OBJECTIVE To investigate the protective effect of Codonopsis Pilosula Polysaccharide (CPPS) on improving of the memory consolidation disorder induced by Cycloheximide and its possible mechanisms in mice. METHODS The mice was divided into five groups, as normal control group, cycloheximid model group, piracetam positive control group, CPPS 300 mg · kg- 1 group, and CPPS 150 mg·kg-1 group. The mice respectively were given saline, piracetam, and CPPS for 15 d. The memory consolidation disorder model in mice was established by ip. Cyclohexylamine, and orally administered CPPS(300 mg·kg-1 or 150 mg·kg-1) every day. Then experimental groups were subjected Morris Water Maze test. Western blotting analysis were used to analysis the expression of CaMKⅡ/CREB signaling pathways. RESULTS Morris water maze experiment showed that cyclohexylamine can cause memory consolidation disorder(P<0.01), and giving piracetam and CPPS (300 mg · kg- 1) can improve spatial memory impairment in mice(P<0.05, P<0.01). Western blotting experiment results show that compared with normal control group, CaMKⅡ and CREB contents of brain in model group mice had significant decreased(P<0.001); Compared with model group, CaMK Ⅱ and CREB contents of brain tissue in piracetam and CPPS groups increased significantly(P<0.05,P<0.01,P<0.001). CONCLUSION Cyclo?heximide can induce the memory consolidation disorder, and its effect in mice related to CaMK/CREB signaling pathways. CPPS can improved this memory disorder by influence CaMKⅡ/CREB signaling pathways.