A radical approach to stroke therapy

McCulloch, James; Dewar, Deborah

doi:10.1073/pnas.211430898

Cited by 30 publications

(16 citation statements)

References 24 publications

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“…Cross-tolerance is significant because it affords the opportunity to “mimic” IPC’s neuroprotection, and therefore, has potential direct clinical relevance. Multiple mechanisms leading to ischemic damage render it difficult to design effective neuroprotection (McCulloch and Dewar 2001). Exogenously administered neuroprotectants may be toxic or non-specific.…”

Section: Introductionmentioning

confidence: 99%

Post-ischemic conditioning in the rat retina is dependent upon ischemia duration and is not additive with ischemic pre-conditioning

Dreixler

Shaikh

Alexander

et al. 2010

Experimental Eye Research

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Ischemic pre-conditioning (IPC) provides neuroprotection in the rat retina from the damaging effects of severe ischemia. Recently, neuroprotection by retinal ischemic post-conditioning (Post-C), i.e., transient ischemia after more lengthy, damaging ischemia, was described, but its mechanisms are not yet known. One possible explanation of the effectiveness of Post-C is that it augments intrinsic neuroprotective mechanisms initiated during ischemia. Increasing duration of the damaging ischemic insult may therefore impact the effectiveness of Post-C. IPC, in contrast, sets in motion a series of neuroprotective events prior to the onset of ischemia. Thus, IPC and Post-C may operate by differing mechanisms. Accordingly, we examined the effect of retinal ischemic duration on post-ischemic outcome in vivo in rats after adding Post-C, and the impact of combining pre- and post-conditioning. Recovery after ischemia performed 24 h after IPC, or after Post-C performed 5 min after ischemia ended, was assessed functionally (electroretinography) and histologically at 7 days after ischemia. Durations of ischemia of 45 and 55 min were studied. Since recovery with IPC or Post-C alone, with 55 min of ischemia, did not achieve the same degree of effect (i.e., not complete recovery) exhibited in our previous studies of IPC using a different ischemia model, we also combined IPC and Post-C to test the hypothesis of the possible additive effects of the IPC and Post-C. We found that the recovery after Post-C was enhanced to a greater degree when ischemia was of longer duration. Post-C led to greater post-ischemic recovery compared to IPC. Both IPC and Post-C also attenuated structural damage to the retina. Contrary to our hypothesis, IPC and Post-C did not combine to enhance recovery after ischemia. In earlier studies, IPC attenuated post-ischemic apoptosis. To begin to examine the mechanism of Post-C, we studied its impact on apoptosis following ischemia. We examined apoptosis by determining the percentage of TUNEL-positive cells at 24 h after ischemia. Post-C attenuated apoptosis, but when combined with IPC, TUNEL was similar in the combined group to that of ischemia alone. We also examined the role of the recruitment of an inflammatory response in ischemia and Post-C. We found that inflammatory markers increased by ischemia were not altered by Post-C. We conclude that Post-C effectiveness depends upon the duration of ischemia; Post-C is not additive with IPC, and Post-C functions, in part, by preventing apoptotic damage to the inner retina. Post-C has considerable promise for clinical translation to eye diseases that cause blindness by ischemia.

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Section: Introductionmentioning

confidence: 99%

Post-ischemic conditioning in the rat retina is dependent upon ischemia duration and is not additive with ischemic pre-conditioning

Dreixler

Shaikh

Alexander

et al. 2010

Experimental Eye Research

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“…The brain is particularly sensitive to ROS accumulation and oxidative stress is implicated in the pathogenesis of many chronic neurodegenerative diseases as well as acute neuronal injury such as stroke (McCulloch and Dewar, 2001). Importantly, oxidative stress alters many metabolic and signaling pathways through effects on protein redox state and indirectly through triggering the release of intracellular stores of metal ions such as Zn 2+ (Sensi and Jeng 2004).…”

mentioning

confidence: 99%

Selective Inhibition of Mitogen-Activated Protein Kinase Phosphatases by Zinc Accounts for Extracellular Signal-Regulated Kinase 1/2-Dependent Oxidative Neuronal Cell Death

Samarasinghe²,

Knoch³

et al. 2008

Molecular Pharmacology

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Oxidative stress induced by glutathione depletion in the mouse HT22 neuroblastoma cell line and embryonic rat immature cortical neurons causes a delayed, sustained activation of extracellular signal-regulated kinase (ERK) 1/2, which is required for cell death. This sustained activation of ERK1/2 is mediated primarily by a selective inhibition of distinct ERK1/2-directed phosphatases either by enhanced degradation (i.e., for mitogenactivated protein kinase phosphatase-1) or as shown here by reductions in enzymatic activity (i.e., for protein phosphatase type 2A). The inhibition of ERK1/2 phosphatases in HT22 cells and immature neurons subjected to glutathione depletion results from oxidative stress because phosphatase activity is restored in cells treated with the antioxidant butylated hydroxyanisole. This leads to reduced ERK1/2 activation and neuroprotection. Furthermore, an increase in free intracellular zinc that accompanies glutathioneinduced oxidative stress in HT22 cells and immature neurons contributes to selective inhibition of ERK1/2 phosphatase activity and cell death. Finally, ERK1/2 also functions to maintain elevated levels of zinc. Thus, the elevation of intracellular zinc within neurons subjected to oxidative stress can trigger a robust positive feedback loop operating through activated ERK1/2 that rapidly sets into motion a zinc-dependent pathway of cell death.

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“…3,4 Although remarkable insight into the pathogenic mechanisms of ischemic brain damage has been achieved in the last decade, [5][6][7][8] no cerebroprotective agent is proven to be efficacious in controlled clinical trials. 1 There is a need for safe and effective cerebroprotective agents that will benefit all stroke patients.…”

mentioning

confidence: 99%

“…5,7 Accumulating evidence suggests that oxidative damage does not occur in isolation but has complex interactions with excitotoxicity, apoptosis, and inflammation. 8 Pharmacological modification of oxidative damage may protect against ischemia. Melatonin (N-acetyl-5-methoxytryptamine) is a potent free radical scavenger as well as indirect antioxidant.…”

mentioning

confidence: 99%

Administration of Melatonin After Onset of Ischemia Reduces the Volume of Cerebral Infarction in a Rat Middle Cerebral Artery Occlusion Stroke Model

Pei

Pang

Cheung

2003

Stroke

117

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Background and Purpose-In both permanent and transient 3-hour middle cerebral artery occlusion rat stroke models, a single intraperitoneal injection of melatonin at 5 or 15 mg/kg given before ischemia was shown to reduce infarct volume at 72 hours. The present study was conducted to examine the treatment time window when melatonin was commenced after onset of ischemia. Methods-Adult male Sprague-Dawley rats were anesthetized to undergo right-sided middle cerebral artery occlusion for 3 hours. A single intraperitoneal injection of vehicle or melatonin at 5 mg/kg was given at 0, 1, or 3 hours after onset of ischemia. Other groups received multiple injections of vehicle or melatonin at 5 mg/kg with the first injection given at 1, 2, or 3 hours after onset of ischemia and the second and third injections at 24 and 48 hours, respectively. Multiple injections of melatonin at 15 mg/kg with the first injection given at 3 hours were also made. The infarct volume was determined at 72 hours. Results-A single dose of melatonin at 5 mg/kg given at 0 or 1 but not 3 hours after onset of ischemia reduced the infarct volume. Multiple doses of melatonin at 5 mg/kg also reduced the infarct volume when the first dose was given at 1 or 2 but not 3 hours after onset. Significant hemodynamic effects were not observed. Conclusions-Our

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A radical approach to stroke therapy

Cited by 30 publications

References 24 publications

Post-ischemic conditioning in the rat retina is dependent upon ischemia duration and is not additive with ischemic pre-conditioning

Post-ischemic conditioning in the rat retina is dependent upon ischemia duration and is not additive with ischemic pre-conditioning

Selective Inhibition of Mitogen-Activated Protein Kinase Phosphatases by Zinc Accounts for Extracellular Signal-Regulated Kinase 1/2-Dependent Oxidative Neuronal Cell Death

Administration of Melatonin After Onset of Ischemia Reduces the Volume of Cerebral Infarction in a Rat Middle Cerebral Artery Occlusion Stroke Model

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