Ischemic tolerance in the brain

Chen, Jun; Simon, Roger P.

doi:10.1212/wnl.48.2.306

Cited by 246 publications

(158 citation statements)

References 35 publications

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“…As mentioned above, HSP70 itself has been suggested to be involved in the neuroprotective effect of IPC (Kirino et al, 1991), and a number of studies, including this study, have shown that IPC induces the production of HSP70 in neurons (Chen et al, 1996;Chen and Simon, 1997). Prolonged cerebral ischemia up-regulates HSP70 in endothelial cells in normal rats and, to a reduced extent, IPC-treated rats, as shown in the current study and previous studies (Kinouchi et al, 1993a;Lindsberg et al, 1996).…”

Section: T Masada Et Al 30supporting

confidence: 83%

“…Many substances are produced after IPC through induction of gene expression (Chen and Simon, 1997); these include interleukin-1 receptor antagonist and free radical scavengers (Barone et al, 1998;Kato et al, 1995;Ohtsuki et al, 1996;Toyoda et al, 1997) that might reduce inflammation-and free radical-induced damage. Although these substances are involved in the parenchymal cell protective effect, they may also contribute to the cerebrovascular protective effect.…”

Section: T Masada Et Al 30mentioning

confidence: 99%

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Attenuation of Ischemic Brain EDEMA and Cerebrovascular Injury after Ischemic Preconditioning in the Rat

Masada

Hua

et al. 2001

J Cereb Blood Flow Metab

112

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Summary: Ischemic preconditioning (IPC) induces neuroprotection to subsequent severe ischemia, but its effect on the cerebrovasculature has not been studied extensively. This study evaluated the effects of IPC on brain edema formation and endothelial cell damage that follows subsequent permanent focal cerebral ischemia in the rat. Transient (15 minute) middle cerebral artery occlusion (MCAO) was used for IPC. Three days after IPC or a sham operation, permanent MCAO was induced. Twenty-four hours after permanent MCAO, neurologic deficit, infarction volume, and water and ion content were evaluated. Six hours post-ischemia, blood-brain barrier (BBB) permeability was examined using [ 3 H]-inulin. Water, ion contents, and BBB permeability were assessed in three zones (core, intermediate, and outer) depending on their relation to the MCA territory. Heat shock protein 70 (HSP70) was also examined as a potential marker of vascular injury. The model of IPC significantly reduced brain infarction and neurologic deficit. Compared with a sham operation, IPC also significantly attenuated brain edema formation in the intermediate (sham and IPC water contents: 5.99 ± 0.65 vs. 4.99 ± 0.81 g/g dry weight; P < 0.01) and outer zones (5.02 ± 0.48 vs. 4.37 ± 0.42 g/g dry weight; P < 0.01) of the ipsilateral hemisphere but not in the core zone. Blood-brain barrier disruption assessed by [ 3 H]-inulin was significantly attenuated in the IPC group and the number of blood vessels that displayed HSP70 immunoreactivity was also reduced. Thus, IPC significantly attenuates ischemic brain edema formation, BBB disruption, and, as assessed by HSP70, vascular injury. Understanding the mechanisms involved in IPC may provide insight into methods for preserving cerebrovascular function during ischemia. Key Words: Brain ischemia-Ischemic preconditioning-Brain edema-Blood-brain barrier-HSP70.

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Section: T Masada Et Al 30supporting

confidence: 83%

Section: T Masada Et Al 30mentioning

confidence: 99%

Attenuation of Ischemic Brain EDEMA and Cerebrovascular Injury after Ischemic Preconditioning in the Rat

Masada

Hua

et al. 2001

J Cereb Blood Flow Metab

112

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“…In addition, resistance to oxidative stressors could be mediated by other factors, including the redox-sensitive transcription factor NF-kB (65). Interestingly, a similar resistance phenomenon has been observed during ischemic pre-conditioning, a condition whereby neurons exposed to sublethal cerebral ischemia become resistant to a subsequent lethal ischemic insult (66). In this case, enhanced mitochondrial calcium sequestration and/or calcium efflux is thought to be an important compensatory mechanism (67).…”

Section: Discussionmentioning

confidence: 85%

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line

Lotharius¹,

Barg²,

Wiekop³

et al. 2002

Journal of Biological Chemistry

326

266

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Mutations in ␣-synuclein have been linked to rare, autosomal dominant forms of Parkinson's disease. Despite its ubiquitous expression, mutant ␣-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. ␣-Synuclein is a presynaptic nerve terminal protein of unknown function, although several studies suggest it is important for synaptic plasticity and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant ␣-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wildtype human ␣-synuclein. Lentivirus-induced overexpression of A53T mutant ␣-synuclein in differentiated MESC2.10 cells resulted in down-regulation of the vesicular dopamine transporter (VMAT2), decreased potassium-induced and increased amphetamine-induced dopamine release, enhanced cytoplasmic dopamine immunofluorescence, and increased intracellular levels of superoxide. These results suggest that mutant ␣-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium. Interestingly, cells expressing A53T mutant ␣-synuclein were resistant to amphetamine-induced toxicity. Because extravesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in ␣-synuclein might lead to Parkinson's disease by triggering protracted, low grade dopamine toxicity resulting in terminal degeneration and ultimately cell death.

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“…At longer intervals (Ͼ4 hr), adenosine levels may be at least partially replenished. Even longer inter-episode intervals (24 hr) give rise to ischemic preconditioning (Chen and Simon, 1997) wherein neuropathology is reduced. Given the long delay before protective preconditioning is seen in vivo and the requirement for protein synthesis, the extent to which protective preconditioning can be studied in vitro, over the time course of the present experiments, is questionable.…”

Section: Implications For Neuroprotection By Adenosinementioning

confidence: 99%

A Depletable Pool of Adenosine in Area CA1 of the Rat Hippocampus

et al. 2001

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Adenosine plays a major modulatory and neuroprotective role in the mammalian CNS. During cerebral metabolic stress, such as hypoxia or ischemia, the increase in extracellular adenosine inhibits excitatory synaptic transmission onto vulnerable neurons via presynaptic adenosine A 1 receptors, thereby reducing the activation of postsynaptic glutamate receptors. Using a combination of extracellular and whole-cell recordings in the CA1 region of hippocampal slices from 12-to 24-d-old rats, we have found that this protective depression of synaptic transmission weakens with repeated exposure to hypoxia, thereby allowing potentially damaging excitation to both persist for longer during oxygen deprivation and recover more rapidly on reoxygenation. This phenomenon is unlikely to involve A 1 receptor desensitization or impaired nucleoside transport. Instead, by using the selective A 1 antagonist 8-cyclopentyl-1,3-dipropylxanthine and a novel adenosine sensor, we demonstrate that adenosine production is reduced with repeated episodes of hypoxia. Furthermore, this adenosine depletion can be reversed at least partially either by the application of exogenous adenosine, but not by a stable A 1 agonist, N 6 -cyclopentyladenosine, or by endogenous means by prolonged (2 hr) recovery between hypoxic episodes. Given the vital neuroprotective role of adenosine, these findings suggest that depletion of adenosine may underlie the increased neuronal vulnerability to repetitive or secondary hypoxia/ischemia in cerebrovascular disease and head injury.Key words: adenosine; hypoxia; ischemia; sensor; depletion; replenishment; glutamate; hippocampus; head injury; TBI; stroke; TIA; neuroprotection; adenosine deaminase; nucleoside phosphorylase; xanthine oxidase Extracellular adenosine in the CNS increases during pathological stimuli such as head injury (Nilsson et al., 1990;Headrick et al., 1994), epileptic seizures (Winn et al., 1980;Dunwiddie, 1999), and hypoxia/ischemia (Berne et al., 1974;Rudolphi et al., 1992;Sweeney, 1997;Von Lubitz, 1999). The increase in extracellular adenosine inhibits glutamate release via presynaptic adenosine A 1 receptors (Fowler, 1989;Katchman and Hershkowitz, 1993;Zhu and Krnjevic, 1993;Pearson and Frenguelli, 2000). In addition, simultaneous activation of postsynaptic A 1 receptors activates a potassium conductance leading to membrane hyperpolarization, thereby intensifying the magnesium block of the NMDA subtype of glutamate receptor (Erdemli et al., 1998;Von Lubitz, 1999). Together, these actions exert a powerful neuroprotective "retaliatory" (Newby, 1984) influence during traumatic or metabolic stress.Manipulations that increase extracellular adenosine, such as adenosine uptake inhibition (Gidday et al., 1995), inhibition of adenosine metabolizing enzymes (Phillis and O'Regan, 1989;Miller et al., 1996;Jiang et al., 1997), or activation of A 1 receptors by exogenous A 1 agonists (Rudolphi et al., 1992;Sweeney, 1997;Von Lubitz, 1999;de Mendonca et al., 2000) are all neuroprotective. Conversely, antagonism of ...

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Ischemic tolerance in the brain

Cited by 246 publications

References 35 publications

Attenuation of Ischemic Brain EDEMA and Cerebrovascular Injury after Ischemic Preconditioning in the Rat

Attenuation of Ischemic Brain EDEMA and Cerebrovascular Injury after Ischemic Preconditioning in the Rat

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line

A Depletable Pool of Adenosine in Area CA1 of the Rat Hippocampus

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