Attenuation of Focal Ischemic Brain Injury in Mice Deficient in the ε1 (NR2A) Subunit of NMDA Receptor
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The role of glutamate neurotoxicity in cerebral ischemia has long been advocated but still remains controversial, because various glutamate receptor (GluR) antagonists showed inconsistent protective efficacy in brain ischemia models. To address this central issue of ischemic brain damage more directly, we used mutant mice deficient in the GluRepsilon1 (NR2A) subunit of NMDA receptor with or without additional heterozygous mutation in the GluRepsilon2 (NR2B) subunit. Those mutant mice, as well as their littermates, were subjected to focal cerebral ischemia by introducing a 6-0 nylon suture from left common carotid artery. Brain injury volumes after 2 hr of suture insertion, as evaluated by 2,3,5-triphenyltetrazolium chloride staining at 24 hr after ischemia, revealed significantly smaller injury size in GluRepsilon1 subunit knock-out mice compared with their wild-type littermates. The reduction in injury volume was not attributable to differences in body temperature or in blood flow during ischemia. Additional heterozygous GluRepsilon2 subunit disruption did not result in further reduction in injury volume. These data directly demonstrate relevance of NMDA receptor-mediated tissue injury after brain ischemia and provide evidence that GluRepsilon1 subunit is involved in these injurious mechanisms.Keywords:
Brain damage
Brain ischemia
To study the pathogenetic and clinical significance of factors of hypoxic brain damage and inflammatory mediators in the development of stroke, to improve the diagnosis using laboratory markers of brain damage and inflammation in patients with acute cerebrovascular accident.We examined 55 people with stroke of the ischemic type at the age of 74 (67; 80) years, the comparison group consisted of 25 volunteers at the age of 65.0 (62.0; 66.5) years. Depending on the outcome of ischemic stroke, patients were assigned to the discharged group or to the deceased group. Blood serum and cerebrospinal fluid (CSF) S100b protein, glial fibrillar acidic protein and interleukin-6 (IL-6); blood serum neurospecific enolase, and cortisol and C-reactive protein (CRP) were determined. Clinical blood test and assessment of fibrinogen content were performed on days 1, 3 and 10 of stroke.There is an increase in the levels of markers of brain tissue damage and systemic inflammation in the blood and CSF in response to cerebral ischemia that reflects the synergy of these pathological processes in patients with stroke, their association with the severity of stroke and its outcome.The results indicate that the postischemic release of neurospecific proteins, an increase in the content of IL-6, CRP, and cortisol make it possible to additionally characterize the severity of stroke and the body's response to damage, and predict the outcome of the disease.Изучение патогенетического и клинического значения факторов гипоксического повреждения мозга и медиаторов воспаления в развитии церебрального инсульта, совершенствование диагностики с использованием лабораторных маркеров повреждения мозга и воспаления у больных с острым нарушением мозгового кровообращения (ОНМК).Обследовали 55 пациентов с ОНМК по ишемическому типу в возрасте 74 (67; 80) лет, группа сравнения — 25 человек без ОНМК в возрасте 65 (62; 66,5) лет. В зависимости от исхода ОНМК были сформированы группы пациентов: выписанные и умершие. Для оценки неврологического статуса пациентов использовали стандартные шкалы и индекс коморбидности. Определяли содержание белка S100b, глиального фибриллярного кислого протеина (ГФКП) и интерлейкина-6 (ИЛ-6) в сыворотке крови и цереброспинальной жидкости (ЦСЖ); нейроспецифической енолазы (НСЕ) и кортизола в сыворотке крови методом иммуноферментного анализа (ИФА), проводился клинический анализ крови, оценивалось содержание фибриногена на 1, 3 и 10-е сутки ОНМК.Увеличение содержания в крови и ЦСЖ маркеров повреждения мозговой ткани и системного воспаления в ответ на ишемию мозга отражает синергию этих патологических процессов у пациентов с ОНМК, их ассоциацию с тяжестью церебрального инсульта и его исходом.Полученные данные свидетельствуют о том, что постишемическое высвобождение нейроспецифических белков, увеличение содержания ИЛ-6, С-реактивного белка (СРБ) и кортизола позволяют дополнительно характеризовать тяжесть церебрального инсульта и реакцию организма на повреждение, прогнозировать исход заболевания.
Brain damage
Enolase
Stroke
Brain ischemia
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Perinatal brain damage is a major clinical problem. Recent studies suggest that excitatory amino acids (EAAs) may be important for the development of hypoxic-ischemic brain injury in the newborn. Experimental work demonstrates that the immature brain is hypersensitive to the toxic effects EAA ('excitotoxicity'), hypoxic-ischemia is accompanied by an extracellular overflow of EAAs and hypoxic-ischemic brain damage is reduced by EAA receptor antagonists. Clinical investigations demonstrate the presence of EAA receptors in vulnerable areas of the newborn human brain and the concentrations of EAAs in the cerebrospinal fluid are higher in asphyxiated than in control infants. Clincial studies are warranted to evaluate the importance of excitotoxicity for development of brain lesions after severe asphyxia.
Excitotoxicity
Brain damage
Brain ischemia
Perinatal asphyxia
Hypoxia
Asphyxia Neonatorum
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Stroke is a serious medical condition that requires emergency care. In the case of ischemic stroke, ischemia may lead to damage to the blood–brain barrier (BBB); the damage in turn may exacerbate the condition. Therefore, noninvasive detection of BBB damage represents a challenge for experimental and clinical researchers. In this study, we assessed the onset of BBB disruption by means of T1-weighted images with administration of the contrast enhancement agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and related BBB breakdown to brain metabolite changes in proton magnetic resonance spectrum (1H-MRS) in the infarcted site following middle cerebral artery occlusion (MCAO) in rats. It was shown that MCAO for 30 min and 1.5 h caused no Gd-DTPA signal change in the T1-weighted images, whereas MCAO for 1 h significantly altered some of 1H-MRS brain metabolites, suggesting that brain metabolite changes occurred earlier than BBB damage after ischemic stroke. MCAO for 2 h caused BBB breakdown, which was related to changes in the levels of some brain metabolites detected by 1H-MRS. Between the second and the third hour after MCAO, brain metabolite changes continued as the result of BBB breakdown and the concurrent overperfusion to the infarcted site, which may ameliorate the metabolite changes, thus compensating for the functional failures of the brain after stroke.
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Excitotoxicity
Brain ischemia
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Perinatal brain damage is associated not only with hypoxic-ischemic insults but also with intrauterine inflammation. A combination of antenatal inflammation and asphyxia increases the risk of cerebral palsy >70 times. The aim of the present study was to determine the effect of intracisternal (i.c.) administration of endotoxin [lipopolysaccharides (LPS)] on subsequent hypoxic-ischemic brain damage in neonatal rats. Seven-day-old Wistar rats were subjected to i.c. application of NaCl or LPS (5 microg/pup). One hour later, the left common carotid artery was exposed through a midline neck incision and ligated with 6-0 surgical silk. After another hour of recovery, the pups were subjected to a hypoxic gas mixture (8% oxygen/92% nitrogen) for 60 min. The animals were randomized to four experimental groups: 1) sham control group, left common carotid artery exposed but not ligated (n = 5); 2) LPS group, subjected to i.c. application of LPS (n = 7); 3) hypoxic-ischemic study group, i.c. injection of NaCl and exposure to hypoxia after ligation of the left carotid artery (n = 17); or 4) hypoxic-ischemic/LPS study group, i.c. injection of LPS and exposure to hypoxia after ligation of the left carotid artery (n = 19). Seven days later, neonatal brains were assessed for neuronal cell damage. In a second set of experiments, rat pups received an i.c. injection of LPS (5 microg/pup) and were evaluated for tumor necrosis factor-alpha expression by immunohistochemistry. Neuronal cell damage could not be observed in the sham control or in the LPS group. In the hypoxic-ischemic/LPS group, neuronal injury in the cerebral cortex was significantly higher than in animals that were subjected to hypoxia/ischemia after i.c. application of NaCl. Injecting LPS intracisternally caused a marked expression of tumor necrosis factor-alpha in the leptomeninges. Applying LPS intracisternally sensitizes the immature rat brain to a subsequent hypoxic-ischemic insult.
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Hypoxia
Sham surgery
Perinatal asphyxia
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Aim. To determine the brain damage markers levels in serum during the first 24 hours of the brain ischemic stroke.Methods and results.115 patients in acute period of brain ischemic stroke were examined.Conclusion. It was established that development of brain ischemic stroke is followed by increase of serum level of neuronspecificenolase(Δ%=1010; p<0,05), myelin basic protein (Δ%=440; p<0,05) and S100 protein (Δ%=310; p<0,05) in the first 24 hours of disease onset.
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Microdialysis
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In cerebellar granule Cell cultures, glutamate and N‐methyl‐D‐aspartate (NMDA) caused either neurotoxic or trophic effects, depending on the developmental stage of the neurones. Ethanol (100 mM) partly inhibited delayed neurotoxicity induced by the excitatory amino acids (25μM glutamate for 15 min or 100/tM NMDA for 30 min) assessed 24 h after the incubations in mature cultures in the absence of Mg 2t . Glycine (5 μM) potentiated the toxicity of glutamate and the ethanol inhibition, and was routinely added in these experiments. The viability of neurones in the presence of 25 mM K + and 0.8 mM Mg 2t was not impaired when maintained in 40–50 mM ethanol for the whole culture period of 7 days. However, ethanol almost completely inhibited the trophic effects of NMDA on developing cultures in 12.5 mM Kμ0.8 mM Mg 2+ medium. Glutamate (25 μM) and NMDA (100μM) potently induced 45 Ca 2+ uptake by granule cells from day 2 in vitro onward. Sixty‐five per cent of the 15‐min 45 Ca 2f influx induced by glutamate and 80% of that induced by NMDA were inhibited by ethanol (100 mM). MK‐801 (a non‐competitive antagonist of NMDA receptors; 100 nM) completely inhibited the toxic and trophic actions of glutamate and NMDA, as well as the 45 Ca 2+ influx induced by NMDA, but only 80% of the 45 Ca 2f influx induced by glutamate. These results show that the toxic and trophic actions of glutamate are mediated mainly by Ca 2+ influx through NMDA receptors. Both of these actions and the underlying Ca 2+ influx are significantly inhibited by ethanol at pharmacological concentrations (< 100 mM), although the mechanisms of inhibition still need further study.
Neurotoxicity
Granule (geology)
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