Sildenafil provides sustained neuroprotection in the absence of learning recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats

Abstract

In this study, we tested whether the phosphodiesterase-5 inhibitor sildenafil protects against neurodegeneration and facilitates recovery from learning deficits examined long after chronic cerebral hypoperfusion (CCH) induced by the 4-vessel occlusion/internal carotid artery (4-VO/ICA) model in middle-aged rats. Male Wistar rats (12-15 months of age) were subjected to permanent 3-stage 4-VO/ICA with an interstage interval of 4 days. Sildenafil (3 mg/kg, p.o.) was administered at one dose per day for 10 days, beginning soon after the first occlusion stage. Three months later, learning in a non-food-rewarded, eight-arm radial maze task was tested. Learning performance is expressed as the latency to find a goal box and the number of reference or working memory errors. Histological examination was performed 1-3 days after behavioral testing. In the vehicle-treated group, permanent 4-VO/ICA markedly disrupted learning performance and caused moderate-to-severe neurodegeneration in the CA1-CA4 subfields of the hippocampus (56.2%), dentate gyrus (DG; 19.2%), retrosplenial cortex (RS cortex; 47.4%), and parietal association cortex (PtA cortex; 38.2%). Sildenafil treatment did not prevent 4-VO/ICA-induced learning deficits, whereas neurodegeneration was significantly reduced in the CA1-CA4 subfields (30.5%), DG (7.2%), RS cortex (11.8%), and PtA cortex (6.5%). Advancing previous findings from our laboratory, this study suggests that while sildenafil can provide important neuroprotection in different brain regions of middle-aged rats subjected to CCH, such histological effect does not translate into cognitive recovery.