| Objective:Mesial temporal lobe epilepsy(MTLE)is the most common form of medically refractory epilepsy.It is crucial to search for new AEDs with better efficacy and tolerability especially point at the drug refractory epilepsy.The discovery and development of a new AED relies heavily on the animal models of epilepsy.In the past 60 years,the maximal electroshock seizure(MES)and pentylenetetrazole(PTZ)seizure tests are considered the "gold standard" for discovering AEDs.The two models were successfully used to discover many of our currently used AEDs acting on ion channel or receptor targets.However it has been a contro versial issue that the AEDs which discover by MES/PTZ model may have no effect on refractory epilepsies.The reasons mainly lie in the same simple screening models are models of acute epileptic seizures rather than models of epilepsy.Epilepsy is character by spontaneous recurrent seizures(SRS).However the test such as the MES test is induced an acute seizure by electrical stimulation in a normal non-epileptic animal.In recent years,researchers attempt to apply the chronic epilepsy model.Intracerebral injection of KA model(the KA model at another time)is the best model to reconstruct the SRS and histopathologic alterations of mTLE.However,whether the KA is refractory to current AEDs is until not known.Clustering of the EEG seizures would result repeatedly attacks during one period and none during another period.So it is unbelievable to evaluate the AEDs by single injection or short-term treatment.Long-term treatment is indispensable.We aim at to examine the phannacological responsiveness of current AEDs on the spontaneous seizures in KA models by long-term(3weeks)treatment of valproate(VPA),lamotrigine(LTG)and carbamazepine(CBZ)and further to explore whether the KA model is a model of refractory epilepsy.True refractory epilepsy models is vital for developing new AEDs.Methods:We first establish the KA epilepsy model by micro injection of KA in unilateral hippocampus(Injection coordinate:AP:-2.0、ML:-1.8、DV:-2.3 mm).Four weeks after the first surgery,we carried on the second surgery to implanted electrodes.Each of the mice were three weeks of baseline and three weeks of drug treatment,during this time we ensure the 24h continuous EEG monitoring for recording the number of seizures.After the drug treatment,the brain tissue of mice was taken,and then explore the change of hippocampal sclerosis by HE staining,immunohistochemical staining and Timm staining.Results:We found that:1.KA modelis the best model to reconstruct the SRS and histopathologic alterations of mTLE.2.KA model had a certain degree of resistance to common AEDs,and the effective rates of anti-epileptic were 12.5%in valproate sodium group,25%in Lamotrigine group,and 12.5%in carbamazepine group(rescue the inhibition of y-GABA).3.Drug tolerance after prolonged exposure of AEDs is existed.Anti-epileptic function was noticeable on the first few days of drug-treated,but the drug resistance and the frequency of epilepsy seizures of KA model mouse was significantly improved subsequently.4.These three drugs exhibited no effect to rescue the hippocampal sclerosis 5.Three conventional anti-epileptic drugs have no effect on hippocampus sclerosis,a typical clinicopathologic characteristics of TLE.Stated thus,we suggest that the KA model was an intractable epilepsy model can be used as drug screening 6.The ceftriaxone can reduce the seizures but did not significantly enhance the expression of GLT-1 which test by Western blot.Conclusion:In this study,the chronic epilepsy model was confirmed as a drug refractory epilepsy model by long-term injection of three commonly used antiepileptic drugs.It is suggested that this model should be used in the screening of new antiepileptic drugs in the future.Ceftriaxone sodium can not significantly enhance the expression of GLT-1 in the kainic acid model,but also can not play a significant role in anti epilepsy,it is recommended to look for more effective GLT-1 expression of drugs. |
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