microscopy and a chilled 3CCD color camera, and analyzed with 2D graphics analysis software. N-methyl-D-aspartate (NMDA) (50 microM, 2 hr) induced a 2.5-fold increase in apoptosis of hippocampal neurons compared with controls when analyzed 24 hr after NMDA treatment. Hippocampal neurons receiving rPAF-AH (20 microg/ml) before, during, and after NMDA treatment demonstrated a concentration-dependent neuroprotective effect which resulted in 47% and 30% neuroprotection against 50 and 100 microM NMDA, respectively. The noncompetitive NMDA receptor antagonist MK-801(300 nM) completely inhibited apoptosis caused by NMDA. The neuroprotective effect of rPAF-AH against NMDA-induced apoptosis was confirmed using as additional criteria, histone release, electron microscopy, and DNA laddering. Neuroprotection elicited by rPAF-AH demonstrates that PAF is an injury mediator in NMDA-induced neuronal apoptosis and that the recombinant protein is potentially useful as a therapeutic approach.
 ...
PMID:Recombinant plasma-type platelet-activating factor acetylhydrolase attenuates NMDA-induced hippocampal neuronal apoptosis. 975 96

The brain includes glial cells (astrocytes, microglia and oligodendrocytes) and endothelial cells in addition to neurons. Under some pathological conditions, it is invaded by leukocytes such as neutrophils, monocytes/macrophages and lymphocytes. Intercellular communication across these cell species is supposed to play crucial roles both in the brain functions and dysfunctions. However, the molecular basis of such intercellular communication remains unclear. We have studied the roles of cytokines and chemokines, which have been investigated as essential mediators in the immune and inflammatory systems, in intercellular communication across neurons, glial cells, endothelial cells and leukocytes. Messenger RNA expression of cytokines such as interleukin-1 beta was induced in brain microglia by i.p. injection of excitotoxin and neurostimulant, at least, partly via catecholaminergic systems. Messenger RNA of other cytokines such as leukemia inhibitory factor was induced in astrocytes. This cytokine specifically induced nociceptin mRNA in the cultured cortical neurons. Constitutive expression of some chemokines such as fractalkine and stromal cell derived factor-1 alpha was observed in the brain, suggesting that they play important roles in maintenance of brain homeostasis or determination of the patterning of neurons and/or glial cells in the developing and adult brains. Cytokines such as interleukin-1 beta and chemokines such as monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 alpha were produced in ischemic brain and implicated in ischemic brain injury. In addition to ischemia, cytokines, chemokines and their receptors have been shown to be involved in various neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and AIDS dementia syndrome. They are potential targets for therapeutic intervention for neurodegenerative diseases.
 ...
PMID:[Cytokines and chemokines: mediators for intercellular communication in the brain]. 1176 2