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

We report a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) who harbored a novel missense mutation at mtDNA position 9957 in the gene specifying subunit III of cytochrome c oxidase (COX III). This T-->C transition converted Phe-251, a highly conserved amino acid in the C-terminus of the polypeptide, to Leu. The mutation, which was not present in 107 normal controls or in 57 patients with various mitochondrial diseases, was heteroplasmic in both muscle and blood of the proband and in blood from his asymptomatic mother. These results provide evidence that the MELAS clinical phenotype can be due not only to mutations in mtDNA-encoded tRNA genes, but in polypeptide-coding genes as well.
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PMID:A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene. 749 73

We report a 47-year-old female patient showing clinical features of chronic progressive external ophthalmoplegia (CPEO) without stroke-like episodes. Large scale deletion of mitochondrial DNA (mtDNA) was not found in her biopsied muscle, whereas the A-->G transition at position 3243 (A3243G) was detected. The patient's mother had diabetes mellitus, suggesting maternal inheritance. This mutation is usually associated with MELAS, but wide clinical variety of the mutation has been recognized. Although several patients of CPEO with A3243G mutation (CPEO3243) have been found in the Western countries, only one case has been reported in detail in Japan. The CPEO3243 patients, including ours, show retinopathy less frequently, but diabetes mellitus and hearing loss more frequently than CPEO patients with deletions of mtDNA (CPEO delta). CPEO3243 is usually inherited maternally, but almost all CPEO delta is sporadic. With regard to COX activity of biopsied muscles, CPEO3243 resembles CPEO delta more than MELAS3243. This suggests that how the mutant mtDNA is distributed among cells or tissues may have more significant effect on clinical phenotype than what type of mtDNA mutation exists. The presence of such a CPEO3243 patient like ours could be an important suggestion toward further understanding of mitochondrial diseases.
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PMID:[A case of mitochondrial encephalomyopathy showing ophthalmoplegia, diabetes mellitus and hearing loss associated with the A3243G mutation of mitochondrial DNA]. 924 43

Acetylsalicylic acid (ASA, Aspirin) is an anti-inflammatory drug with a wide spectrum of pharmacological activities and multiple sites of action. Apart from its preventive actions against stroke due to its antithrombotic properties, recent data in the literature suggest that high concentrations of ASA also exert direct neuroprotective effects. We have used an in vitro model of brain ischaemia using rat forebrain slices deprived of oxygen and glucose to test ASA neuroprotective properties. We have found that ASA inhibits neuronal damage at concentrations lower than those previously reported (0.1-0.5 mM), and that these effects correlate with the inhibition of excitatory amino acid release, of NF-kappaB translocation to the nucleus and iNOS expression caused by ASA. All of these three mechanisms may mediate the neuroprotective effects of this drug. Our results also show that the effects of ASA are independent of COX inhibition. Taken together, our present findings show that ASA is neuroprotective in an in vitro model of brain ischaemia at doses close to those recommended for its antithrombotic effects.
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PMID:Mechanisms of the neuroprotective effect of aspirin after oxygen and glucose deprivation in rat forebrain slices. 1076 Mar 73

Cytochrome-c oxidase subunit VIaH (COXVIaH) has been implicated in the modulation of COX activity. A gene-targeting strategy was undertaken to generate mice that lacked COXVIaH to determine its role in regulation of oxidative energy production and mechanical performance in cardiac muscle. Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered assembly of the holoenzyme COX. However, total myocardial ATP was not significantly different in wild-type and mutant mice. Myocardial performance was examined using the isolated working heart preparation. As left atrial filling pressure increased, hearts from mutant mice were unable to generate equivalent stroke work compared with hearts from wild-type mice. Direct measurement of left ventricular end-diastolic volume using magnetic resonance imaging revealed that cardiac dysfunction was a consequence of impaired ventricular filling or diastolic dysfunction. These findings suggest that a genetic deficiency of COXVIaH has a measurable impact on myocardial diastolic performance despite the presence of normal cellular ATP levels.
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PMID:Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH. 1178 23

Age has a powerful effect on enhanced susceptibility to neurodegenerative diseases, including susceptibility to stroke and cognitive impairment (CI) even in optimally healthy individuals. We critically evaluated the notion that oxidative stress increases in aging brain. Rigorous studies show logarithmic age-dependent increases in oxidized proteins and oxidized DNA lesions. Decreased activity of antioxidant protective enzymes does not account for the observed increases. The reactivity of the lipid oxidation product 4-hydroxy-2-nonenal (HNE) with key mitochondria enzymes may be important in the age-dependent loss in energy generation and enhanced susceptibility of neurons to apoptosis. Age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) show significant promise. Vitamin E supplementation did not show major beneficial effect on cognitive functions. Major clinical trials for Alzheimer's disease (AD) involving cycloxygenase-II (COX II) inhibitors and amyloid-beta vaccination have been discontinued. Novel therapeutics based on blocking neuron damaging neuroinflammatory processes show great promise for abating dementia progression although they have yet to make it to clinical practice.
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PMID:Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. 1239 83

In vivo studies have indicated that systemically administered bilobalide, a sesquiterpene trilactone constituent of Ginkgo biloba leaf extracts, can reduce cerebral edema produced by triethyltin, decrease cortical infarct volume in certain stroke models, and reduce cerebral ischemia. In vitro and ex vivo studies indicate that bilobalide has multiple mechanisms of action that may be associated with neuroprotection, including its preservation of mitochondrial ATP synthesis, its inhibition of apoptotic damage induced by staurosporine or by serum-free medium, its suppression of hypoxia-induced membrane deterioration in the brain, and its actions of increasing the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome c oxidase and the ND1 subunit of NADH dehydrogenase. As multiple modes of action may apply to bilobalide, it could be useful in developing therapy for disorders involving cerebral ischemia and neurodegeneration.
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PMID:Bilobalide and neuroprotection. 1245 32

Non steroidal anti-inflammatory drugs (NSAIDs) are one of the categories of drugs most frequently used by elderly people, and maybe the most self-prescribed drugs. Both coronary events, and stroke, can be prevented by daily aspirin assumption. Other NSAIDs, except selective COX-2 inhibitors (coxibs), seem to reduce the incidence of cardiovascular events, but a definitive judgement is yet impossible. Moreover, these drugs cause more than 100,000 serious gastric adverse events each year in the US, and the risk increases exponentially in the elderly. Coxibs cause less gastric damage, but their cost is very high. Moreover, NSAIDs inhibit renal function and reduce the efficacy of diuretics and angiotensin converting enzyme (ACE) inhibitors, often used by elderly patients. Recent studies show that even COX-2 is important in the renal physiology, so that even coxibs appear not to be avoided of renal toxicity. Both gastric and renal toxicity induced by traditional NSAIDs and coxibs seem to be related to the fact that these drugs inhibit the synthesis of prostaglandins (PGs), but not those of leukotrienes (LTs), important mediators of inflammation and of many other physiopatological events. Newly developed anti-inflammatory drugs block both COX and the 5-LOX metabolic pathways, inhibiting the formation of PGs, thromboxanes (TXs) and LTs. The inhibition of the LT synthesis increases the anti-inflammatory efficacy (especially in pneumological and rheumatological diseases), reducing the risk of gastric damage. Even if preliminary data seem to be very interesting, further clinical safety data on these drugs obtained from elderly oriented trials need to be available before to give a final evaluation.
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PMID:Clinical perspectives of anti-inflammatory therapy in the elderly: the lipoxigenase (LOX)/cycloxigenase (COX) inhibition concept. 1506 7

Inhibition of neuronal cyclooxygenase-2 (COX-2) and hence prostaglandin E2 (PGE2) synthesis by non-steroidal anti-inflammatory drugs has been suggested to protect neuronal cells in a variety of pathophysiological situations including Alzheimer's disease and ischemic stroke. Ascorbic acid (vitamin C) has also been shown to protect cerebral tissue in a variety of experimental conditions, which has been attributed to its antioxidant capacity. In the present study, we show that ascorbic acid dose-dependently inhibited interleukin-1beta (IL-1beta)-mediated PGE2 synthesis in the human neuronal cell line, SK-N-SH. Furthermore, in combination with aspirin, ascorbic acid augmented the inhibitory effect of aspirin on PGE2 synthesis. However, ascorbic acid had no synergistic effect along with other COX inhibitors (SC-58125 and indomethacin). The inhibition of IL-1beta-mediated PGE2 synthesis by ascorbic acid was not due to the inhibition of the expression of COX-2 or microsomal prostaglandin E synthase (mPGES-1). Rather, ascorbic acid dose-dependently (0.1-100 microM) produced a significant reduction in IL-1beta-mediated production of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a reliable indicator of free radical formation, suggesting that the effects of ascorbic acid on COX-2-mediated PGE2 biosynthesis may be the result of the maintenance of the neuronal redox status since COX activity is known to be enhanced by oxidative stress. Our results provide in vitro evidence that the neuroprotective effects of ascorbic acid may depend, at least in part, on its ability to reduce neuronal COX-2 activity and PGE2 synthesis, owing to its antioxidant properties. Further, these experiments suggest that a combination of aspirin with ascorbic acid constitutes a novel approach to render COX-2 more sensitive to inhibition by aspirin, allowing an anti-inflammatory therapy with lower doses of aspirin, thereby avoiding the side effects of the usually high dose aspirin treatment.
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PMID:Ascorbic acid enhances the inhibitory effect of aspirin on neuronal cyclooxygenase-2-mediated prostaglandin E2 production. 1652 23

We investigated the mechanisms by which inhibitors of prostaglandin G/H synthase-2 (PGHS-2; known colloquially as COX-2) increase the incidence of myocardial infarction and stroke. These inhibitors are believed to exert both their beneficial and their adverse effects by suppression of PGHS-2-derived prostacyclin (PGI(2)) and PGE(2). Therefore, the challenge remains to identify a mechanism whereby PGI(2) and PGE(2) expression can be suppressed while avoiding adverse cardiovascular events. Here, selective inhibition, knockout, or mutation of PGHS-2, or deletion of the receptor for PGHS-2-derived PGI(2), was shown to accelerate thrombogenesis and elevate blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin. PGE(2) biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). We show that deletion of mPGES-1 depressed PGE(2) expression, augmented PGI(2) expression, and had no effect on thromboxane biosynthesis in vivo. Most importantly, mPGES-1 deletion affected neither thrombogenesis nor blood pressure. These results suggest that inhibitors of mPGES-1 may retain their antiinflammatory efficacy by depressing PGE(2), while avoiding the adverse cardiovascular consequences associated with PGHS-2-mediated PGI(2) suppression.
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PMID:Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. 1661 56

Induction of COX-2 expression and enzymatic activity promotes neuronal injury in a number of models of neurological disease. Inhibition of COX-2 activity, either genetically or pharmacologically, has been shown to be neuroprotective in rodent models of stroke, Parkinson's disease, and amyotrophic lateral sclerosis. Inhibition of COX activity with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces inflammation and amyloid accumulation in murine transgenic models of Familial Alzheimer's disease, and the use of NSAIDs decreases the risk of developing Alzheimer's disease in healthy aging populations. COX-mediated neuronal injury is presumed be due to downstream effects of one or more prostaglandin products including PGE2, PGD2, PGF2alpha, PGI2 (prostacylin) and TXA2 (thromboxane) that effect cellular changes through activation of specific prostaglandin receptor subtypes and second messenger systems. In this proceeding, we review recent data demonstrating effects of prostaglandin signaling on neuronal viability that are paradoxically protective, when taken in the context that COX-2 induces neuronal injury in the setting of excitotoxicity. Conversely, in the context of an inflammatory stimulus, the EP2 receptor enhances neuronal injury. These findings argue for an additional level of complexity in the prostaglandin response in neurological disease.
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PMID:Function of COX-2 and prostaglandins in neurological disease. 1790 52


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