[Inhibition of cathepsin K improves the learning and memory function of the vascular dementia model rats through blocking pyroptosis pathway].

Abstract

The study aimed to investigate the mechanism of cathepsin K (CatK) on hippocampal learning and memory dysfunction in rats with vascular dementia (VD). Sprague-Dawley (SD) male rats were randomly divided into control group (Control), control+ CatK blocker group (Control+CatKⅡ), VD model group (VD), and VD model + CatK blocker group (VD+CatKⅡ). Four weeks after the establishment of the VD model by permanent ligation of bilateral common carotid arteries, CatK inhibitor Ⅱ (CatKⅡ) or equivalent artificial cerebrospinal fluid was injected into the dentate gyrus of hippocampus. Oxygen glucose deprivation (OGD) cell model was established using the HT22 cells. Morris water maze (MWM) experiment was used to observe the spatial learning and memory abilities of rats, and the expression levels of CatK, NLRP3, GSDMD, Caspase-1 and other pyroptosis-related proteins were detected by Western blot assay. The MWM place navigation test showed that the daily escape latency of the VD group was significantly longer than that of the Control group. The escape latency of the VD+CatKⅡ group was significantly shorter than that of the VD group on days 3 and 4 (P < 0.05). The space exploration test showed that the frequency of crossing the original platform area and the percentage of residence time in the target quadrant in the VD group were significantly less than those in the Control group (P < 0.05), while those in the VD+CatKⅡ group were significantly increased compared with the VD group (P < 0.05). Western blot analysis showed that the expression of NLRP3, GSDMD, Caspase-1, IL-18 and IL-1β in the VD+CatKⅡ group was significantly decreased compared with those in the VD group (P < 0.05). It was also observed in the OGD HT22 cell experiment that the levels of Caspase-1 and other pyroptosis-related proteins were significantly decreased when CatK was inhibited by pharmacological or gene interference methods. In conclusion, CatK can affect the learning and memory function of VD model rats. Inhibition of CatK can attenuate cell pyroptosis pathway to improve the learning and memory impairment of the VD model rats.