Robust and enduring atorvastatin-mediated memory recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats

Abstract

Chronic cerebral hypoperfusion (CCH) is a common condition associated with the development and/or worsening of age-related dementia. We previously reported persistent memory loss and neurodegeneration after CCH in middle-aged rats. Statin-mediated neuroprotection has been reported after acute cerebral ischemia. Unknown, however, is whether statins can alleviate the outcome of CCH. The present study investigated whether atorvastatin attenuates the cognitive and neurohistological outcome of CCH. Rats (12–15months old) were trained in a non-food-rewarded radial maze, and then subjected to CCH. Atorvastatin (10mg/kg, p.o.) was administered for 42days or 15days, beginning 5h after the first occlusion stage. Retrograde memory performance was assessed at 7, 14, 21, 28, and 35days of CCH, and expressed by “latency,” “number of reference memory errors” and “number of working memory errors.” Neurodegeneration was then examined at the hippocampus and cerebral cortex. Compared to sham, CCH caused profound and persistent memory loss in the vehicle-treated groups, as indicated by increased latency (91.2% to 107.3%) and number of errors (123.5% to 2508.2%), effects from which the animals did not spontaneously recover across time. This CCH-induced retrograde amnesia was completely prevented by atorvastatin (latency: −4.3% to 3.3%; reference/working errors: −2.5% to 45.7%), regardless of the treatment duration. This effect was sustained during the entire behavioral testing period (5weeks), even after discontinuing treatment. This robust and sustained memory-protective effect of atorvastatin occurred in the absence of neuronal rescue (39.58% to 56.45% cell loss). We suggest that atorvastatin may be promising for the treatment of cognitive sequelae associated with CCH.