Inhibition of interleukin 1 beta 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.


Available from: Hideaki Hara, Apr 23, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Brain infarction causes tissue death by ischemia due to occlusion of the cerebral vessels and recent work has shown that post stroke inflammation contributes significantly to the development of the ischemic pathology. Because secondary damage by brain inflammation may have longer therapeutic time window compared to the rescue of primary damage following arterial occlusion, controlling inflammation would be an obvious therapeutic target. A substantial amount of experimentally progress in this area has been made in recent years. However, it is difficult to elucidate the precise mechanisms of the inflammatory responses following ischemic stroke because inflammation is a complex series of interactions between inflammatory cells and molecules, all of which could be either detrimental or beneficial. We review recent advances in neuroinflammation and the modulation of inflammatory signaling pathways in brain ischemia. Potential targets for treatment of ischemic stroke will also be covered. The roles of the immune system and brain damage versus repair will help to clarify how immune modulation may treat stroke.
    Current Medicinal Chemistry 02/2015; 22(10). · 3.72 Impact Factor
  • Source
    [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; DOI:10.1016/j.npep.2014.12.004 · 2.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Thalidomide has shown protective effects in different models of ischemia/reperfusion damage. To elucidate the mechanisms of such protection, this study assessed the effects of thalidomide on the oxidative stress and inflammatory response induced by ischemia/reperfusion episodes in rats. Rats underwent middle cerebral artery occlusion (MCAO) for 2hours. All animals were sacrificed after different reperfusion times. Rats were administered either DMSO or thalidomide (20mg/kg (i.p.)) at different times before or during reperfusion: 1) 1h before reperfusion; the infarct area was measured 2h after reperfusion. 2) 10min before reperfusion and 80min after reperfusion; the infarct area was measured 24h after reperfusion; and 3) 10min before reperfusion and 1h, 24h, 48h, and 68h after reperfusion; the infarct area was measured 72h after reperfusion. Thalidomide reduced the infarct area 24h and 72h after MCAO, and decreased the neurological deficit in all groups with respect to controls. Thalidomide also lowered significantly the number of TUNEL-positive cells, levels of Bax, caspase-3, lipoperoxidation, and pro-inflammatory cytokines, and increased the levels of SOD1, Bcl-2 and pAkt. These results show that thalidomide has neuroprotective effects, apparently due to its anti-apoptotic, anti-oxidant, and anti-inflammatory effects. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of the neurological sciences 03/2015; DOI:10.1016/j.jns.2015.02.043 · 2.26 Impact Factor