| Epilepsy,a complex chronic brain disease,is characterized by recurrent,epileptic seizures and the neurobiological abnormalities.?-asaronol was discovered to be one of the important metabolites of ?-asarone in vivo,which is the active component of Traditional Chinese Medicine Acorus calamus with effective treatment in epilepsy.?-asaronol with efficient antiepileptic activity and low toxic effects has been proved in our previous study.However,the antiepileptic molecular mechanism of ?-asaronol need to be known if to become a new antiepileptic medicine.In this thesis,the antiepileptic efficacy of ?-asaronol was evaluated.NMR based metabonomics was then applied to investigate the dynamic process of epileptic occurrence and development,and the metabolic pattern of epileptic rats with the oral administration of ?-asaronol to enhance understanding of the whole process of epilepsy disease and the antiepileptic molecular mechanism of ?-asaronol,which is of great significance in developing ?-asaronol into a new antiepileptic drug derived from Traditional Chinese Medicines.(1)Anti-epilepsy effects of ?-asaronol(50 mg/kg i.g)on rats induced by pentaerythrazole(PTZ,35 mg/kg i.p)were assessed based on seizure score,latent time of seizures,neurotransmitter level in brain tissue,electroencephalography and histopathology.The results indicated that ?-asaronol can significantly reduce the seizure scores,prolong the latency of seizure,inhibit abnormal brain discharge,regulate neurotransmitter disorders,and protect neurons from damage.It was shown that ?-asaronol has anti-epileptic activity,which is comparable to that of clinical medicine phenytoin sodium and superior to that of Traditional Chinese Medicine ?-asarone.(2)NMR based metabonomics was used to analyze the metabolic pattens of plasma,urine and fecal extracts in rats with PTZ induced chronic epilepsy at pre-kindling phase(Day0),early kindling phase(Day5),kindling phase(Day15)and fully kindled phase(Day29).Some potential biomarkers associated with the development of epilepsy in rats were screened,including 24 metabolites in plasma,14 metabolites in urine and 30 metabolites in fecal samples.These metabolites are mainly involved in amino acid metabolism,fatty acid metabolism and energy metabolism in epileptic rats.It is inferred that the occurrence and development of epileptic disease are related to energy deficiency,neuroinflammation,neurotoxicity and abnormal mitochondrial function.(3)NMR based metabonomics was used to analyze the metabolic patterns of plasma,urine,faecal extract,and brain tissue extracts from the PTZ-induced epilepsy rat treated with ?-asaronol,?-asarone and phenytoin sodium.The results showed that these three drugs can regulate metabonomic levels of epileptic rats to normal animals,but the regulatory effect of ?-asaronol is different from that of ?-asarone and phenytoin sodium.Six main metabolic pathways were associated with antiepileptic effects of ?-asaronol,such as alanine,aspartate and glutamate metabolism,D-glutamine and D-glutamate metabolism,ketone body metabolism,glycine,serine and threonine metabolism,phenylalanine metabolism,niacin and nicotinamide metabolism.?-asaronol plays a vital role in regulating the balance of excitatory and inhibitory neurotransmitters,improving mitochondrial function,enhancing energy metabolism in brain tissue,and increasing the level of nicotinamide to reduce dopamine and glutamate toxicity in striatum. |
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