Effects of Dl-3-n-butylphthalide on cognitive functions and blood–brain barrier in chronic cerebral hypoperfusion rats

Abstract Purpose Vascular cognitive impairment (VCI) has been one of the major types of cognitive impairment. Blood-brain barrier damage plays an essential part in the pathogenesis of VCI. At present, the treatment to VCI mainly focused on prevention, with no drug clinically approved for the treatment of VCI. This study aimed to investigate the effects of DL-3-n-butylphthalide (NBP) on VCI rats. Methods A modified bilateral common carotid artery occlusion (mBCCAO) model was applied to mimic VCI. The feasibility of the mBCCAO model was verified by laser Doppler, 13N-Ammonia-Positron Emission Computed Tomography (PET) and Morris Water Maze. Subsequently, Morris water maze experiment, Evans blue staining and western blot of tight junction protein were performed to evaluate the effect of different doses of NBP (40mg/kg, 80mg/kg) on the improvement of cognitive impairment and BBB disruption induced by mBCCAO. Immunofluorescence was employed to examine the changes of pericyte coverage in mBCCAO model and the effect of NBP on pericyte coverage were preliminarily explored. Results mBCCAO surgery led to obvious cognitive impairment and the decrease of whole cerebral blood flow, 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, alleviated Evans blue leakage and reduced 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. Conclusions High-dose NBP improved cognitive function in mBCCAO rats. High-dose NBP protected the integrity of BBB by upregulating TJ protein expression, rather than regulating pericyte coverage ratio. NBP could be a potential drug for the treatment of VCI.