Inhibition of interleukin 1β converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage

Hara, Hideaki; Friedlander, Robert M.; Gagliardini, Valeria; Ayata, Cenk; Fink, Klaus; Huang, Zhihong; Shimizu‐Sasamata, Masao; Yuan, Junying; Moskowitz, Michael A.

doi:10.1073/pnas.94.5.2007

Cited by 795 publications

(504 citation statements)

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“…This tetrapeptide, when administered intracerebroventricularly, showed marked neuroprotective actions, as indicated by both improvement of neurological recovery and reduction of internucleosomal DNA fragmentation. Recently, Hara et al (1997) showed that central administration of a caspase-3 inhibitor, or caspase-1 inhibitors, reduced infarct volume and neurological deficits in mice subjected to focal cerebral ischemia. Our present findings extend the observations of Hara and colleagues with respect to the protective effects of caspase-3 inhibition to another injury model and species.…”

Section: Discussionmentioning

confidence: 99%

“…Secondary injury involves a cascade of biochemical changes that contribute to delayed tissue damage and cell death (Faden, 1996). Although the focus of research on secondary brain injury historically has been on mechanisms related to necrosis (Trump and Bulger, 1967), recent studies have suggested a potential role for apoptosis in cell loss after stroke, spinal cord injury, or traumatic brain injury (TBI) (Linnik et al, 1993;MacManus et al, 1993;K ihara et al, 1994;Sei et al, 1994;Beilharz et al, 1995;Hill et al, 1995;Islam et al, 1995;Iwai et al, 1995;Li et al, 1995a,b;Rink et al, 1995;Hara et al, 1997).…”

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confidence: 99%

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Activation of CPP32-Like Caspases Contributes to Neuronal Apoptosis and Neurological Dysfunction after Traumatic Brain Injury

et al. 1997

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We examined the temporal profile of apoptosis after fluid percussion-induced traumatic brain injury (TBI) in rats and investigated the potential pathophysiological role of caspase-3-like proteases in this process. DNA fragmentation was observed in samples from injured cortex and hippocampus, but not from contralateral tissue, beginning 4 hr after TBI and continuing for at least 3 d. Double labeling of brain with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and an antibody directed to neuronal nuclear protein identified apoptotic neurons with high frequency in both traumatized rat cortex and hippocampus. Cytosolic extracts from injured cortex and hippocampus, but not from contralateral or control tissue, induced internucleosomal DNA fragmentation in isolated nuclei with temporal profiles consistent with those of DNA fragmentation observed in vivo. Caspase-3 mRNA levels, estimated by semiquantitative RT-PCR, were elevated fivefold in ipsilateral cortex and twofold in hippocampus by 24 hr after TBI. Caspase-1 mRNA content also was increased after trauma, but to a lesser extent in cortex. Increased caspase-3-like, but not caspase-1-like, enzymatic activity was found in cytosolic extracts from injured cortex. Intracerebroventricular administration of z-DEVD-fmk-a specific tetrapeptide inhibitor of caspase-3-before and after injury markedly reduced post-traumatic apoptosis, as demonstrated by DNA electrophoresis and TUNEL staining, and significantly improved neurological recovery. Together, these results implicate caspase-3-like proteases in neuronal apoptosis induced by TBI and suggest that the blockade of such caspases can reduce post-traumatic apoptosis and associated neurological dysfunction.

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Section: Discussionmentioning

confidence: 99%

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Activation of CPP32-Like Caspases Contributes to Neuronal Apoptosis and Neurological Dysfunction after Traumatic Brain Injury

et al. 1997

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“…The infarct volume and brain swelling were calculated using formulas specified in a previous report. 13 …”

Section: Evaluation Of Infarct Area and Edema Volumementioning

confidence: 99%

Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema

et al. 2010

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Release of neutrophil elastase is one of the harmful inflammatory reactions in acute cerebral ischemia. Therefore, inhibition of elastase released from neutrophils could be a useful strategy for the treatment of acute stroke. To evaluate this hypothesis, the effect of sivelestat, a selective neutrophil elastase inhibitor was examined in a mouse model of focal ischemia. The results obtained indicate that sivelestat reduced brain edema and vascular permeability, and subsequently improved the neurological deficit in an acute focal ischemia. The architecture of microvessels was analyzed by identifying vascular endothelial cells, which were prelabeled by injecting fluorescein-labeled Griffonia simplicifolia lectin I-isolectin B4 into a tail vein. Most of the microvessels in the infarcted area were structurally destroyed in the control group. In sharp contrast, microvessels in the boundary zone were well maintained in the sivelestat-treated group. Moreover, the expression of angiopoietin-1 was elevated at the ischemic margin in the sivelestat-treated group. Furthermore, the neutrophil elastase inhibitor rescued human brain microvascular endothelial cells in culture from neutrophil elastase-induced damage. These results suggest that neutrophil elastase inhibition could protect blood-brain barrier function in acute cerebral ischemia by augmentation of angiopoietin-1 expression and survival of endothelial cells.

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“…While IL-1β can cause neuronal toxicity in vivo after CNS damage, the cytokine is not directly neurotoxic to neurons in culture, but exacerbates neuronal damage by other agents [58,69]. For example, IL-1β increased excitotoxicity in vitro [39,73] and in vivo [26]. IL-1β induced neurotoxicity in vitro has been recently shown to be mediated by glia and requires free radical release and caspase activation [69].…”

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Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Tong

Balázs

Soi-ampornkul³

et al. 2008

Neurobiology of Aging

185

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The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1β renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1β compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ ERK, but not PLCγ, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1β. As the cytokine did not influence TrkB receptor and PLCγ activation, IL-1β might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1β suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1β places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. Keywords IL-1β; BDNF; signal transduction; cortical neuronsInterleukin-1 (IL-1) is a pluripotent proinflammatory cytokine that is a potent activator of host defense responses to infection and injury both in the periphery and the CNS [59]. However, IL-1 can also exacerbate damage in the CNS resulting from acute insults, such as © 2007 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral ischemia and trauma, and circumstantial evidence is consistent with a similar role in chronic neurological diseases, such as multiple sclerosis, Parkinson's disease and Alzheimer's disease (AD) [48]. Furthermore, recent genetic studies highlighted the relevance of IL-1 in AD pathogenesis, showing that specific polymorphisms in the IL-1 gene cluster are associated with greatly increased risk for AD, especially for the earlier onset of the disease [23,50]. The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the a...

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Inhibition of interleukin 1β converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage

Cited by 795 publications

References 47 publications

Activation of CPP32-Like Caspases Contributes to Neuronal Apoptosis and Neurological Dysfunction after Traumatic Brain Injury

Activation of CPP32-Like Caspases Contributes to Neuronal Apoptosis and Neurological Dysfunction after Traumatic Brain Injury

Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

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