Vascular dementia (VD) is a degenerative cerebrovascular disease that leads to a progressive decline in memory and cognitive function.Neurotoxicity of excitatory amino acid ,free radical damage and apoptosis of neurons are regarded as the most important molecular biology mechanism of VD.Tetramethylpyrazine (TMP) is the major efficient component of the Chuanxiong, which is used in China as a new kind of calcium antagonist and an antioxidant for the treatment of cardiovascular diseases.CXC137 is a TMP piperazine derivate, was synthesized through replacing the methyl group of TMP molecules with the pharmacophores of Flunarizine, a second-generation piperazine calcium channel blocker.We here investigate the protective effect and mechanisms of CXC137 on SH-SY5Y cells damaged by NMDA and on rats with vascular dementia induced by repeated bilateral common carotid arteries occlusion.CXC137 enhanced the cells viability, attenuated NMDA-induced early apoptosis, brought down the activity and expression of caspase-3, suppressed accumulation of reactive oxygen species and intracellular free Ca2 +.CXC137 also counteracted theNMDA-induced nitric oxide increase and overexpression of iNOS and tNOS.In addition, CXC137 improved action ability, spatial learning and memory capability of vascular dementia rats.CXC137 reduced Glu content in VD rats; improved anti-oxidative capability and mitochondria function of the VD rats.Our results show that the protective effects of CXC137 might be partly due to its antioxidant action in decreasing oxidative stress and improving mitochondria function.