Colchicine alleviates ischemic white matter lesions and cognitive deficits by inhibiting microglia inflammation via the TAK1/MAPK/NF-κB signaling pathway

Abstract

White matter lesions (WMLs) caused by chronic cerebral hypoperfusion (CCH) are closely related to the activation of microglia. Inhibition of microglia overactivation is considered as a protective strategy for WMLs. Based on its anti-inflammatory properties and clinical benefits, colchicine has become a hot spot in the drug treatment and research of vascular diseases. However, its role in vascular cognitive impairment (VCI) remains unclear. In this study, BCAS model was established to induce CCH, simulate subcortical white matter lesions, and examine the effect of colchicine on WMLs after BCAS. The basic parameters of body weight and blood pressure were monitored. Behavioral evaluation included the Open Field test, Y maze and Morris Water Maze to evaluate the motor ability and cognitive level of mice respectively. The cerebral blood flow was detected by Laser Speckle Imaging (LSI). Transmission Electron Microscopy, LFB staining, corpus callosum MBP and MAG western blot levels, and mouse brain T2-weighted imaging were used to detect demyelination and white matter changes. The expression of IBA1 was determined by immunohistochemistry and western blot, and the correlation between IBA1 staining and behavioral parameters was analyzed. The expression of brain inflammatory factors was detected by Elisa. It was found that colchicine may alleviates VCI through MAPK/NF-κB pathway by means of network pharmacology enrichment analysis from the perspective of inflammation, and the classical inflammatory proteins TAK1, p38, JNK, and p65 of this pathway were subsequently detected in in vivo and in vitro models. The anti-inflammatory spectrum of colchicine, including IL-1β, IL-6, COX2, CD86 and anti-inflammatory effects, were extensively evaluated by RT-qPCR, western blot, wound healing and transwell tests on BV2 microglia stimulated by low concentration of LPS in vitro. This study shows that colchicine can improve the cognitive impairment of BCAS mice, and the specific mechanism is to regulate the inflammation of microglia by inhibiting the classical inflammatory pathway of TAK1/MAPK/NF-κB, thereby reducing WMLs and improving the cognitive impairment behavior.

Keywords: Cerebral hypoperfusion; Colchicine; Demyelination; Microglia; inflammation.