The Pharmacodynamical And Pharmacokinetical Studies Of ZLA,a New Multi-target-directed Agent For Alzheimer’s Disease

Alzheimer’s disease（AD）is one of the most devastating neurodegenerative disorders among the elderly people,with the progressive cognitive dysfunction and memory impairment as the main symptoms.AD seriously undermines the quality of life of the elderly,and causes the heavy burden of the family and society.Given the complex pathological and biochemical processes involved in AD pathogenesis,single-targeted drugs are difficult to effectively reverse the progression of AD.Our previous studies have shown that ZLA is a dual AChE inhibitor with additional complexing activity for metal ions（especially copper ions）.Being a new multi-target-directed agent,ZLA is the potential candidate of treatment of AD.In the present study,we further explored pharmacological activity and pharmacokinetic characteristics of ZLA.The results of pharmacodynamics showed that ZLA could inhibit the catalytic activity of neuron-derived AChE as well as AChE-induced form of fibrillar Aβ.Moreover,it also restrained the activation of microglial cells induced by Cu²⁺stimulation.Furthermore,ZLA effectively improved the learning and memory dysfunction caused by intraperitoneal injection of scopolamine or intra-hippocampal microinjection of Cu²⁺.A rapid,specific and sensitive LC-MS/MS method was developed for quantifying ZLA.The specificity,accuracy and precision of the method met the requirement of the bioanalytical guidance of CFDA.Using this method,we investigated the pharmacokinetic characteristics of intraperitoneal injection and intravenous injection of ZLA in mice.Taken together,the pharmacodynamical effects of ZLA as well as the pharmacokinetical characteristics were evaluated in this study.These results may provide important preclinical information for further research of ZLA.