Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral hypoxia in the fetus and newborn results in neonatal morbidity and mortality as well as long-term sequelae such as mental retardation, seizure disorders, and cerebral palsy. In the developing brain, determinants of susceptibility to hypoxia should include the lipid composition of the brain cell membrane, the rate of lipid peroxidation, the presence of antioxidant defenses, and the development and modulation of excitatory amino acid neurotransmitter receptors such as the N-methyl-D-aspartate (NMDA) receptor, the intracellular Ca2+, and the intranuclear Ca(2+)-dependent mechanisms. In addition to the developmental status of these cellular components, the response of these potential mechanisms to hypoxia determines the fate of the hypoxic brain cell in the developing brain. Using electron spin resonance spectroscopy of alpha-phenyl-N-tert-butyl-nitrone spin adducts, studies from our laboratory demonstrated that tissue hypoxia results in increased free radical generation in the cortex of fetal guinea pigs and newborn piglets. Pretreatment with MgSO4 significantly decreased the hypoxia-induced increase in free radical generation in the term fetal brain. We also showed that brain tissue hypoxia modifies the NMDA receptor ion-channel recognition and modulatory sites. Furthermore, a higher increase in NMDA receptor agonist-dependent Ca2+ in synaptosomes was demonstrated. The increase in intracellular Ca2+ may activate several enzymatic pathways such as phospholipase A2 and metabolism of archidonic acid by cyclooxygenase and lipoxygenase, conversion of xanthine dehydrogenase to xanthine oxidase by proteases, and activation of nitric oxide synthase. Using inhibitors of each of these enzymes such as cyclooxygenase (indomethacin), lipoxygenase (nordihydroguaiaretic acid), xanthine oxidase (allopurinol), and nitric oxide synthase (N-nitro-L-arginine), studies have shown that these enzyme reactions result in oxygen free radical generation, membrane peroxidation, and cell membrane dysfunction in the hypoxic brain. Specifically, generation of nitric oxide free radicals during hypoxia may lead to nitration and nitrosylation of specific membrane proteins and receptors, resulting in dysfunction of receptors and enzymes. We conclude that hypoxia-induced modification of the NMDA receptor leading to increased intracellular Ca2+ results in free radical generation and cell injury. We suggest that during hypoxia the increased intracellular Ca2+ may lead to increased intranuclear Ca2+ concentration and alter nuclear events including transcription of specific apoptotic genes and activation of endonucleases, resulting in programmed cell death.
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PMID:Mechanisms of perinatal cerebral injury in fetus and newborn. 1081 2

Neonatal hypoxic-ischaemic encephalopathy due to the lack of oxygen at birth can have severe neurological consequences, such as cerebral palsy, or even the death of the asphyxiated newborn. Hypothermia is currently the only therapy included in intensive care neonatal units. This shows a clinical benefit in neonates suffering from hypoxic-ischaemic encephalopathy, mainly because of its ability to decrease the accumulation of excitatory amino acids and its anti-inflammatory, antioxidant, and anti-apoptotic effects. However, hypothermia is not effective in half of the cases, making it necessary to search for new, or to optimize current therapies, with the aim on reducing asphyxia-derived neurological consequences, either as single treatments or in combination with cooling. Within current potential therapies, melatonin, allopurinol, and erythropoietin stand out among the others, with clinical trials on the way. While, stem cells, N-acetylcysteine and noble gases have obtained promising pre-clinical results. Melatonin produces a powerful antioxidant and anti-inflammatory effect, acting as free radical scavenger and regulating pro-inflammatory mediators. Through the inhibition of xanthine oxidase, allopurinol can decrease oxidative stress. Erythropoietin has cell death and neurogenesis as its main therapeutic targets. Keeping in mind the whole scenario of current therapies, management of neonates suffering from neonatal asphyxia could rely on the combination of one or some of these treatments, together with therapeutic hypothermia.
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PMID:[Combined therapy in neonatal hypoxic-ischaemic encephalopathy]. 3110 85