Increased mitochondrial reactive oxygen species production in newborn brain during hypoglycemia

McGowan, Jane E.; Chen, Lei; Gao, Daqing; Trush, Michael A.; Wei, Chiming

doi:10.1016/j.neulet.2006.01.034

Cited by 78 publications

(53 citation statements)

References 22 publications

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“…The source of ROS produced during HG was not evaluated in the present studies, but a prior report suggests that brain mitochondria isolated during HG (without GR) produce more ROS than control mitochondria (21). However, the present results suggest that NADPH oxidase, rather than mitochondria, are the primary source of superoxide production during the GR period.…”

Section: Figurecontrasting

confidence: 61%

“…Mitochondria have been implicated as a source of ROS in many disorders, including ischemia-reperfusion (20), and mitochondria taken from brain during HG exhibit increased capacity to generate ROS (21); however, ROS can be generated by several sources other than mitochondria. Among these sources is NADPH oxidase, a superoxide-generating enzyme long recognized as crucial for the bactericidal function of neutrophils (22).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

Suh¹,

Gum²,

Hamby³

et al. 2007

J. Clin. Invest.

371

317

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Hypoglycemic coma and brain injury are potential complications of insulin therapy. Certain neurons in the hippocampus and cerebral cortex are uniquely vulnerable to hypoglycemic cell death, and oxidative stress is a key event in this cell death process. Here we show that hypoglycemia-induced oxidative stress and neuronal death are attributable primarily to the activation of neuronal NADPH oxidase during glucose reperfusion. Superoxide production and neuronal death were blocked by the NADPH oxidase inhibitor apocynin in both cell culture and in vivo models of insulin-induced hypoglycemia. Superoxide production and neuronal death were also blocked in studies using mice or cultured neurons deficient in the p47 phox subunit of NADPH oxidase. Chelation of zinc with calcium disodium EDTA blocked both the assembly of the neuronal NADPH oxidase complex and superoxide production. Inhibition of the hexose monophosphate shunt, which utilizes glucose to regenerate NADPH, also prevented superoxide formation and neuronal death, suggesting a mechanism linking glucose reperfusion to superoxide formation. Moreover, the degree of superoxide production and neuronal death increased with increasing glucose concentrations during the reperfusion period. These results suggest that high blood glucose concentrations following hypoglycemic coma can initiate neuronal death by a mechanism involving extracellular zinc release and activation of neuronal NADPH oxidase.

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Section: Figurecontrasting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

Suh¹,

Gum²,

Hamby³

et al. 2007

J. Clin. Invest.

371

317

View full text Add to dashboard Cite

show abstract

“…Earlier studies demonstrated that hypoglycemia leads to an increase in mitochondrial reactive oxygen species production and decrease in mitochondrial membrane potential. 25,26 In view of this, we tested the hypothesis that RH-induced impaired mitochondrial function makes brains of diabetic individuals more sensitive to cerebral ischemic damage. To test this hypothesis, first we measured the relative quantities of mitochondrial proteins using Multidimensional Protein Identification Technology/iTRAQ analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Hypoglycemia was initiated by injecting 0. 25 In another set of experiments, hypoglycemia was induced by intraperitoneal injection of insulin 8 U/kg body weight with the aim of maintaining blood glucose levels between 55 to 65 mg/dL for 30 minutes. 18 An additional 1 to 2 U of insulin was given if the target glucose level was not achieved within 30 minutes.…”

Section: Induction Of Hypoglycemiamentioning

confidence: 99%

Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Streptozotocin-Induced Diabetic Rats

Dave

Tamariz

Desai

et al. 2011

Stroke

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Background and Purpose-Stroke and heart disease are the most serious complications of diabetes accounting for Ͼ65% of mortality among diabetics. Although intensive insulin therapy has significantly improved the prognosis of diabetes and its complications, it is associated with an elevated risk of recurrent hypoglycemia (RH). We tested the hypothesis that RH exacerbates cerebral ischemic damage in a rodent model of diabetes. Method-We determined the extent of neuronal death in CA1 hippocampus after global cerebral ischemia in control and streptozotocin-induced diabetic rats. Diabetic animals included an insulin-treated streptozotocin-diabetic (ITD) group and a group of ITD rats exposed also to 10 episodes of hypoglycemia (ITDϩrecurrent hypoglycemia: RH). Hypoglycemia (55 to 65 mg/dL blood glucose) was induced twice daily for 5 consecutive days. Results-As expected, uncontrolled diabetes (streptozotocin-diabetes, untreated animals) resulted in a 70% increase in ischemic damage as compared with the control group. Insulin treatment was able to lower ischemic damage by 64% as compared with the diabetic group. However, ITDϩRH rats had 44% more damage when compared with the ITD group. We also observed that free radical release from mitochondria is increased in ITDϩRH rats. Conclusions-This is the first report on the impact of RH in exacerbating cerebral ischemic damage in diabetic animals.Our results suggest that increased free radical release from mitochondria may be responsible for observed increased ischemic damage in ITDϩRH rats. RH thus may be an unexplored but important factor responsible for increased ischemic damage in diabetes. (Stroke. 2011;42:1404-1411.)Key Words: brain ischemia Ⅲ cardiac arrest Ⅲ diabetes Ⅲ free radicals Ⅲ glucose Ⅲ mitochondria Ⅲ stroke D iabetes is a devastating disease of epidemic proportions. It is estimated that 220 million patients are affected by diabetes worldwide. 1 Stroke and heart disease are the most serious complications of diabetes, because they account for approximately 65% of mortality among diabetics. 2 Epidemiological studies suggest that long-term diabetes increases the risk of cerebral ischemia as well as cardiovascular disease by 2 to 4 times as compared with the nondiabetic population. [3][4][5] The incidence of cerebral ischemia is greater in patients with Type 2 diabetes mellitus than Type 1 diabetes mellitus (T1DM). 3 Furthermore, cerebral infarction after ischemia is more extensive and common in diabetics, who also display slower recovery and worse survival rates than nondiabetic subjects. 6 Animal models corroborate these clinical observations and provide mechanistic insights into the pathophysiology of the effect of diabetes on cerebral ischemia. 7,8 It has been recognized that a high plasma glucose level is a key factor for the poor outcome observed after cerebral ischemia in diabetics. 9 Attaining tight glycemic control is a desirable goal for both patients with T1DM and Type 2 diabetes mellitus. Aggressive therapeutic interventions able to normalize glycohemog...

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“…ROS production was detected with a chemiluminescence detector (19). The cortex of each group's brain was weighed and homogenized, and then its chemiluminescence was measured (Luminex 200; Luminex Corp., Austin, TX).…”

Section: Methodsmentioning

confidence: 99%

Lipopolysaccharide Preconditioning Reduces Neuroinflammation Against Hypoxic Ischemia and Provides Long-Term Outcome of Neuroprotection in Neonatal Rat

2009

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Hypoxic ischemia (HI) in newborns causes long-term neurologic abnormalities. Systemic lipopolysaccharide (LPS) is neuroprotective in neonatal rats when injected 24 h before HI. However, the effect on HI-induced neuroinflammation and the long-term outcome of LPS preconditioning in neonatal rats have not been examined. In a rat-pup HI model, compared with normal saline (NS), 0.3 mg/kg of LPS injected 24 h before HI greatly increased microglial cell and macrophage activation and up-regulated TNF-alpha and inducible NOS expression 12-h postinjection and resulted in high mortality during HI. In contrast, 0.05 mg/kg of LPS elicited very little microglia and macrophage activation and TNF-alpha and inducible NOS expression and resulted in low mortality. Given 24 h before HI, low-dose (0.05 mg/kg) LPS greatly reduced microglia and macrophage activation, TNF-alpha expression, and reactive oxygen species production 24-h post-HI compared with NS-treated rats. Rats in the low-dose LPS group also showed significantly better learning and memory and less brain damage in adulthood. Learning and memory performance among the LPS-HI, LPS, and NS groups was not significantly different. We conclude that low-dose LPS preconditioning in neonatal rats greatly reduces HI-induced neuroinflammation and provides long-term neuroprotection against behavioral and pathologic abnormalities. T wenty percent of newborns with hypoxic ischemia (HI) die and an additional 25% have long-term neurodevelopmental handicaps (1). Although hypothermia has been used to treat newborns with HI encephalopathy, there is no effective pharmacological therapy. Sublethal lipopolysaccharide (LPS) stimulation, preconditioning, protects against subsequent lethal injury. Elucidating the neuroprotective mechanisms of LPS preconditioning may offer potential therapies against HI brain injury (2,3).Systemic LPS preconditioning (0.5 to 0.9 mg/kg) 48 to 72 h before ischemic insults protected adult rats against cerebral ischemia (4,5). LPS (0.3 or 1 mg/kg) sensitized neonatal Wistar rats and worsened HI brain injury when given 4, 6, or 72 h before HI (6). In contrast, 0.3 mg/kg of LPS 24 h before HI protected them (7,8). There are several neuroprotective preconditioning models for the neonatal brain (7,9 -13), but there are only few evaluations of long-term outcomes of LPS preconditioning at behavioral and pathologic levels.Inflammatory responses are important for developing neonatal HI brain injury (1). Up-regulated reactive oxygen species (ROS) production is also critical in inducing HI damage in the neonatal brain (1,14). One study (15) of adult rats showed that low-dose (0.05 mg/kg) LPS pretreatment 24 h before transient middle-cerebral-artery occlusion decreased ischemic infarct size despite increases of inflammatory cells in the ischemic hemisphere. In contrast, another study (16) suggested that LPS (0.2 mg/kg) preconditioning 48 h before transient middlecerebral-artery occlusion suppressed neuroinflammatory responses. Although up-regulating endogenous corticost...

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Increased mitochondrial reactive oxygen species production in newborn brain during hypoglycemia

Cited by 78 publications

References 22 publications

Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Streptozotocin-Induced Diabetic Rats

Lipopolysaccharide Preconditioning Reduces Neuroinflammation Against Hypoxic Ischemia and Provides Long-Term Outcome of Neuroprotection in Neonatal Rat

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