Significance of Brain Tissue Oxygenation and the Arachidonic Acid Cascade in Stroke

Rink, Cameron; Khanna, Savita

doi:10.1089/ars.2010.3474

Cited by 166 publications

(113 citation statements)

References 179 publications

(158 reference statements)

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“…ALOX5AP and COX-2 are important enzymes in the metabolism of arachidonic acid, and their activities are encoded and regulated by the ALOX5AP and COX-2 genes. Therefore, the interactions between the ALOX5AP and COX-2 genes may lead to over-production of arachidonic acid metabolites such as leukotrienes, PGE2, and TXA2, initiation of the arachidonic acid cascade, and effect on the pathogenesis of cerebral infarction (Cimino et al, 2008;Rink and Khanna, 2011;Ward et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Interaction between ALOX5AP-SG13S114A/T and COX-2-765G/C increases susceptibility to cerebral infarction in a Chinese population

Zhou²,

J³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. We made a case-control study to investigate a possible association between ALOX5AP-SG13S114A/T, COX-2-765G/C, and COX-1-50C/T polymorphisms with cerebral infarction in a Chinese population. A total of 411 cases with cerebral infarction were included; 411 controls matched for age, gender, and risk factors were also selected. The ALOX5AP-SG13S114A/T (rs10507391), COX-2-765G/C (rs20417), and COX-1-50C/T (rs3842787) polymorphisms were determined using PCR-RFLP. The generalized multifactor dimensionality reduction method was employed to detect gene-gene interactions. Based on single-gene analysis, there were no significant differences in the genotype and allele frequency distributions of ALOX5AP-SG13S114A/T, COX-2-765G/C, and COX-1-50C/T between the cerebral infarction group and controls. However, in those cases carrying ALOX5AP-SG13S114AA as well as COX-2-765CC, the risk of cerebral infarction increased significantly by 2.84 times (95%CI = 1.324-6.543). The single-gene ALOX5AP-SG13S114A/T, COX-2-765G/C, and COX-1-50C/T polymorphisms appear not to be associated with the development of cerebral infarction in Chinese populations. However, the interaction between ALOX5AP-

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Section: Discussionmentioning

confidence: 99%

Interaction between ALOX5AP-SG13S114A/T and COX-2-765G/C increases susceptibility to cerebral infarction in a Chinese population

Zhou²,

J³

et al. 2013

Genet. Mol. Res.

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“…These results indicate that the COX-1 C50T and COX-2 G765C variants may increase the activity of COX, lead to too much thromboxane production, initiate the AA cascade, and be involved in the pathogenesis of cerebral infarction 39) . In summary, AR is common in Chinese stroke patients and is likely to be multifactorial in origin.…”

Section: Genotype and Platelet Response To Aspirinmentioning

confidence: 91%

Platelet Response to Aspirin in Chinese Stroke Patients is Independent of Genetic Polymorphisms of COX-1 C50T and COX-2 G765C

Zhou

Lin

et al. 2013

JAT

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Aim: Aspirin resistance (AR) is common in Chinese stroke patients taking antiplatelet medications; however, few studies have documented the role of cyclooxygenase (COX)-1 C50T and COX-2 G765C polymorphisms in AR. The aim of this study was to investigate the prevalence of AR in Chinese stroke patients and the relationships between AR and COX-1 C50T and COX-2 G765C polymorphisms, and to evaluate the effect of these polymorphisms on platelet response to aspirin. Methods: We prospectively enrolled 634 Chinese stroke patients. Platelet aggregation testing was performed before and after aspirin administration. The pre-and post-aspirin levels of 11-dehydrothromboxane B2 (11-dTxB2) were determined in urine samples. COX-1 C50T and COX-2 G765C genotypes were determined by a polymerase chain reaction-allelic restriction assay. Results: AR was detected in 129 patients (20.4%), aspirin semi-resistance (ASR) was detected in 28 patients (4.4%), and aspirin sensitivity (AS) was detected in 477 patients (75.2%). There was no association between COX-1 C50T or COX-2 G765C polymorphisms and ASR＋AR. Aspirin could efficiently reduce 11-dTxB2 production by approximately 75%. In addition, platelet aggregation, both in response to arachidonic acid (AA) and adenosine 5'-diphosphate (ADP), was inhibited by more than 80% and 40%, respectively; however, the percentage reduction in platelet aggregation and 11-dTxB2 levels was not significantly different between the COX-1 C50T and COX-2 G765C genotypes (p＞0.05). Conclusions: There was no association between COX-1 C50T and COX-2 G765C polymorphisms and AR in Chinese stroke patients. In addition, COX-1 C50T and COX-2 G765C polymorphisms had no effect on the platelet response to aspirin. J Atheroscler Thromb, 2013; 20:65-72.

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“…In spite of only accounting for 2% of total body weight and not performing the metabolically demanding mechanical work of skeletal muscle, the energy demands of the brain are among the highest of all organs (73). Under normal physiological conditions the metabolic activity of the brain requires 15% of cardiac output (800 ml/min) and 20-25% of total oxygen (49 ml/min) intake (73,81).…”

Section: Hallmarks Of Ischemic Stroke Pathophysiology and Glutamate Rmentioning

confidence: 99%

“…Under normal physiological conditions the metabolic activity of the brain requires 15% of cardiac output (800 ml/min) and 20-25% of total oxygen (49 ml/min) intake (73,81). The majority (*60%) of aerobic oxidation of glucose in brain tissue is requisite for the maintenance and restoration of ionic gradients used for neuronal membrane depolarization and repolarization (81).…”

Section: Hallmarks Of Ischemic Stroke Pathophysiology and Glutamate Rmentioning

confidence: 99%

Inducible Glutamate Oxaloacetate Transaminase as a Therapeutic Target Against Ischemic Stroke

Khanna

Briggs

Rink

2015

Antioxidants & Redox Signaling

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Significance: Glutamate serves multi-faceted (patho)physiological functions in the central nervous system as the most abundant excitatory neurotransmitter and under pathological conditions as a potent neurotoxin. Regarding the latter, elevated extracellular glutamate is known to play a central role in ischemic stroke brain injury. Recent Advances: Glutamate oxaloacetate transaminase (GOT) has emerged as a new therapeutic target in protecting against ischemic stroke injury. Oxygen-sensitive induction of GOT expression and activity during ischemic stroke lowers glutamate levels at the stroke site while sustaining adenosine triphosphate levels in brain. The energy demands of the brain are among the highest of all organs underscoring the need to quickly mobilize alternative carbon skeletons for metabolism in the absence of glucose during ischemic stroke. Recent work builds on the important observation of Hans Krebs that GOT-mediated metabolism of glutamate generates tri-carboxylic acid (TCA) cycle intermediates in brain tissue. Taken together, outcomes suggest GOT may enable the transformative switch of otherwise excitotoxic glutamate into life-sustaining TCA cycle intermediates during ischemic stroke. Critical Issues: Neuroprotective strategies that focus solely on blocking mechanisms of glutamatemediated excitotoxicity have historically failed in clinical trials. That GOT can enable glutamate to assume the role of a survival factor represents a paradigm shift necessary to develop the overall significance of glutamate in stroke biology. Future Directions: Ongoing efforts are focused to develop the therapeutic significance of GOT in stroke-affected brain. Small molecules that target induction of GOT expression and activity in the ischemic penumbra are the focus of ongoing studies. Antioxid. Redox Signal. 22, 175-186.Neurotransmitter Glutamate I n modern neuroscience, glutamate is best known as the principle excitatory neurotransmitter of the mammalian central nervous system. The seminal observation published in 1954 by Hayashi that intracranial and endovascular delivery of glutamate produced seizures (36) sparked an entire field of research on excitatory amino acids and their receptors. Pioneering work from the late 1950's through the 1980's further characterized glutamatergic synaptic transmission (22,29,62) and led to identification of ionotropic (37) and metabotropic (58, 85) receptors, and mechanisms of glutamate uptake (6, 57) and transport (11, 94). As the neurotransmitter role of glutamate was discovered on the basis of pathological seizure activity (36), it is perhaps not surprising that research efforts since have continued to characterize the patho-physiological significance of neurotransmitter glutamate in neurologic disease. In 1957, the first neurotoxic effects of glutamate were described in mouse retina (52). Today, glutamate-mediated neurotoxicity has been implicated in a number of diseases affecting the central nervous system, including epilepsy, Parkinson's disease, multiple sclerosis, and t...

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Significance of Brain Tissue Oxygenation and the Arachidonic Acid Cascade in Stroke

Cited by 166 publications

References 179 publications

Interaction between ALOX5AP-SG13S114A/T and COX-2-765G/C increases susceptibility to cerebral infarction in a Chinese population

Interaction between ALOX5AP-SG13S114A/T and COX-2-765G/C increases susceptibility to cerebral infarction in a Chinese population

Platelet Response to Aspirin in Chinese Stroke Patients is Independent of Genetic Polymorphisms of COX-1 C50T and COX-2 G765C

Inducible Glutamate Oxaloacetate Transaminase as a Therapeutic Target Against Ischemic Stroke

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