Cognitive function after transient forebrain ischemia: Preliminary assessment of reversal by darbepoetin alfa

Abstract

Stroke is the leading cause of disability in adults. Stroke survivors endure neurologic deficits including impairments in cognitive function. In the present study, we investigated the use of a novel therapeutic for improving cognitive deficits in the four vessel occlusion (4-VO) model of transient global cerebral ischemia, an animal model of stroke. The Barnes maze, a test of spatial memory, was used to assess cognition. In this test, rodents are motivated to find a hidden escape box using spatial cues. After several trials the rodent will inherently locate the escape box faster and with fewer errors if spatial memory is unaffected.  Using immunohistochemistry for the neuronal marker NeuN and cresyl violet staining, we have shown that 12 minutes of global ischemia selectively kills greater than 90% of CA1 neurons in the dorsal hippocampus of adult rats. Furthermore, animals in which there was a bilateral loss of hippocampal CA1 neurons display more errors and longer escape latency in the Barnes maze compared to sham-operated controls. The erythropoietin analog, darbepoetin alfa, has been shown to improve cognitive deficits in animal models of schizophrenia and may be able to improve the memory deficits of 4-VO treated rats. Preliminary results regarding the ability of darbepoietin alfa to enhance the performance of 4-VO treated rats in the Barnes maze will be presented.