Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.
 ...
PMID:Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. 926 33

Overexpression of Cu,Zn superoxide dismutase (SOD1) reduces ischemic injury in some stroke models but exacerbates injury in a neonatal stroke model and in other settings. The current study used a SOD1 transgenic (SOD1-Tg) murine cortical culture system, derived from the same mouse strain previously used for the stroke models, to identify conditions that determine whether SOD1 overexpression in neurons is protective or detrimental. The nitric oxide (NO) donors S-nitroso-N-acetylpenicillamine, spermine-NONOate, and diethylamine-NONOate produced less death in SOD1-Tg neurons than in wild-type neurons (p < 0.01). Also, NO produced markedly less 3-nitrotyosine in SOD1-Tg cells. In contrast, the superoxide generator menadione produced significantly greater death and nearly twice as much 2'7'-dichlorofluorescein fluorescence in SOD1-Tg neurons than in wild-type neurons, suggesting increased peroxide formation in the SOD1-Tg cells. No significant difference was observed in the vulnerability of the two cell types to H2O2, the product of the SOD reaction. Overexpression of SOD1 also had no effect on neuronal vulnerability to glutamate, N-methyl-D-aspartate, or kainate. These observations suggest that SOD1 overexpression can reduce neuronal death under conditions where peroxynitrite formation is a significant factor, but may exacerbate neuronal death under conditions of rapid intracellular superoxide formation or impaired H2O2 disposal.
 ...
PMID:Differing effects of copper,zinc superoxide dismutase overexpression on neurotoxicity elicited by nitric oxide, reactive oxygen species, and excitotoxins. 1069 74

Patient-supported foundations have had a significant impact on the scope of therapy development for the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). In addition to sponsoring the investigation of potential curative therapies, the ALS Therapy Development Foundation (ALS-TDF) has also created an independent in vivo animal screening laboratory and is systematically evaluating the potential therapeutic benefit of drugs already approved by the FDA. A stepwise process of approved drug database development, in vitro drug screening using cell cultures, and 'theoretical' drug screening based on known drug mechanisms of action has narrowed the field from 1600 FDA-approved drugs to 90 candidates with potential therapeutic benefit. These drugs are now being evaluated in vivo using two animal models of ALS-the rat 'stroke' model and the transgenic SOD1 mouse model. Drug candidates showing significant benefit in these models compared with the current standard treatment for ALS will be selected for application in human patients.
 ...
PMID:A patient-supported strategy for therapy development in amyotrophic lateral sclerosis (ALS). 1155 74

Oxidative stress generated during stroke is a critical event leading to blood-brain barrier (BBB) disruption with secondary vasogenic edema and hemorrhagic transformation of infarcted brain tissue, restricting the benefit of thrombolytic reperfusion. In this study, the authors demonstrate that ischemia-reperfusion-induced BBB disruption in mice deficient in copper/zinc-superoxide dismutase (SOD1) was reduced by 88% ( P < 0.0001) and 73% ( P < 0.01), respectively, after 3 and 7 hours of reperfusion occurring after 1 hour of ischemia by the inhibition of matrix metalloproteinases. Accordingly, the authors show that local metalloproteinase-generated proteolytic imbalance is more intense in ischemic regions of SOD1 mice than in wild-type litter mates. Moreover, active in situ proteolysis is, for the first time, demonstrated in ischemic leaking capillaries that produce reactive oxygen species. By showing that oxidative stress mediates BBB disruption through metalloproteinase activation in experimental ischemic stroke, this study provides a new target for future therapeutic strategies to prevent BBB disruption and potentially reperfusion-triggered intracerebral hemorrhage.
 ...
PMID:Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. 1174 Feb

Mitochondria are the powerhouse of the cell. Their primary physiological function is to generate ATP through oxidative phosphorylation via the electron transport chain. Reactive oxygen radicals generated from mitochondria have been implicated in acute brain injuries, like stroke and neurodegeneration. Recent studies have shown that mitochondrially formed oxidants are mediators of molecular signaling and have implicated mitochondria-dependent apoptosis involving pro- and antiapoptotic protein binding, the release of cytochrome c and Smac, the activation of downstream caspase-9 and -3, and the fragmentation of DNA. Oxidative stress and the redox state are also implicated in the survival signaling pathway that involves phosphatidylinositol 3-kinase (PI3-K)/Akt and downstream signaling molecular bindings like Bad/Bcl-X(L) and phosphorylated Bad/14-3-3. Genetically modified mice (SOD1, SOD2) or rats that overexpress or are deficient in superoxide dismutase have provided strong evidence in support of the role of mitochondrial dysfunction and oxidative stress as determinants of neuronal death/survival after stroke and neurodegeneration.
 ...
PMID:Mitochondrial dysfunction and oxidative stress as determinants of cell death/survival in stroke. 1596 64

Epigallocatechin gallate (EGCG) is a constituent of green tea, and increasing evidence suggests that EGCG has neuroprotective effects on oxidative stress-injured neuronal cells, especially motoneurons. Although the neuroprotective effects of EGCG have been demonstrated in Parkinson's and Alzheimer's diseases and ischemic stroke models, there has been no report on the effect of EGCG on an in vivo model of amyotrophic lateral sclerosis (ALS). This study was undertaken to evaluate the effect of EGCG on ALS model mice with the human G93A mutated Cu/Zn-superoxide dismutase (SOD1) gene. We treated each group of 11 ALS model mice with EGCG (1.5, 2.9, and 5.8 microg/g body weight), dissolved in 0.5 ml of 0.9% sterile NaCl, and one group of 11 with 0.5 ml of 0.9% sterile NaCl (control group) intraorally every day after 60 days of age (presymptomatic treatment). The treatment of more than 2.9 microg EGCG/g body weight significantly prolonged the symptom onset and life span, preserved more survival signals, and attenuated death signals. These data suggest that EGCG could be a potential therapeutic candidate for ALS as a disease-modifying agent.
 ...
PMID:The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice. 1635 50

Nuclear factor-kappa B (NF-kappaB) is activated by oxidative stress such as that induced by transient focal cerebral ischemia (tFCI). Whether NF-kappaB has a role in cell survival or death in stroke is a matter of debate. We proposed that the status of oxidative stress may determine its role in cell death or survival after focal ischemia. To characterize the coordinated expression of genes in NF-kappaB signaling after mild cerebral ischemia, we investigated the temporal profile of a NF-kappaB-pathway-focused DNA array after 30 mins of tFCI in wild-type (WT) mice and human copper/zinc-superoxide dismutase transgenic (SOD1 Tg) mice that had a significantly reduced level of superoxide. Differentially expressed genes among 96 NF-kappaB-related genes were further confirmed and compared in the WT and SOD1 Tg mice using quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. Persistent upregulation of NF-kappaB seen at 7 days in the WT mice was decreased in the SOD1 Tg mice. Lymphocytotrophic cytokine genes such as interleukin-2, interleukin-12, and interferon-alpha1 were increased in the SOD1 Tg mice compared with the WT mice after tFCI. In addition, antiapoptosis factors bcl-2 and tumor necrosis factor receptor-associated factor 1 rapidly increased in the SOD1 Tg mice compared with the WT mice. This study indicates that reduced oxidative stress by SOD1 overexpression increased NF-kappaB-related rapid defenses, such as immune response and antiapoptosis factors, and prevented brain damage after tFCI-induced oxidative stress.
 ...
PMID:Reduced oxidative stress promotes NF-kappaB-mediated neuroprotective gene expression after transient focal cerebral ischemia: lymphocytotrophic cytokines and antiapoptotic factors. 1686 54

The pathogenesis of cerebral malaria, a major complication of Plasmodium falciparum infection, relies on mechanisms such as cytokine production and cytoadherence of parasitized red blood cells (PRBCs) on microvascular endothelial cells. In this way parasites avoid spleen clearance by sequestration in post-capillary venules of various organs including the brain. Infected erythrocytes adhesion has also been shown to have molecular signaling consequences providing insight on how tissue homeostasis could be comprised by endothelium perturbation. Our previous work demonstrated that PRBCs adhesion to human lung endothelial cells (HLEC) induces caspases activation, oxidative stress and apoptosis. Cytoplasmic Cu/Zn superoxide dismutase (SOD1), which provides the first line of defense against oxidative stress within a cell, is now used as a treatment of numerous diseases including traumatic brain injury and ischemic stroke. In this report, we demonstrated that transient supplementation of SOD1 protects endothelial cells against P. falciparum induced oxidative stress and apoptosis. We also showed a significant decrease in PRBCs cytoadherence through a downregulation of ICAM-1 and an induction of iNOS. Protection of endothelium via antioxidant delivery may constitute a relevant strategy in cerebral malaria treatment.
 ...
PMID:Transient supplementation of superoxide dismutase protects endothelial cells against Plasmodium falciparum-induced oxidative stress. 1693 Jul 39

Reactive oxygen species contribute to neuronal death following cerebral ischemia. Prior studies using transgenic animals have demonstrated the neuroprotective effect of the antioxidant, copper/zinc superoxide dismutase (SOD1). In this study, we investigated whether SOD1 overexpression using gene therapy techniques in non-transgenic animals would increase neuronal survival. A neurotropic, herpes simplex virus-1 (HSV-1) vector containing the SOD1 gene was injected into the striatum either before or after transient focal cerebral ischemia. Striatal neuron survival at 2 days was improved by 52% when vector was delivered 12-15 h prior to ischemia and by 53% when vector delivery was delayed 2 h following ischemia. These data add to the growing literature, which suggests that an antioxidant approach, perhaps by employing gene therapy techniques, may be beneficial in the treatment of stroke.
 ...
PMID:Gene therapy using SOD1 protects striatal neurons from experimental stroke. 1711 31

Extracellular superoxide dismutase (SOD3) is a homotetrameric copper- and zinc-containing glycoprotein with affinity for heparin. The level of SOD3 is particularly high in blood vessel walls and in the lungs. The enzyme has multiple roles including protection of the lungs against hyperoxia and preservation of nitric oxide. The common mutation R213G, which reduces the heparin affinity of SOD3, is associated with increased risk of myocardial infarctions and stroke. We report the first crystal structure of human SOD3 at 1.7 A resolution. The overall subunit fold and the subunit-subunit interface of the SOD3 dimer are similar to the corresponding structures in Cu-Zn SOD (SOD1). The metal-binding sites are similar to those found in SOD1, but with Asn180 replacing Thr137 at the Cu-binding site and a much shorter loop at the zinc-binding site. The dimers form a functional homotetramer that is fashioned through contacts between two extended loops on each subunit. The N- and C-terminal end regions required for tetramerisation and heparin binding, respectively, are highly flexible. Two grooves fashioned by the tetramer interface are suggestive as the probable sites for heparin and collagen binding.
 ...
PMID:The structure of human extracellular copper-zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collagen binding. 1928 27


1 2 3 Next >>