Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

Haan, Harmen H. de; Ijzermans, Anke C M; Haan, J. de; Belle, H. Van; Hasaart, T. H. M.

doi:10.1203/00006450-199411000-00010

Cited by 15 publications

(6 citation statements)

References 21 publications

(25 reference statements)

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“…This was confirmed by the low concentrations of purine and pyrimidine metabolites in the siblings. These concentrations were comparable to the baseline CSF purine concentrations in fetal lambs as observed by De Haan et al (34). The umbilical cords of the instrumented lambs were clamped to mimic delivery.…”

Section: Discussionsupporting

confidence: 58%

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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Section: Discussionsupporting

confidence: 58%

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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“…This was confi rmed by the low concentrations of purine and pyrimidine metabolites in the siblings. These concentrations were comparable to the normotensive CSF purine metabolite concentrations in fetal lambs as observed by De Haan et al [25] . The umbilical cords of the instrumented lambs were clamped to mimic delivery.…”

Section: Discussionsupporting

confidence: 70%

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

Os¹,

Abreu

Hopman

et al. 2006

Neonatology

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Background: Insufficient cerebral O₂ supply leads to cellular energy failure and loss of brain cell function. The relationship between the severity of cellular energy failure due to hemorrhagic hypotension and the loss of electrocortical brain activity (ECBA), as a measure of brain cell function, is not yet fully elucidated in near-term born lambs. Objectives: To study the relationship between cerebral purine and pyrimidine metabolism, as a measure of brain cell energy failure, and brain cell function after hemorrhagic hypotension in near-term born lambs. Methods: Eight near-term lambs (term 147 days) were delivered at 131 days of gestation. After a stabilization period, mean arterial blood pressure was reduced till 30% of baseline by withdrawal of blood. Cerebrospinal fluid (CSF) was obtained at the end of the hypotensive period (2.5 h). CSF from 8 siblings was used for comparison. HPLC was used to determine purine and pyrimidine metabolites in CSF, as a measure of cellular energy failure. ECBA was calculated as the root mean square value of a band-filtered (2–16 Hz) one-channel EEG. Results: Values of guanosine, inosine, hypoxanthine, xanthine and uridine were significantly higher, while ECBA was significantly lower after hemorrhagic hypotension than control values. The concentrations of inosine, hypoxanthine, xanthine and uridine were significantly negatively linearly related to ECBA. Conclusions: Brain cell function is negatively related to concentrations of inosine, hypoxanthine, xanthine and uridine in the CSF after hemorrhagic hypotension in near-term born lambs.

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“…High levels of adenosine and hypoxanthine accumulate in a few minutes. During reperfusion, these metabolic products are further metabolized by xanthine oxidase to xanthine and uric acid [57], resulting in their build up in blood and tissues such as the brain [58]. The activity of xanthine oxidase in the resting brain is very low [59], but during cerebral ischemia, a massive conversion of xanthine dehydrogenase to xanthine oxidase takes place, regulated by the calciumdependent protease calpain [60].…”

Section: Free Radicals During the Reperfusion Phasementioning

confidence: 99%

Free Radicals and Brain Damage in the Newborn

Buonocore

Perrone²,

Bracci³

2001

Neonatology

180

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Newborns and particularly preterm infants are at high risk of oxidative stress and they are very susceptible to free radical oxidative damage. Indeed, there is evidence of an imbalance between antioxidant- and oxidant-generating systems which causes oxidative damage. The brain may be especially at risk of free radical-mediated injury because neuronal membranes are rich in polyunsaturated fatty acids and because the human newborn has a relative deficiency of brain superoxide dismutase and glutathione peroxidase. The brain of the term fetus is at higher risk of oxidative stress than that of the preterm fetus, as a consequence of its higher concentration of polyunsaturated fatty acids and the maturity of the N-methyl-D-aspartate receptor system at term. There seems to be a maturation-dependent window of vulnerability to free radical attack during oligodendrocyte development. Early in its differentiation, the oligodendrocyte may be vulnerable because of active acquisition of iron for differentiation at a time of relative delay in the development of certain key antioxidant defenses in the brain. Excess free iron and deficient iron-binding and -metabolizing capacity are additional features favoring oxidant stress in premature infants. Free radicals may be generated by different mechanisms, such as ischemia-reperfusion, neutrophil and macrophage activation, Fenton chemistry, endothelial cell xanthine oxidase, free fatty acid and prostaglandin metabolism and hypoxia. Reactive oxidant production by these different mechanisms contributes in a piecewise manner to the pathogenesis of perinatal brain injury.

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Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

Cited by 15 publications

References 21 publications

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

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

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

Free Radicals and Brain Damage in the Newborn

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