Changes in Levels of Purine and Pyrimidine Nucleotides During Acute Hypoxia and Recovery in Neonatal Rat Brain

Hisanaga, Kinya; Oda, Hiroshi; Kogure, Kyuya

doi:10.1111/j.1471-4159.1986.tb00763.x

Cited by 53 publications

(25 citation statements)

References 31 publications

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“…The low levels of most purine and pyrimidine compounds in colon tissues may indicate a relatively slower colon cell growth compared with stomach cells, as a recent study has shown that the nucleotide pools continuously decrease as the growth stage moves from the exponential to stationary phase in Escherichia coli (41). A challenging but intriguing alternative is that the levels of nucleotide pools may reflect the oxygen availability and its dependency in each tissue because hypoxic stress has been found to reduce purine and pyrimidine pools (42). The high-energy charge in colon tissues, despite the low total adenylate level, might be maintained by AMP deaminase reaction, which is known to stabilize the energy charge by decomposing adenylate (43).…”

Section: Resultsmentioning

confidence: 99%

Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-Flight Mass Spectrometry

et al. 2009

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Most cancer cells predominantly produce energy by glycolysis rather than oxidative phosphorylation via the tricarboxylic acid (TCA) cycle, even in the presence of an adequate oxygen supply (Warburg effect). However, little has been reported regarding the direct measurements of global metabolites in clinical tumor tissues. Here, we applied capillary electrophoresis time-of-flight mass spectrometry, which enables comprehensive and quantitative analysis of charged metabolites, to simultaneously measure their levels in tumor and grossly normal tissues obtained from 16 colon and 12 stomach cancer patients. Quantification of 94 metabolites in colon and 95 metabolites in stomach involved in glycolysis, the pentose phosphate pathway, the TCA and urea cycles, and amino acid and nucleotide metabolisms resulted in the identification of several cancer-specific metabolic traits. Extremely low glucose and high lactate and glycolytic intermediate concentrations were found in both colon and stomach tumor tissues, which indicated enhanced glycolysis and thus confirmed the Warburg effect. Significant accumulation of all amino acids except glutamine in the tumors implied autophagic degradation of proteins and active glutamine breakdown for energy production, i.e., glutaminolysis. In addition, significant organ-specific differences were found in the levels of TCA cycle intermediates, which reflected the dependency of each tissue on aerobic respiration according to oxygen availability. The results uncovered unexpectedly poor nutritional conditions in the actual tumor microenvironment and showed that capillary electrophoresis coupled to mass spectrometry-based metabolomics, which is capable of quantifying the levels of energy metabolites in tissues, could be a powerful tool for the development of novel anticancer agents that target cancerspecific metabolism. [Cancer Res 2009;69(11):4918-25]

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Section: Resultsmentioning

confidence: 99%

Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-Flight Mass Spectrometry

et al. 2009

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“…Purine and pyrimidine metabolite concentrations are known to increase after a severe reduction in cerebral O 2 supply in the fetus (6, 34, 50 -53), newborn (7,54), and adult (5,41,53,55). However, it appears that there is a difference between the immature and the mature brain in the relationship between the breakdown of ATP and cerebral function during hypoxemia.…”

Section: Purine and Pyrimidine Metabolism And Eegmentioning

confidence: 85%

“…Because the synthesis of uridine triphosphate (UTP) and cytidine triphosphate (CTP) also depends on the ATP level, it is therefore to be expected that the decline in ATP content during hypoxemia is also followed by an accumulation of pyrimidine catabolites, at the expense of UTP and CTP contents (7).…”

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confidence: 99%

Purine and Pyrimidine Metabolism and Electrocortical Brain Activity during Hypoxemia in Near-Term Lambs

Os¹,

Abreu²,

Hopman³

et al. 2004

Pediatr Res

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Insufficient cerebral O 2 supply leads to brain cell damage and loss of brain cell function. The relationship between the severity of hypoxemic brain cell damage and the loss of electrocortical brain activity (ECBA), as measure of brain cell function, is not yet fully elucidated in near-term newborns. We hypothesized that there is a strong relationship between cerebral purine and pyrimidine metabolism, as measures of brain cell damage, and brain cell function during hypoxemia. Nine near-term lambs (term, 147 d) were delivered at 131 (range, 120-141) d of gestation. After a stabilization period, prolonged hypoxemia (fraction of inspired oxygen, 0.10; duration, 2.5 h) was induced. Mean values of carotid artery blood flow, as a measure of cerebral blood flow, and ECBA were calculated over the last 3 min of hypoxemia. At the end of the hypoxemic period, cerebral arterial and venous blood gases were determined and CSF was obtained. CSF from 11 normoxemic siblings was used for baseline values. HPLC was used to determine purine and pyrimidine metabolites in CSF, as measures of brain cell damage. Concentrations of purine and pyrimidine metabolites were significantly higher in hypoxemic lambs than in their siblings, whereas ECBA was lower in hypoxemic lambs. Significant negative linear relationships were found between purine and pyrimidine metabolite concentrations and, respectively, cerebral O 2 supply, cerebral O 2 consumption, and ECBA. We conclude that brain cell function is related to concentrations of purine and pyrimidine metabolites in the CSF. Reduction of ECBA indeed reflects the measure of brain damage due to hypoxemia in near-term newborn lambs. Despite the increase in survival of preterm infants, long-term morbidity has not changed (1). Hypoxia-ischemia-related brain damage is an important contributor to perinatal mortality and long-term morbidity in survivors (2).The immature brain is very vulnerable to disturbances in cerebral oxygenation and hemodynamics. Cerebral O 2 supply depends on both CaO 2 and CBF. Cerebral hypoxia is defined as an insufficient O 2 supply to the brain, resulting from either hypoxemia (decreased CaO 2 ) or hypoperfusion (decreased CBF). During hypoxemia, the brain is considered to be protected adequately from injury by an increase in CBF to preserve cerebral O 2 supply and to stabilize brain metabolism, unless cerebral ischemia occurs from supervening systemic hypotension. With the neuronal oxygen and glucose debts arising from severe hypoxemia, oxidative metabolism shifts to anaerobic glycolysis, with its inefficient generation of highenergy phosphate reserves, necessary to maintain cellular ionic gradients and other metabolic processes. However, when hypoxemia progresses, cellular energy failure ultimately occurs, which, if not promptly reversed, results in decreased neuronal viability and death of the cell (3).During insufficient cerebral O 2 supply, an accumulation of purine metabolites, which are the degradation products from high-energy phosphate compounds (ATP, ADP, and AMP),...

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“…Astrocytes generally express low levels of GluRs (e.g., [5]) but robustly express P2 nucleotide adenosine triphosphate (ATP) receptors (see [6]). ATP can also act as an excitotoxin via activation of P2 receptors [7,8] and extracellular ATP is significantly elevated both in vitro and in vivo under hypoxic and ischemic conditions [9][10][11][12][13][14][15][16]. Prolonged application of ATP or ATP analogues produces necrotic and delayed cell damage in both neurons and astrocytes in vitro and in vivo [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Cooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protection

et al. 2018

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Excitotoxicity is the principle mechanism of acute injury during stroke. It is defined as the unregulated accumulation of excitatory neurotransmitters such as glutamate within the extracellular space, leading to over-activation of receptors, ionic disruption, cell swelling, cytotoxic Ca 2+ elevation and a feed-forward loop where membrane depolarisation evokes further neurotransmitter release. Glutamate-mediated excitotoxicity is well documented in neurons and oligodendrocytes but drugs targeting glutamate excitotoxicity have failed clinically which may be due to their inability to protect astrocytes. Astrocytes make up~50% of the brain volume and express high levels of P2 adenosine triphosphate (ATP)-receptors which have excitotoxic potential, suggesting that glutamate and ATP may mediate parallel excitotoxic cascades in neurons and astrocytes, respectively. Mono-cultures of astrocytes expressed an array of P2X and P2Y receptors can produce large rises in [Ca 2+ ]i; mono-cultured neurons showed lower levels of functional P2 receptors. Using high-density 1:1 neuron:astrocyte co-cultures, ischemia (modelled as oxygen-glucose deprivation: OGD) evoked a rise in extracellular ATP, while P2 blockers were highly protective of both cell types. GluR blockers were only protective of neurons. Neither astrocyte nor neuronal mono-cultures showed significant ATP release during OGD, showing that cell type interactions are required for ischemic release. P2 blockers were also protective in normal-density co-cultures, while low doses of combined P2/GluR blockers where highly protective. These results highlight the potential of combined P2/GluR block for protection of neurons and glia.

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Changes in Levels of Purine and Pyrimidine Nucleotides During Acute Hypoxia and Recovery in Neonatal Rat Brain

Cited by 53 publications

References 31 publications

Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-Flight Mass Spectrometry

Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-Flight Mass Spectrometry

Purine and Pyrimidine Metabolism and Electrocortical Brain Activity during Hypoxemia in Near-Term Lambs

Cooperation between NMDA-Type Glutamate and P2 Receptors for Neuroprotection during Stroke: Combining Astrocyte and Neuronal Protection

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