Investigating the cerebral vascular integrity in a chronic cerebral hypoperfusion mouse model of vascular dementia: Pathophysiology and the intermittent fasting treatment.

Abstract

Chronic cerebral hypoperfusion (CCH) is an important pathophysiological mechanism in Vascular Dementia (VaD). The heterogeneous nature of CCH complicates the establishment of a stand-alone pharmacological therapy against the disease. Intermittent Fasting (IF) is neuroprotective in physiological and disease conditions, but its effects against CCH-induced BBB and vascular damage remains unknown. We investigate the effects of IF in alleviating vascular damage in a CCH model. We hypothesize that CCH would decrease BBB and vascular integrity and these changes are prevented by IF. Male C57BL/6 mice were subjected to ad libitum feeding (AL) or IF (16h fasting per day) for 4 months before surgery. In both the fasted and fed groups, CCH was experimentally induced by the bilateral carotid artery stenosis (BCAS) surgery via microcoil insertion for 30days. As controls, SHAM groups were prepared. BBB permeability, tight junction, extracellular matrix components and microvascular changes were determined from the mouse brains. AL-BCAS mice had a significantly higher extent of Evans Blue extravasation compared to AL-SHAM mice, while the IF-BCAS had significant alleviation in the extent of BBB permeability compared to their corresponding AL-BCAS timepoints, indicating that IF preserves the physiological permeability of the BBB. AL-BCAS mice also had lower gene expression of tight junction proteins (ZO-1, Occludin, Claudin-5 and JAM-A), higher expression of matrix metalloproteinases (MMP-2 and MMP-9), lower density of microvascular structures in the brain as compared to as compared to AL-SHAM, and IF-BCAS mice showed opposing trends in these proteins compared to their corresponding AL-BCAS timepoints. This further suggests that IF has a protective effect in the brain against CCH. IF has neuroprotective effects in a mouse CCH model of VaD by preserving BBB permeability and microvascular density. IF is effective in human and rodent studies of several diseases which have been reported to be risk factors of cognitive decline. Other significant findings from animal studies of IF demonstrate positive effects against mechanisms of dementia. Although IF has yet to be assessed in VaD, we suggest that IF may be an effective means of preventing the onset or suppressing the development of VaD.