Modification of hypoxia-induced injury in cultured rat astrocytes by high levels of glucose.

Kelleher, Judith A.; Chan, Pak H.; Chan, Thelma Y.-Y.; Gregory, George

doi:10.1161/01.str.24.6.855

Cited by 55 publications

(38 citation statements)

References 66 publications

(8 reference statements)

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“…(1991a, b & 1992). It is unlikely that hyperosmolarity accounted for fructose-I ,6-bisphosphate's protective or injurious effects, since we found no evidence that fructose-l,6-bisphosphate induced hyperosmolarity in vivo (Sola et al 1996) nor did we find hyperosmolar-induced injury in primary cultures of astrocytes (Kelleher et al 1993).…”

Section: Discussioncontrasting

confidence: 63%

“…Perinatal hypoxia-ischaemia is associated with alterations in phosphate concentrations, ATP/phosphate ratios, and calcium concentrations of the brain (Vannucci 1993). Giving fructose-I ,6-bisphosphate during or immediately after hypoxia-ischaemia reduces ATP loss from the heart (Horster & Lewy 1970;Ichikawa et al 1979) and from cultured astrocytes Kelleher et al 1993Kelleher et al & 1994. The mechanism of this protection is unknown, but the present studies in rat pups and those in brain slices (Bickler & Kelleher 1992), myocardial tissue (Galzinga et al 1989), and spermatozoa (Fasolato et a/.…”

Section: Discussionmentioning

confidence: 72%

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Toxicity of Fructose‐1, 6‐Bisphosphate in Developing Normoxic Rats

Vexler

Berrios

Ursell³

et al. 1999

Pharmacology & Toxicology

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Giving 500 mg/kg of fructose‐1, 6‐bisphosphate intraperitoneally decreases hypoxic/ischaemic CNS injury of neonatal rats. Before administering fructose‐1, 6‐bisphosphate to human neonates, its toxicity must be determined in neonatal animals. Thus, saline or 4,000, 6,000, or 8,000 mg/kg of fructose‐1, 6‐bisphosphate was given intraperitoneally to normoxic 7 days old rats. One, 2, and 24 hr and 7 days later, blood Ca2+, P043–, blood urea nitrogen, and creatinine concentrations, and aspartate aminotransferase activity were measured. Organ pathology was determined at necropsy. Pups receiving 4,000 mg/kg of fructose‐1, 6‐bisphosphate survived without evidence of injury or toxicity. All animals receiving 8,000 mg/kg and 27 percent of those receiving 6,000 mg/kg of fructose‐1, 6‐bisphosphate died. Surviving fructose‐1, 6‐bisphosphate‐treated animals grew at the same rates and had similar weights as saline‐treated animals. Nineteen percent of pups given 6,000 or 8,000 mg/kg of fructose‐1, 6‐bisphosphate had mild perivascular fluid cuffing and/or microscopic pulmonary haemorrhage, but none of the animals given 4,000 mg/kg of the compound had evidence of injury. No other organ pathology was found in any of the animals. Renal and hepatic function were normal in all animals. Fructose‐1, 6‐bisphosphate administration was associated with a significant increase in the fructose‐1, 6‐bisphosphate concentration of blood. Administering 4,000 to 8,000 mg/kg of fructose‐1, 6‐bisphosphate significantly decreased Ca2+ concentrations and increased P043– concentrations 1 and 2 hrs after fructose‐1, 6‐bisphosphate administration. Similar changes in Ca2+ and P043– concentrations occurred after the administration of 10 mmol/kg of sodium phosphate. The wide margin of safety for fructose‐1, 6‐bisphosphate (8 times the dose needed to prevent or reduce CNS injury) may render fructose‐1, 6‐bisphosphate safe for use in neonates.

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 72%

Toxicity of Fructose‐1, 6‐Bisphosphate in Developing Normoxic Rats

Vexler

Berrios

Ursell³

et al. 1999

Pharmacology & Toxicology

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“…This might aid in maintaining the intracellular ATP levels in hypoxic astrocytic cultures at levels sufficient for survival (Yager et al, 1994). Furthermore, hyperglycemia promotes survival of astrocytes exposed to hypoxia/ischemia (Callahan et al, 1990;Kelleher et al, 1993). Some studies have shown that neurons may actually be more resistant than astrocytes to hypoxic stress.…”

Section: Discussionmentioning

confidence: 99%

Effects of continuous hypoxia on energy metabolism in cultured cerebro-cortical neurons

et al. 2008

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Mechanisms underlying hypoxia-induced neuronal adaptation have not been fully elucidated. In the present study we investigated glucose metabolism and the activities of glycolytic and TCA cycle enzymes in cerebro-cortical neurons exposed to hypoxia (3 days in 1% of O 2 ) or normoxia (room air). Hypoxia led to increased activities of LDH (251%), PK (90%), and HK (24%) and decreased activities of CS (15%) and GDH (34%). Neurons were incubated with [1-13 C]glucose for 45 and 120 min under normoxic or hypoxic (120 min only) conditions and 13 C enrichment determined in the medium and cell extract using 1 H-{ 13 C}-NMR. In hypoxia-treated neurons [3-13 C]lactate release into the medium was 428% greater than in normoxia-treated controls (45-min normoxic incubation) and total flux through lactate was increased by 425%. In contrast glucose oxidation was reduced significantly in hypoxia-treated neurons, even when expressed relative to total cellular protein, which correlated with the reduced activities of the measured mitochondrial enzymes. The results suggest that surviving neurons adapt to prolonged hypoxia by up-regulation of glycolysis and downregulation of oxidative energy metabolism, similar to certain other cell types. The factors leading to adaptation and survival for some neurons but not others remains to be determined.

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“…In hypoxia and hypoxic related injuries to the brain, astrocytes although moderately resilient to injury undergo changes that compromise their abilities to provide support and can even act as executioners of cellular demise. Astrocytes themselves in in vitro models can survive severe hypoxia for up to 96 hours and anoxia for 12-24 hours (Yu et al, 1989;Kelleher et al, 1993;Sochocka et al, 1994). In Middle Cerebral Artery Occlusion (MCAO) rat models, astrocytes experience morphological changes and swelling as early as 30 minutes after occlusion, followed by an increase in GFAP reactivity by six hours and astrocyte death at 24 hours (Garcia et al, 1993).…”

Section: Astrocytes: Targets For Neuroprotection In Cns Diseasesmentioning

confidence: 99%