Pharmacokinetics And Antiepileptic Effect Of α-asaronol By Intranasal Administration

Epilepsy is a chronic disease of brain dysfunction caused by abnormal discharge of brain neurons.α-asaronol,which was discovered to be a metabolite of α-asaroneas one of the active components of Acorus tatarinowii,has better antiepileptic activity and lower toxicity than α-asarone,stevalol and carbamazepine.Conventional administration routes,such as intragastric administration,intravenous injection and intramuscular injection,result in low bioavailability and poor brain targeting of drugs due to the existence of blood-brain barrier.However,intranasal administration can bypass the blood-brain barrier and import drugs directly into the brain which has many advantages with non-invasive drug delivery,higher brain tatgeting and high bioavailability.In this thesis,the pharmacokinetics of α-asaronol in rat plasma,the distribution of α-asaronol in different brain tissues,and the evaluation of the antiepileptic effect of α-asaronol were investigated.(1)The pharmacokinetics of α-asaronol in rat plasma was analyzed by HPLC.The results showed that the peak time and maximum concentration of α-asaronol by intranasal administration in plasma were 2 min and 11.39±1.30 μg/ml,respectively,whileas those by intragastric administration were 10 min and 6.71±0.78 μg/ml.Compared with intravenous injection,the absolute bioavailability of α-asaronol by intranasal and intragastric administration were 70.57% and 19.31%,respectively.It was suggested that α-asaronol had rapid onset and high bioavailability.(2)HPLC was applied to investigate the distribution of α-asaronol by intranasal administration,intragastric administration and intravenous injection in brain tissues,such as olfactory region,olfactory bulb,hippocampus,cerebellum and cerebral cortex.The brain targeting index and brain targeting potential of α-asaronol by different administration routes were calculated.The results showed that,α-asaronol was distributed in all of five brain regions after intranasal administration,their brain targeting index of all brain regions except olfactory region was greater than 1,and the brain targeting potential was greater than 0,however,α-asaronol after intragastric administration was only found in olfactory region,hippocampus and cerebellum.It was confered that α-asaronol by intranasal administration was better brain targeting than that by intragastric administration.(3)Anti-epilepsy effect of α-asaronol by intranasal administration and intragastric administration on rats induced by pentaerythrazole(PTZ,35 mg/kg i.p)were assessed based on behavior,latent time of seizures,electroencephalography and histopathology.The results showed that α-asaronol by intranasal administration can significantly reduce the seizure scores,prolong the latency of seizure,decrease the frequency of epileptic waves,and protect brain neuron from damage.The therapeutic effect of α-asaronol by intranasal administration is better than that by intragastric administration,indicating that intranasal administration of α-asaronol is an effective route to treat epilepsy.