β-hydroxybutyrate improves cognitive impairment caused by chronic cerebral hypoperfusion via amelioration of neuroinflammation and blood-brain barrier damage

Vascular cognitive impairment (VCI) is the second most common type of dementia after Alzheimer's disease (AD) in elderly people. Chronic cerebral hypoperfusion (CCH) is the early pathophysiological basis of VCI. β-Hydroxybutyrate (BHB) is one of the important components of ketone bodies, an intermediate product of endogenous energy metabolism, which can mitigate neuroinflammation in stroke and neurodegenerative diseases. The present study aimed to investigate whether BHB can improve cognitive impairment caused by CCH and the underlying mechanism.The CCH model was established by permanent bilateral common carotid artery occlusion (2VO). CCH rats were intraperitoneally injected with BHB (1.5 mmol/kg/d) every day for 8 consecutive weeks from 2 weeks before surgery. The hippocampal blood flow of rats was measured by using a laser Doppler velocimetry. Used the Morris water maze test (MWM) to assess spatial learning and memory of rats, and harvested brain tissues for molecular, biochemical, and pathological tests.We found that BHB intervention for 8 weeks could effectively restore hippocampal blood flow and improve spatial learning and memory in CCH rats. BHB can protect the blood-brain barrier (BBB), as manifested by reducing the ultrastructural damage and leakage of the BBB, restoring the expression of tight junction-related proteins and reducing the expression of Matrix Metalloproteinases-9 (MMP-9). Additionally, after BHB intervention, microglia activation was reduced, oligodendrocyte motility was active, and the expression levels of pro-inflammatory factors such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), nuclear factor-κB (NF-κB) and advanced glycation end-products (RAGE) were lower, which also indicated that BHB had a beneficial effect in mitigating neuroinflammation.BHB can improve the cognitive impairment caused by CCH. The potential mechanisms of BHB may be through reducing neuroinflammation and protecting BBB.