Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang ZH, Shimizu-Sasamata M, Yuan JY, Moskowitz MAInhibition of interleukin 1-beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA 94:2007-2012

Harvard University, Cambridge, Massachusetts, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/1997; 94(5):2007-12. DOI: 10.1073/pnas.94.5.2007
Source: PubMed


The interleukin 1beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1beta (IL-1beta) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1beta levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1beta levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.

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Available from: Hideaki Hara, Oct 05, 2015
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    • "ning ( Ding et al . , 2005 , 2006 ; Guo et al . , 2008b ) . IL - 1 is a proinflammatory cytokine that plays a pivotal role in the neurodegenerative processes triggered by the ischemic insult ( Olsson et al . , 2012 ; Dénes et al . , 2013 ) . Cerebral levels of both IL - 1α and IL - 1β are elevated within hours of reperfusion after focal ischemia ( Hara et al . , 1997 ; Amantea et al . , 2007 , 2010 ; Luheshi et al . , 2011 ) . IL - 1α is mainly induced in microglia , whereas IL - 1β can be released by all the elements of the neurovascular unit , including neurons , astrocytes , microglia / macrophages and endothelial cells , being its cellular source strongly dependent on the spatio - temporal evolut"
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    ABSTRACT: The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs) that contribute to blood-brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF)-beta, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate towards several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13 or TGF-beta. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction.
    Frontiers in Neuroscience 04/2015; 9. DOI:10.3389/fnins.2015.00147 · 3.66 Impact Factor
    • "We came to the conclusion that treatment with visfatin (100 ng, ICV) significantly improves passive avoidance memory in ischemic rats after ischemia-induced neuronal damages in the hippocampus. The CA1 neurons are particularly sensitive and undergo selective and delayed degeneration in response to global cerebral ischemia (Kirino, 1982) and apoptosis is the most important process in CA1 neurons which are exposed to transient global ischemia (Hara et al., 1997). As mentioned before, the pyramidal Fig. 3 "
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    ABSTRACT: Visfatin is a novel adipocytokine with insulin-mimetic effect which plays a role in glucose-lowering effect of insulin and improves insulin sensitivity. It has been linked to a variety of cellular processes and its plays important roles in cell apoptosis and survival. Moreover, cerebral ischemia causes loss of hippocampus pyramidal cells, therefore, in this study; we investigated the neuroprotective effect of visfatin after global cerebral ischemia in male rats. Both common carotid arteries were occluded for 20 minutes followed by 4 days of reperfusion. Animals were treated with either the Visfatin (intracerebro-ventricular; 100ng) or saline vehicle (2µl) at the time of reperfusion. Behavioral examination, apoptosis and necrosis assessment were performed 4 days after ischemia. Visfatin significantly reduced Caspase-3 activation (P<0.001), TUNEL positive cells (P<0.05) and necrotic cell death in the CA1 region of the hippocampus (P<0.001). Moreover, treatment with visfatin significantly improved memory deficits of cerebral ischemia-reperfusion rats (P<0.05). The results suggest that visfatin via its antiapoptotic properties has significant neuroprotective effects on cerebral ischemia reperfusion injury in rats.
    Neuropeptides 01/2015; 49. DOI:10.1016/j.npep.2014.12.004 · 2.64 Impact Factor
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    • "These slices were immersed in a 2% solution of 2,3,5-triphenyltetrazolium chloride (TTC) (Sigma-Aldrich, St Louis, MO, USA) for 20 min. Image- J image-processing software was used to measure the unstained areas of the total infarctions, and the infarct volume was calculated as reported previously [34] (Control; n = 7, Diabetes; n = 6). "
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    ABSTRACT: Diabetes is a crucial risk factor for stroke and is associated with increased frequency and poor prognosis. Although endothelial dysfunction is a known contributor of stroke, the underlying mechanisms have not been elucidated. The aim of this study was to elucidate the mechanism by which chronic hyperglycemia may contribute to the worsened prognosis following stroke, especially focusing on mitochondrial alterations. We examined the effect of hyperglycemia on hemorrhagic transformation at 24 hours after middle cerebral artery occlusion (MCAO) in streptozotocin (STZ) -induced diabetic mice. We also examined the effects of high-glucose exposure for 6 days on cell death, mitochondrial functions and morphology in human brain microvascular endothelial cells (HBMVECs) or human endothelial cells derived from induced pluripotent stem cells (iCell endothelial cells). Hyperglycemia aggravated hemorrhagic transformation, but not infarction following stroke. High-glucose exposure increased apoptosis, capase-3 activity, and release of apoptosis inducing factor (AIF) and cytochrome c in HBMVECs as well as affected mitochondrial functions (decreased cell proliferation, ATP contents, mitochondrial membrane potential, and increased matrix metalloproteinase (MMP)-9 activity, but not reactive oxygen species production). Furthermore, morphological aberration of mitochondria was observed in diabetic cells (a great deal of fragmentation, vacuolation, and cristae disruption). A similar phenomena were seen also in iCell endothelial cells. In conclusion, chronic hyperglycemia aggravated hemorrhagic transformation after stroke through mitochondrial dysfunction and morphological alteration, partially via MMP-9 activation, leading to caspase-dependent apoptosis of endothelial cells of diabetic mice. Mitochondria-targeting therapy may be a clinically innovative therapeutic strategy for diabetic complications in the future.
    PLoS ONE 08/2014; 9(8):e103818. DOI:10.1371/journal.pone.0103818 · 3.23 Impact Factor
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