Long‐term protection of brain tissue from cerebral ischemia by peripherally administered peptidomimetic caspase inhibitors

Deckwerth, Thomas L.; Adams, Lisa M.; Wiessner, Christoph; Allegrini, Peter R.; Rudin, Markus; Sauter, André; Hengerer, Bastian; Sayers, Robert O.; Rovelli, Giorgio; Aja, Teresa; May, Rachel; Nalley, Kip; Linton, Steve; Karanewsky, Donald S.; Wu, Joe C.; Roggo, Silvio; Schmitz, A.; Contreras, Patricia C.; Tomaselli, Kevin J.

doi:10.1002/ddr.1161.abs

Cited by 7 publications

(9 citation statements)

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“…apoptotic signaling (caspase-3 immunoreactivity/ protein expression), microglial activation (ED-1 immunoreactivity) and promoted neuronal cell survival. Previous studies have shown that a significant proportion of neuronal cell death in brain development and pathology has features of apoptosis, with prominent caspase-3 activation (Roth and D'Sa, 2001;Silverstein et al, 1997;Pulera et al, 1998;Gill et al, 2002;Deckwerth et al, 2001;McDonald et al, 1997;Hu et al, 2000;Wang et al, 2001;Morrison et al, 1998;Northington et al, 2001;Cheng et al, 1998;Nakajima et al, 2000). Cleaved caspase-3 immunoreactivity was found in both hemispheres of the neonatal brain subjected to HI.…”

Section: Discussionmentioning

confidence: 91%

Doxycycline Reduces Cleaved Caspase-3 and Microglial Activation in An Animal Model of Neonatal Hypoxia-Ischemia

Jantzie

Cheung

Todd

2005

J Cereb Blood Flow Metab

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Neonatal hypoxia-ischemia (HI) is a major contributor to many perinatal neurologic disorders and, thus, the search for therapies and effective treatments for the associated brain damage has become increasingly important. The tetracycline derivative, doxycycline (DOXY), has been reported to be neuroprotective in adult animal models of cerebral ischemia. To investigate the putative neuroprotective effects of DOXY in an animal model of neonatal HI, a time-course study was run such that pups received either DOXY (10 mg/kg) or VEH immediately before hypoxia, 1, 2, or 3 hours after HI (n=6). At 7 days after injury, the pups were euthanized, and the brains were removed and processed for immunohistochemical and Western blot analyses using antibodies against specific markers for neurons, apoptotic markers, microglia, oligodendrocytes, and astrocytes. Results showed that in vulnerable brain regions including the hippocampal formation, thalamus, striatum, cerebral cortex and white matter tracts, DOXY significantly decreased caspase-3 immunoreactivity (a marker of apoptosis), promoted neuronal survival, inhibited microglial activation and reduced reactive astrocytosis compared with VEH-treated HI pups. These effects were found to occur in a time-dependent manner. Taken together, these results strongly suggest that doxycycline has potential as a pharmacological treatment for mild HI in neonates.

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Section: Discussionmentioning

confidence: 91%

Doxycycline Reduces Cleaved Caspase-3 and Microglial Activation in An Animal Model of Neonatal Hypoxia-Ischemia

Jantzie

Cheung

Todd

2005

J Cereb Blood Flow Metab

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“…In both organs, ischemia/reperfusion triggers the activation of caspases and DNA fragmentation, two key biochemical markers of apoptosis. The development of these markers, as well as the resulting cell death, can be reduced by Z‐VAD(OMe)‐fmk and the tetrapeptide caspase inhibitors, as well as a peptidomimetic caspase inhibitor ( Hara et al , 1997 ; Mocanu et al , 2000 ; Deckwerth et al , 2001 ). It is important to note that with MX1013 we were able to achieve large, statistically significant reductions in brain infarct size with i.v.…”

Section: Discussionmentioning

confidence: 99%

“…However, there are a few caspase inhibitors that have been reported to be active by the i.v. route in the brain ischemia model ( Deckwerth et al , 2001 ), and it has been suggested that clinical studies of caspase inhibitors for cerebral ischemia have not yet been performed due to the lack of synthetic caspase inhibitors that cross the blood–brain barrier ( Schulz et al , 1999 ). Therefore, the ability of MX1013 to provide neuroprotection by i.v.…”

Section: Discussionmentioning

confidence: 99%

MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity

Yang¹,

Guastella²,

Huang³

et al. 2003

British J Pharmacology

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1 Caspases play a critical role in apoptosis, and are considered to be key targets for the design of cytoprotective drugs. As part of our antiapoptotic drug-discovery effort, we have synthesized and characterized Z-VD-fmk, MX1013, as a potent, irreversible dipeptide caspase inhibitor. 2 MX1013 inhibits caspases 1, 3, 6, 7, 8, and 9, with IC 50 values ranging from 5 to 20 nm. MX1013 is selective for caspases, and is a poor inhibitor of noncaspase proteases, such as cathepsin B, calpain I, or Factor Xa (IC 50 values 410 mm). 3 In several cell culture models of apoptosis, including caspase 3 processing, PARP cleavage, and DNA fragmentation, MX1013 is more active than tetrapeptide-and tripeptide-based caspase inhibitors, and blocked apoptosis at concentrations as low as 0.5 mm. 4 MX1013 is more aqueous soluble than tripeptide-based caspase inhibitors such as Z-VAD-fmk. 5 At a dose of 1 mg kg À1 i.v., MX1013 prevented liver damage and the lethality caused by Fas death receptor activation in the anti-Fas mouse-liver apoptosis model, a widely used model of liver failure. 6 At a dose of 20 mg kg À1 (i.v. bolus) followed by i.v. infusion for 6 or 12 h, MX1013 reduced cortical damage by approximately 50% in a model of brain ischemia/reperfusion injury. 7 At a dose of 20 mg kg À1 (i.v. bolus) followed by i.v. infusion for 12 h, MX1013 reduced heart damage by approximately 50% in a model of acute myocardial infarction. 8 Based on these studies, we conclude that MX1013, a dipeptide pan-caspase inhibitor, has a good combination of in vitro and in vivo properties. It has the ability to protect cells from a variety of apoptotic insults, and is systemically active in three animal models of apoptosis, including brain ischemia.

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“…Our work in developing PCIs has evolved from early leads taken from tetrapeptide inhibitors, indolyl dipeptide (2) 7 and oxo-azepino indole aspartyl inhibitors (3), 8 to acyloxy dipeptides (4), 9 and ultimately to an irreversible 10 oxamyl dipeptide 11 inhibitor (1, Figure 1). After extensive evaluation, our data suggested that potent, irreversible inhibition of caspases was very successful in achieving effective anti-apoptotic activity.…”

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confidence: 99%

First-in-Class Pan Caspase Inhibitor Developed for the Treatment of Liver Disease

Linton¹,

Aja²,

Armstrong³

et al. 2005

J. Med. Chem.

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A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.

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Long‐term protection of brain tissue from cerebral ischemia by peripherally administered peptidomimetic caspase inhibitors

Cited by 7 publications

References 0 publications

Doxycycline Reduces Cleaved Caspase-3 and Microglial Activation in An Animal Model of Neonatal Hypoxia-Ischemia

Doxycycline Reduces Cleaved Caspase-3 and Microglial Activation in An Animal Model of Neonatal Hypoxia-Ischemia

MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity

First-in-Class Pan Caspase Inhibitor Developed for the Treatment of Liver Disease

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