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.

Ischemia-Reperfusion Programming of Alzheimer’s Disease-Related Genes—A New Perspective on Brain Neurodegeneration after Cardiac Arrest

“…After cardiac arrest, neuronal death is observed in the hippocampus, cerebral cortex, basal ganglia, thalamus, and amygdala, structures responsible for memory, as well as general brain atrophy and, ultimately, progressive dementia of Alzheimer's disease phenotype (Figure 1) [51,52,59,77]. One proposal explaining the above changes suggests that long non-coding RNA increases the expression of the adapter protein ShcA in the hippocampus, which causes cognitive impairment after cardiac arrest as a result of neuroinflammation and apoptosis of pyramidal neurons [112][113][114].…”

“…Cognitive functions depend on complex interactions between cortical and subcortical areas through various brain networks (Figure 1) [13]. Cognitive problems develop in 42-50% of patients who survive cardiac arrest up to several years after discharge from hospital [13,59]. Other studies have reported that in people who survived cardiac arrest, 50-100% of them experienced cognitive, mood, and functioning disorders [6,7,60].…”

“…Other studies have reported that in people who survived cardiac arrest, 50-100% of them experienced cognitive, mood, and functioning disorders [6,7,60]. Even among patients who returned to good neurological condition after discharge from the hospital, 29% experienced memory problems (short-term memory and spatial or contextual memory) and 43% experienced cognitive impairment [28,59].…”