Neuronal damage, central cholinergic dysfunction and oxidative damage correlate with cognitive deficits in rats with chronic cerebral hypoperfusion

Abstract

Chronic cerebral hypoperfusion has been identified to be a risk factor for cognitive decline in aging, vascular dementia, and Alzheimer's disease. Substantial evidence has shown that chronic cerebral hypoperfusion may cause cognitive impairment, but the underlying neurobiological mechanism is poorly understood so far. In this study, we used a rat model of chronic cerebral hypoperfusion by permanent bilateral common carotid artery occlusion (BCCAO) to investigate the alterations of neuronal damage, glial activation oxidative stress and central cholinergic dysfunction, and their causal relationship with the cognitive deficits induced by chronic cerebral hypoperfusion. We found that BCCAO rats exhibited spatial learning and memory impairments and working memory dysfunction 12 weeks after BCCAO compared with sham-operated rats, simultaneously accompanied by significantly increased neuronal damage and glial cell activation in the cerebral cortex and hippocampus. Twelve weeks of BCCAO treatment in rats resulted in central cholinergic dysfunction and increased oxidative damage compared with sham-operated rats. Correlational analyses revealed that spatial learning and memory impairments and working memory dysfunction were significantly correlated with the measures of neuronal damage, central cholinergic dysfunction and oxidative damage in the cerebral cortex and hippocampus of rats with BCCAO. Moreover, the measures of neuronal damage and central cholinergic dysfunction were significantly correlated with the indexes of oxidative damage in rats with BCCAO. Collectively, this study provides novel evidence that neuronal damage and central cholinergic dysfunction is likely due to increased oxidative stress under the condition of chronic cerebral hypoperfusion. Furthermore, the results of the present study suggest that neuronal damage, central cholinergic dysfunction and oxidative damage in the brain following the reduction of cerebral blood flow could be involved in cognitive deficits induced by chronic cerebral hypoperfusion.

Keywords: Alzheimer’s disease; Cholinergic function; Chronic cerebral hypoperfusion; Cognitive deficit; Oxidative stress; Vascular dementia.