2-iminobiotin, a selective inhibitor of nitric oxide synthase, improves memory and learning in a rat model after four vessel occlusion, mimicking cardiac arrest

Abstract

Survivors of out-of-hospital cardiac arrest (OHCA) experience between 30% and 50% cognitive deficits several years post-discharge. Especially spatial memory is affected due to ischemia-induced neuronal damage in the hippocampus. Aim of this study was to investigate the potential neuroprotective effect of 2-iminobiotin (2-IB), a biotin analogue, on memory and learning in a four-vessel occlusion model of global ischemia using the Water Maze test. Sprague-Dawley rats were randomly assigned to either sham operation (n = 6), vehicle treatment (n = 20), 1.1 (n = 15), 3.3 (n = 14), 10 (n = 14), or 30 mg/kg/dose 2-IB treatment (n = 15). Treatment was subcutaneously (s.c.) administered immediately upon reperfusion, at 12h, and at 24h after reperfusion. Memory function on day 32 was significantly preserved in all doses of 2-IB rats compared to vehicle, as was the learning curve in the 1.1, 3.3 and 30 mg/kg dose group. Adult rats treated s.c. with 3 gifts of 2-IB every 12 h in a dose range of 1.1–30 mg/kg/dose directly upon reperfusion showed significant improved memory and learning after four vessel occlusion compared to vehicle-treated rats. Since 2-IB has already shown to be safe in a phase 1 clinical trial in adult human volunteers, it is a suitable candidate for translation to a human phase 2 study after OHCA.