Decreased cerebral perfusion and oxidative stress result in acute and delayed cognitive impairment

Chronic cerebral hypoperfusion (CCH) is common in the pathogenesis of cognitive impairment, in which oxidative stress plays an important role. Here we describe an alternative rat model for CCH that involves two-stage, three-vessel occlusion (2s-3VO) and compare its effects with those of permanent bilateral occlusion (2VO) of the common carotid arteries. Real-time cerebral blood flow (CBF) during the surgery was monitored. Spatial learning and memory were tested with the Morris water maze, and oxidative damage was evaluated by measuring malondialdehyde (MDA) levels in both the hippocampus and cortex. We found that the CBF drop in the early stage of the 2s-3VO model was more modest than that in the 2VO model. Like 2VO rats, 2s-3VO rats showed impaired spatial learning and memory and increased MDA levels 8 weeks after surgery. Interestingly, when pooling observations from previous studies, we confirmed that oxidative damage appeared later than spatial learning and memory deficits but lasted longer than did cerebral hypoperfusion. Thus, the 2s-3VO model appears to be a suitable model for the study of CCH. Moreover, data support the notion that cognitive impairment in CCH rat models may be induced early by cerebral hypoperfusion early and in a later phase by oxidative stress.