• James R Frederick, Zhaoming Chen, Matthew B Bevers, Lori P Ingleton, Marek Ma, and Robert W Neumar.
• Department of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
• Crit. Care Med. 2008 Nov 1; 36 (11 Suppl): S481-5.

ObjectiveDelayed neurodegeneration after transient global brain ischemia offers a therapeutic window for inhibiting molecular injury mechanisms. One such mechanism is calpain-mediated proteolysis, which peaks 24 to 48 hrs after transient forebrain ischemia in rats. This study tests the hypothesis that delayed calpain inhibitor therapy can reduce brain calpain activity and neurodegeneration after transient forebrain ischemia.DesignProspective randomized placebo-controlled animal trial.SettingUniversity research laboratory.SubjectsAdult male Long-Evans rats.InterventionsRats subjected to 10-min transient forebrain ischemia were randomized to intravenous infusion of calpain inhibitor CEP-3453 or vehicle beginning 22 hrs after injury.Measurements And Main ResultsIn a dose-response study, a 60 mg/kg bolus followed by 30 mg/kg infusion was required to reduce postischemic brain calpain activity measured by Western blot of hippocampal homogenates at 48 hrs after injury. The same dosing protocol decreased degeneration of CA1 pyramidal neurons measured at 72 hrs after injury.ConclusionsThese results suggest a causal role for calpains in delayed postischemic neurodegeneration, and demonstrate a broad therapeutic window for calpain inhibition in this model.

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