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.

Microstructural disruption of the right inferior fronto‐occipital and inferior longitudinal fasciculus contributes to WMH‐related cognitive impairment

“…White matter hyperintensities is perceived as the most common neuroimaging manifestation because WMH is visible in 80% of healthy people over 60 years and almost all the people over 90 years . Different degrees of demyelination, gliosis and loss of fibers and oligodendrocytes are shown in the pathological examination of WMH . Recent studies have found that WMH can lead to vascular cognitive impairment, and in some, may ultimately progress to dementia .…”

DL-3-n-butylphthalide improves cerebral hypoperfusion in patients with large cerebral atherosclerotic stenosis. A single-center, randomized, double-blind, placebo-controlled study.

“…An animal study had showed that NBP increased cerebral microvessels and perfusion, and decreased the volume of the cerebral infarct in the rats of coldinduced ischemic stroke [14]. NBP also accelerated CBF in CCH rats after permanent bilateral common carotid artery occlusion, and prevented CCH-induced white matter damage and cognitive impairment [11,13]. In addition, NBP was found to improve rCBF in the caudate nucleus for the rats subjected to subarachnoid hemorrhage [20].…”

DL-3-n-butylphthalide improves cerebral hypoperfusion in patients with large cerebral artherosclerotic stenosis. A single-center, randomized, double-blind, placebo-controlled study.

“…An animal study had showed that NBP increased cerebral microvessels and perfusion, and decreased the volume of the cerebral infarct in the rats of cold-induced ischemic stroke [14]. NBP also accelerated CBF in the chronic cerebral hypoperfusion (CCH) rats after permanent bilateral common carotid artery occlusion, and prevented CCH-induced white matter damage and cognitive impairment [11,13]. In addition, NBP was found to improve rCBF in the caudate nucleus for the rats subjected to subarachnoid hemorrhage [20].…”

“…The numerous animal studies also showed that NBP decreased the ischemic brain area and improved the neurological deficits. NBP could improve the cerebral microcirculation and cerebral blood flow (CBF) by vasodilatation and angiogenesis in these animal studies [11][12][13][14]. However, there are still no clinic studies to verify that NBP can improve decreased CBF in the human being.…”