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

Harvard University, Cambridge, Massachusetts, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 04/1997; 94(5):2007-12. DOI: 10.1073/pnas.94.5.2007
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Hideaki Hara, Jul 06, 2015
  • Source
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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 · 2.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein reported to have neuroprotective effects in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We investigated whether GPNMB is also neuroprotective against brain ischemia reperfusion injury. Focal ischemia/reperfusion injury was induced via filament middle cerebral artery occlusion for 2 h, followed by reperfusion upon withdrawal of the filament. We assessed the neuroprotective effects of GPNMB using transgenic (Tg) mice which over expressing GPNMB or recombinant GPNMB which has the sequence of human extracellular GPNMB. The results showed that GPNMB was up-regulated after ischemia reperfusion injury, and that genomic over-expression of GPNMB significantly ameliorated infarct volume. Next, we investigated the protective mechanisms of GPNMB via western blotting and immunohistochemistry. Phosphorylation of Extracellular Signal-regulated Kinase 1 and 2 (ERK1/2), and protein kinase B (Akt), were increased in the GPNMB Tg group according to western blotting data. Immunohistochemistry analysis showed that GPNMB was expressed not only in neurons, but also in astrocytes, produced labelling patterns similar to that in human brain ischemia. Furthermore, recombinant GPNMB also decreased the infarction volume. These results indicate that GPNMB protected neurons against ischemia reperfusion injury, and phosphor-Akt and phosphor-ERK might be a part of the protective mechanisms, and that the neuroprotective effect of GPNMB was seemingly induced by the extracellular sequence of GPNMB. In conclusion, these findings indicate that GPNMB has neuroprotective effects against ischemia reperfusion injury, via phosphorylation of ERK1/2 and Akt, suggesting that GPNMB may be a therapeutic target for ischemia reperfusion injuries.
    Neuroscience 07/2014; 277. DOI:10.1016/j.neuroscience.2014.06.065 · 3.33 Impact Factor