Activation of nitric oxide synthase may mediate reversal of cognitive deficits after transient forebrain ischemia produced by darbepoetin alfa

Abstract

Stroke is the leading cause of disability in adults. Stroke survivors endure various neurological deficits including impaired cognitive function. Erythropoietins are able to attenuate cognitive deficits in both animal models of schizophrenia and patients with psychosis. In the present study, we investigated the ability of the erythropoietin analogue, darbepoetin alfa, to reverse pre-existing cognitive deficits in rats that had been subjected to an episode of transient global cerebral ischemia. The Barnes maze was used as a behavioural test to assess spatial memory. In this test, rodents are motivated to find a hidden escape box using spatial cues. After several trials, normal rodents remember the location of the escape box thus locating it more quickly and with fewer errors.  Using immunohistochemistry for the neuronal marker NeuN and cresyl violet staining, we show 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. A single systemic injection of darbepoetin alfa (5000 U/kg, i.p.) 4 hours before behavioural testing, decreased deficits in escape latency. Preliminary results suggest that this improvement in spatial memory was correlated with increased nitric oxide synthase activity in the ventral hippocampus and cortex.  Activation of nitric oxide synthase has been implicated in neurochemical processes responsible for synaptic plasticity, suggesting that elevated levels of nitric oxide may mediate the ability of darbepoetin alfa to reverse pre-existing spatial memory deficits in rats that had sustained dorsal hippopcampal damage following a brief period of transient global ischemia.