dl-3-n-butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion

Abstract

Aims: Effects of dl-3-n-butylphthalide (NBP) on white matter damage and cognitive impairment in vascular cognitive impairment (VCI) have not been well studied. This study aimed to investigate the effects of NBP treatment on chronic cerebral hypoperfusion-induced white matter lesions and cognitive dysfunction in mice. Methods: Mice were subjected to bilateral common carotid artery stenosis (BCAS) for over 30 days. The cerebral blood flow was detected using a laser Doppler flowmetry. Cognitive functions were assessed by several behavioral tests. We also evaluated the effects of NBP on the blood-brain barrier (BBB) disruption and reactive astrogliosis, using Evans Blue extravasation, Western blot, CBA, and immunofluorescence in BCAS mice and cultured astrocytes. Results: The results indicated that NBP treatment attenuated spatial memory dysfunction while promoted cerebral perfusion and white matter integrity in BCAS mice. Moreover, NBP treatment prevented BBB leakage and damage of endothelial cells, as well as disruption of endothelial tight junctions. Furthermore, NBP administration effectively decreased the number of activated astrocytes and pro-inflammatory cytokines, as well as the production of MMPs, in BCAS-induced mice and LPS-stimulated astrocytes. Conclusion: Our results indicated that NBP represents a promising therapy for chronic cerebral hypoperfusion-induced white matter damage and cognitive impairment.