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Long‐term protection of brain tissue from cerebral ischemia by peripherally administered peptidomimetic caspase inhibitors
Author(s) -
Deckwerth Thomas L.,
Adams Lisa M.,
Wiessner Christoph,
Allegrini Peter R.,
Rudin Markus,
Sauter Andre,
Hengerer Bastian,
Sayers Robert O.,
Rovelli Giorgio,
Aja Teresa,
May Rachel,
Nalley Kip,
Linton Steve,
Karanewsky Donald S.,
Wu Joe C.,
Roggo Silvio,
Schmitz Albert,
Contreras Patricia C.,
Tomaselli Kevin J.
Publication year - 2001
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.1161
Subject(s) - ischemia , medicine , pharmacology , caspase , caspase 3 , middle cerebral artery , apoptosis , occlusion , anesthesia , programmed cell death , central nervous system , peptidomimetic , biology , biochemistry , peptide
Apoptotic cell death occurs in the injured and diseased central nervous system. It is mediated by a family of caspases, which are activated by the lethal stimulus and cleave multiple protein substrates that are critical for cell viability. Previous studies demonstrated that caspase‐mediated apoptotic cell death contributes to the loss of brain tissue after experimental cerebral ischemia and that peptidic caspase inhibitors can be efficacious in reducing infarct size after icv administration. Here we present the novel small molecule peptidomimetic caspase inhibitor IDN5370/CGP82630, which belongs to the structural class of oxoazepinoindoline caspase inhibitors. It is 10–100‐fold more potent than current peptidic inhibitors in inhibiting multiple caspases in vitro and promoting neuronal survival. IDN5370 and a derivative, IDN7866, were tested for their ability to reduce infarct size after permanent and transient cerebral ischemia. When administered icv to rats subjected to permanent middle cerebral artery occlusion (MCAO), IDN5370 significantly reduced cortical infarct as measured by magnetic resonance imaging at 2 days after artery occlusion. Protection of brain tissue persisted for 28 days after artery occlusion. To determine whether compounds of this structural class could reduce infarct size after peripheral administration, IDN7866, which penetrates the blood–brain barrier and inhibits caspase 3 in situ in the hippocampus after kainate‐induced seizures, was administered iv in both permanent and transient MCAO models. Infarct size was reduced significantly in both models 24 h after artery occlusion. These results demonstrate that peripherally administered peptidomimetic caspase inhibitors can attenuate brain injury after cerebral ischemia and confer a long‐lasting protective effect on the infarcted brain tissue. Drug Dev. Res. 52:579–586, 2001. © 2001 Wiley‐Liss, Inc.