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

Apoptotic cell death occurs in the injured and diseased central nervous sys tem. It is mediated by a family of caspases, which are activated by the let hal stimulus and cleave multiple protein substrates that are critical for c ell viability. Previous studies demonstrated that caspase-mediated apoptoti c cell death contributes to the loss of brain tissue after experimental cer ebral ischemia and that peptidic caspase inhibitors can be efficacious in r educing infarct size after icy administration. Here we present the novel sm all molecule peptidomimetic caspase inhibitor IDN5370/CGP82630, which belon gs to the structural class of oxoazepinoindoline caspase inhibitors. It is 10-100-fold more potent than current peptidic inhibitors in inhibiting mult iple caspases in vitro and promoting neuronal survival. IDN5370 and a deriv ative, IDN7866, were tested for their ability to reduce infarct size after permanent and transient cerebral ischemia. When administered icy to rats su bjected to permanent middle cerebral artery occlusion (MCAO), IDN5370 signi ficantly 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 str uctural class could reduce infarct size after peripheral administration, ID N7866, which penetrates the blood-brain barrier and inhibits caspase 3 in s itu in the hippocampus after kainate-induced seizures, was administered iv in both permanent and transient MCAO models. Infarct size was reduced signi ficantly in both models 24 h after artery occlusion. These results demonstr ate that peripherally administered peptidomimetic caspase inhibitors can at tenuate brain injury after cerebral ischemia and confer a long-lasting prot ective effect on the infarcted brain tissue. Drug Dev. Res. 52:579-586, 200 1. (C) 2001 Wiley-Liss, Inc.