Protective Role Of L-3-n-Butylphthalide In Cognitive Function And Dysthymic Disorders In Mouse With Chronic Epilepsy

Objective:Epilepsy is one of the most common neurologic disorders,affecting about 70 million people worldwide.The disease is characterized by recurrent seizures,which are due to aberrant neuronal networks resulting in synchronous discharges and associated with psychiatric comorbidity and cognition dysfunction.L-3-n-butylphthalide(NBP),an extract from the seeds of Apium graveolens Linn(Chinese celery),ameliorates cognitive dysfunction in ischemia and/or Alzheimer's disease animal models.However,little is known about epilepsies and its co-morbidities and the role of NBP in epilepsy.Here,using a pilocarpine-induced chronic epileptic mouse model,to study the role of L-3-n-butylphthalide in epileptic and its mechanism.Methods:C57BL/6 mice were intraperitoneally(i.p.)injected with pilocarpine to set up epileptic model.Then,to screen chronic epileptic mice by monitoring electroencephalogram and observing spontaneous seizure of the mice.Chronic epileptic mice were randomly divided into two groups and intraperitoneally injected with NBP or saline.Last,we used behavioral experiment,extracted protein and message RNA(mRNA)from brain tissue and utilized hippocampal sections Nissl staining to study the possible mechanism of NBP in epilepsy.Results:During the Morris water maze(MWM)test,NBP treated mice spent significantly more time in the target quadrant(P<0.01).In black-white box test,mice in pilocarpine NBP group displayed hyperactivity and spent more time in the white box than those in pilocarpine(P<0.001).The tail suspension test showed that NBP treated mice had a profound increase in their reaction to suspension,whereas the pilocarpine treated epilepsy mice developed a characteristic immobile posture following the platform withdrawal(P<0.001).We detected significantly decreased expression levels of Postsynaptic density protein 95(PSD95)and Glutamic acid decarboxylase 65/67(GAD65/67)in the brain of mice treated with pilocarpine,and significantly increased levels of them in NBP treated mice.The mRNA levels of Brain derived neurotrophic factor(Bdnf)and Klotho were strongly upregulated in NBP treated epileptic mice when compared to epileptic mice without NBP treatment(P<0.01),the mRNA levels of Bdnf and Klotho were strongly upregulated in NBP treated epileptic mice.Conclusions:NBP treatment may be a potential strategy for ameliorating epileptogenesis and the comorbidities of cognitive and psychological impairments.