Synthesis,antiepileptic Activity And Mechanism Of ?-asary-laldehyde And Its Main Metabolites

Epilepsy is a group of neurological disorders characterized by sudden and repetitive seizures.Epileptic seizures are the result of excessive and abnormal nerve cell activity in the cortex of the brain.At present,Drug therapy is the main method for treatment of epilepsy in clinic.However,long term medications can cause many side effects,which has restricted the clinical use of antiepileptic drugs.Traditional Chinese medicine has a long history and has been widely used for the treatment of epilepsy with remarkable curative effect and little side effect.Furthermore it was usually used in refractory epilepsy therapeutics.It provides the foundation and materials for the discovery of new drugs from the active components and/or metabolic molecules of these TCM.In this study,we selected ?-asarone,an active ingredient of Acorus tatarinowii,as a starting point,designed and synthesized a-asarone and its series of metabolites(?-asary-laldehyde and 2,4,5-trimethoxy cinnamic acid)and analogs dihydrogen-?-asary-laldehyde.The antiepileptic activity was screened by standard pharmacological methods,and the mechanism of active compounds was discussed from the point of view of energy metabolism.The full text was divided into four chapters;the main contents are as follows:Firstly,we reviewed the pathogenesis and clinical treatment statuson epilepsy,and also summarized and analyzed the progress of epilepsy integrated treatments with Tradtional Chinese and Western Medicine.Then,the effective ingredient,?-asarone,was isolated from the traditional Chinese medicine "Acorus tatarinowii" as a breakthrough.We selected the target molecule including ?-asarone,?-asary-laldehyde,2,4,5-trimethoxy cinnamic acid and dihydrogen-?-asary-laldehyde as the main subjects in our study.In the second chapter,we designed and synthesized four compounds ?-asarone,?-asary-laldehyde,2,4,5-trimethoxy cinnamic acid and dihydrogen-?-asary-laldehyde.Meawhile,the synthesis route of the key product ?-asary-laldehyde was optimized.We established the reasonable additive system and improved the synthesis technology.All the compounds were characterized by hydrogen spectra,carbon spectra and mass spectrometry.In the third chapter,we screened the antiepileptic activity of ?-asarone,?-asary-laldehyde,2,4,5-trimethoxy cinnamic acid and dihydrogen-?-asary-laldehyde,according to the new antiepileptic drug development program adopted by the USA National Institutes of Health(NIH).The main experiments include:using the maximal electroshock seizure test preliminary screening,selecting ?-asary-laldehyde and 2,4,5-trimethoxy cinnamic acid to do pentylenetetrazol and 3-mercaptopropionic acid experiments.Finally,neurotoxicity experiments were carried out on the best activity of a-asary-laldehyde.In the fourth chapter,we research on the mechanism of ?-asary-laldehyde in the treatment of epilepsy.We found that ?-asary-laldehyde could inhibit the activity of lactate dehydrogenase(LDH).Therefore,we hypothesized that ?-asary-laldehyde could control the abnormal discharge of the brain by inhibiting the activity of lactate dehydrogenase in the nerve cells of the brain to treat epilepsy.