Effects of Dl-3-n-butylphthalide on Cognitive Functions and Blood-brain Barrier in Chronic Cerebral Hypoperfusion Rats

Abstract Vascular cognitive impairment (VCI) have been one of the main type of cognitive impairment. Chronic cerebral hypoperfusion (CCH) is the main cause of VCI. Blood-brain barrier damage plays an essential part in the pathogenesis of CCH induced cognitive impairment. At present, the treatment to VCI mainly focused on prevention, there is no drug clinically approved for the treatment of VCI. This study investigated the effects of DL-3-n-butylphthalide (NBP) on cognitive function and blood-brain barrier in chronic cerebral hypoperfusion rats. A modified bilateral common carotid artery occlusion (mBCCAO) model was applied to imitate chronic cerebral hypoperfusion. The feasibility of the model was verified by laser Doppler, 13N-Ammonia-Positron Emission Computed Tomography (PET) and Morris Water Maze. Subsequently, Morris water maze experiment to evaluate the effect of different doses of NBP (40mg/kg, 80mg/kg) on the improvement of cognitive impairment induced by mBCCAO. Evans blue staining and western blot of tight junction protein were conducted to explore the effect of NBP on the blood-brain barrier protection. At the same time, the changes of pericyte coverage in mBCCAO model and the effect of NBP on pericyte coverage were preliminarily explored. We found that, mBCCAO surgery led to obvious cognitive impairment and decreased whole cerebral blood flow in rats, among which the blood flow in cortex, hippocampus and thalamus brain regions decreased more significantly. High-dose NBP (80 mg/kg) improved long-term cognitive function in mBCCAO rats, alleviates Evans blue leakage and reduces the loss of tight junction proteins (ZO-1, Claudin-5) in the early course of the disease, thereby exerting a protective effect on the blood-brain barrier. No significant changes in pericyte coverage were observed after mBCCAO.