Penumbral tissue alkalosis in focal cerebral ischemia: Relationship to energy metabolism, blood flow, and steady potential

Back, Tobias; Hoehn, Mathias; Mies, Günter; Busch, Elmar; Schmitz, Bernd; Kohno, Kanehisa; Hossmann, Konstantin‐Alexander

doi:10.1002/1531-8249(200004)47:4<485::aid-ana12>3.0.co;2-8

Cited by 82 publications

(45 citation statements)

References 60 publications

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“…A greater cell density imposes greater metabolic demands and blood flow requirements that exaggerate the mismatch that develops during ischemia between reduced blood flow (oxygen delivery) and increased tissue metabolism (oxygen demand). In other ischemic paradigms, this disparity causes more ischemic injury (33,34). Taken together, the in vivo and in vitro data support a role for caspase-3 in neuronal death induced by ischemia and the significance of this caspase in rendering cells more resistant to ischemic stress.…”

Section: Discussionmentioning

confidence: 59%

Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation

Huang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

285

196

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Caspase-3 is a major cell death effector protease in the adult and neonatal nervous system. We found a greater number and higher density of cells in the cortex of caspase-3 ؊/؊ adult mice, consistent with a defect in developmental cell death. Caspase-3 ؊/؊ mice were also more resistant to ischemic stress both in vivo and in vitro. After 2 h of ischemia and 48 h of reperfusion, cortical infarct volume was reduced by 55%, and the density of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells was decreased by 36% compared with wild type. When subjected to oxygen-glucose deprivation (2 h), cortical neurons cultured from mice deficient in caspase-3 expression were also more resistant to cell death by 59%. Mutant brains showed caspase-specific poly-(ADP-ribose) polymerase cleavage product (85-kDa fragment) in vivo and in vitro, suggesting redundant mechanisms and persistence of caspase-mediated cell death. In the present study, we found that caspase-8 mediated poly(ADP-ribose) polymerase cleavage in caspase-3 ؊/؊ neurons in vivo and in vitro. In addition, mutant neurons showed no evidence of compensatory activation by caspase-6 or caspase-7 after ischemia. Taken together, these data extend the pharmacological evidence supporting an important role for caspase-3 and caspase-8 as cell death mediators in mammalian cortex and indicate the potential advantages of targeting more than a single caspase family member to treat ischemic cell injury.

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Section: Discussionmentioning

confidence: 59%

Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation

Huang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

285

196

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“…However, it is not known whether changes in pH i have any effect on the activities of these channels. Although pH i also drops during ischemia in general, the degree of pH i changes is not homogeneous across all brain regions, and an alkalization of pH i has been demonstrated in cortical penumbra region following the ischemia (22). Here we demonstrate that the amplitude of ASIC current, its pH-dependent activation and inactivation, as well as current desensitization all are tightly regulated by the level of pH i ; intracellular acidification inhibits whereas alkalization potentiates the activities of ASICs.…”

mentioning

confidence: 63%

“…The large fluctuation of pH o associated with cortical spreading depression as described above suggests that in cortical regions of the brain, ASICs could be activated repeatedly during ischemia. Even in the regions where pH o drop is persistent, ASICs might still be partially functioning because ischemia itself dramatically reduces the desensitization of these channels (10 (20,22). In other regions where the tight regulation of extracellular and intracellular pH via Na ϩ /H ϩ exchange and Cl Ϫ /HCO 3 Ϫ and the availability of intracellular anionic buffers are disturbed, greater diversity of the extracellular and intracellular pH may occur.…”

Section: Tial [K ϩmentioning

confidence: 99%

Modulation of Acid-sensing Ion Channel Currents, Acid-induced Increase of Intracellular Ca2+, and Acidosis-mediated Neuronal Injury by Intracellular pH

Wang

Chu²,

Li³

et al. 2006

Journal of Biological Chemistry

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Acid-sensing ion channels (ASICs), activated by lowering extracellular pH (pH o ), play an important role in normal synaptic transmission in brain and in the pathology of brain ischemia. Like pH o , intracellular pH (pH i ) changes dramatically in both physiological and pathological conditions. Although it is known that a drop in pH o activates the ASICs, it is not clear whether alterations of pH i have an effect on these channels. Here we demonstrate that the overall activities of ASICs, including channel activation, inactivation, and recovery from desensitization, are tightly regulated by pH i . In cultured mouse cortical neurons, bath perfusion of the intracellular alkalizing agent quinine increased the amplitude of the ASIC current by ϳ50%. In contrast, intracellular acidification by withdrawal of NH 4 Cl or perfusion of propionate inhibited the current. Increasing pH buffering capacity in the pipette solution with 40 mM HEPES attenuated the effects of quinine and NH 4 Cl. The effects of intracellular alkalizing/ acidifying agents were mimicked by using intracellular solutions with pH directly buffered at high/low values. Increasing pH i induced a shift in H ؉ dose-response curve toward less acidic pH but a shift in the steady state inactivation curve toward more acidic pH. In addition, alkalizing pH i induced an increase in the recovery rate of ASICs from desensitization. Consistent with its effect on the ASIC current, changing pH i has a significant influence on the acid-induced increase of intracellular Ca 2؉ , membrane depolarization, and acidosismediated neuronal injury. Our findings suggest that changes in pH i may play an important role in determining the overall function of ASICs in both physiological and pathological conditions. Acid-sensing ion channels (ASICs)3 are H ϩ -gated cation channels that belong to the Deg/ENaC superfamily (1). In peripheral sensory neurons, ASICs are implicated in nociception (2, 3), mechanosensation (4, 5), and taste transduction (6). In central neurons, ASICs play an important role in physiological processes such as synaptic transmission, learning, and memory (7-9). In pathological conditions including brain ischemia, ASICs are involved in acidosis-mediated glutamateindependent neuronal injury (10 -12), disclosing a novel therapeutic target for stroke intervention.The activities of ASICs are subjected to modulation by endogenous signaling molecules and biochemical changes associated with pathological conditions. For instance, Zn 2ϩ , an endogenous trace element released during neuronal activity, inhibits ASIC1a-containing channels with high affinity (13), whereas neurochemical components associated with tissue inflammation (e.g. Phe-Met-Arg-Phe (FMRF) amide) (14) and ischemia (e.g. lactate and arachidonic acid) (15-18) potentiate the ASIC currents. Delineating detailed modulation of ASICs by endogenous signaling molecules and biochemical changes is important for better understanding the exact and precise role these channels play in various physiological and pathological...

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“…However, under limiting supply of ADP required for synthesis of ATP through F0F1-ATPase, increased mitochondrial respiration because of supply of nicotinamide adenine dinucleotide from glycolytic pathway, inability of F0F1-ATPase to cope up with the energy demand, and intracellular alkalization as during postischemic reoxygenation may lead to mitochondrial membrane hyperpolarization. (Di Lisa and Bernardi, 1998;Gergely et al, 2002;Back et al, 2000;Iijima et al, 2003b;McLeod et al, 2004;Iijima, 2006). The hyperpolarization during ischemic and long-term hypoxic condition is associated with increased ROS production (Nicholls and Ward, 2000) and mitochondrial Ca 2 + accumulation (Smith et al, 2003).…”

Section: Uncoupling Protein-2 and Mitochondrial Potentialmentioning

confidence: 99%

Neuroprotective Role of Mitochondrial Uncoupling Protein 2 in Cerebral Stroke

Mehta

2009

J Cereb Blood Flow Metab

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The uncoupling proteins (UCPs) are mitochondrial transporter proteins involved in proton conductance across inner mitochondrial membrane (IMM). UCP2, which is one of the members of this class of proteins, has a wide but restricted tissue distribution including brain. Its physiologic role according to emerging evidences, although still not clear, indicate that distribution of UCP2 may be related to regulation of mitochondria membrane potential (DWm), production of reactive oxygen species (ROS), preservation of calcium homeostasis, modulation of neuronal activity, and eventually inhibition of cellular damage. These factors are very important in determining the fate of neurons and damage progression in the brain during various neurodegenerative diseases including cerebral stroke. Recent evidence indicates that an increased expression and activity of UCP2 are well correlated with neuronal survival after stroke and trauma. This review briefly covers the present understanding of UCP2, which eventually may be beneficial to understand the precise role of UCP2 to develop strategy to identify its potential therapeutic application.

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Penumbral tissue alkalosis in focal cerebral ischemia: Relationship to energy metabolism, blood flow, and steady potential

Cited by 82 publications

References 60 publications

Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation

Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation

Modulation of Acid-sensing Ion Channel Currents, Acid-induced Increase of Intracellular Ca2+, and Acidosis-mediated Neuronal Injury by Intracellular pH

Neuroprotective Role of Mitochondrial Uncoupling Protein 2 in Cerebral Stroke

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