【Abstract】 Objective To investigate the protective mechanism of penehychdine hydrochloride against lipopolysaccharide induced brain injury in rats. Methods 40 Wistar rats were randomly divided into group NS，group LPS, group PL and group PH. The group NS was treated with saline. The group LPS was treated with lipopolysaccharide. The group PL was treated with intraperitoneal injection of penehychdine hydrochloride (01mg/kg) while they were induced by intraperitoneal infection of LPS. The group PH, which received intraperitoneal injection of penehychdine hydrochloride (10 mg/kg) just after the infection of LPS. Levels of CDl4 and TLR4 mRNA in brain were determined with RTPCR. The expression of TNFα were detected by enzyme linked immune adsorbing analysis (ELISA). The brain pathologic structure was observed under the optical microscope.Results Group NS had normal structure. The neural cells which in group LPS were arranged disorder, not only had serious pyknosis and apoptosis in brain tissue, but also had a large number of ghost cells. Between cells, there were many loosely tissue and cellfree area. The group PL showed more apoptotic cells , the cells were arranged neat. The pyknosis and ghost cells were significantly less than group LPS. The neurons in group PH had closelyarranged, there had less apoptotic cells and pyknosis, but the extent and scope were lighter than group PL, heavier than group NS. There was significant difference on expression of CD14 and TRL4 in brain of rats among four groups. Compared with NS group, the expression of CD14 and TLR4mRNA of brain tissues in the group LPS increased obviously (P＜005). Compared with LPS group , the level of CD14 and TLR4mRNA of brain tissues in the group PL and PH decreased(P＜005). Furthermore, group PH was lower than that of group PL. Compared with NS group, TNFα increased (P＜005). Compared with LPS group, TNFα decreased in brain tissue of PL group and PH group (P＜005). Compared with PL group, TNFα decreased in PH group (P＜005). Conclusions Penehychdine hydrochloride has the protective effect on Lipopolysaccharide induced brain injury in rats. The mechanisms of the effect are due to its ability of inhibiting the expression of CD14 and TLR4mRNA, thereby inhibit the development of uncontrolled inflammation at the development of Lipopolysaccharide induced brain injury in rats.