Effects Of A Caspase-1 Inhibitor CZL80 In Rodent Epilepsy Models

Epilepsy is a common chronic neurological disorder characterized by clinical sudden and recurrent epileptic seizures.Currently,a wide range of anti-epileptic drugs(AEDs)have been used in the treatment of epileptic seizures in clinic.However,approximately one-third of the patients showed resistance to traditional AEDs who are called drug-resistant epilepsy(also called refractory epilepsy).Once developed drug-resistance,there is almost no effective treatments available.Thus,there remains an urgent need to look for new drug targets for the treatment of epilepsy.Over the past decades,experimental evidence and clinical observations have indicated that inflammation plays an important role in the genesis and development of epilepsy.An important inflammatory enzyme caspase-1 and its associated inflammatory pathway are probably considered to be very important for epilepsy and thus be a potential target for treatments of epilepsy.We previously found that a novel molecular CZL80 is a selective caspase-1 inhibitor.Here,we evaluated the therapeutic potential of CZL80 in several classic rodent models of experimental epilepsy.Results are as follows:CZL80 significantly reduced the duration of tonic-clonic seizures and lowered the mortality rate in maximal electroshock seizure(MES)model.In pentylenetetrazole(PTZ)-induced model,CZL80 lowered the seizure stage and also the mortality rate,prolonged the latency to generalized seizures(GS).Furthermore,CZL80 inhibited the occurrence of spontaneous seizures and shorten the seizure duration in chronic kainic acid(KA)-induced model.The after-discharge threshold(ADT)of drug-resistant model was effectively raised.Besides,CZL80 has shown to efficiently raise the action potential threshold and enhance the inhibitory synaptic transmission of hippocampal CA3 pyramidal neurons in chronic KA mice in vitro.In addition,long-term treatment of CZL80 had no obvious side effects on mice.All the results suggested:a novel molecular CZL80 targeting caspase-1 had therapeutic potential on several rodent models of epilepsy especially temporal lobe epilepsy(TLE)and should be viewed as a promising candidate for the development of novel therapies to treat epilepsy.