| Background:Epilepsy is a common chronic neurological disease,repeated epileptic seizures seriously affect the safety and the quality of life,including the cognitive prognosis of patients.The new anti-epileptic drug Levetiracetam（LEV）has many advantages such as a significant effect on refractory epilepsy and improvement of cognition.LEV specifically interacts with synaptic vesicle glycoprotein 2A（SV2A）and exerts an antiepileptic effect by regulating neurotransmitter release and vesicle recycling.At present,LEV has become one of the broadest-spectrum and most widely applicable antiepileptic drugs,but its efficacy monitoring lacks specific indicators.18F-SynVesT-1 PET imaging agent targeting SV2A was used to monitor the distribution characteristics of SV2A in a lithium-pilocarpine epilepsy rat model from the molecular level and to further evaluate the therapeutic effect of LEV on epileptic rats.Methods:1.Three-month-old SD rats were included in this experiment,and the control group rats（n=9）were subjected to 18F-SynVesT-1 PET imaging on the 1st,14th,and 45th days to figure out the expression of SV2A.PET imaging was performed on the 1st,14th,and 45th day after the establishment of the lithium-pilocarpine epilepsy rat model（n=9）,SUVR（standard uptake value ratio）to explore the distribution of SV2A in the hippocampus of epileptic rats in acute,subacute,and chronic phases.The expression of SV2A in the hippocampus of epilepsy rats was verified by immunohistochemistry and western blotting.Immunohistochemistry（NEUN,TUJ1）and immunofluorescence（GFAP）were used to analyze pathological changes in the rat hippocampus.2.Epileptic rats（n=12）were given normal saline and different dosages of LEV（100mg/Kg/d,200mg/Kg/d,300mg/Kg/d）.The seizure frequency and seizure duration of epileptic rats were recorded.SUVR of18F-Syn Ves T-1,and pathological changes（SV2A,NEUN,TUJ1,GFAP）were conducted to study the LEV efficacy.Finally,correlation analysis was conducted within the SUV（standard uptake value）of 18F-Syn Ves T-1PET,behavioral changes（seizure times,total seizure time）,and the expression of SV2A in the hippocampus.Results:1.There was no significant difference in the SUVR between the control groups on the 1st,14th,and 45th days（P>0.05）.Compared with the control group,the uptake value of 18F-Syn Ves T-1 in the epileptic rats was decreased on the 1st day,the 14th day,and the 45th day,especially on the 14th day（P<0.01）.Compared with the subacute phase,SUVR increased in the chronic phase（P<0.01）.Decreased the expression of NEUN and reactive astrogliosis appeared in the subacute phase.2.In the experiment on LEV treatment of epileptic rats,behavioral studies found that the seizure frequency and the seizure duration in the treatment group were reduced.SUVR of 100mg/Kg/d LEV did not change significantly（P>0.05）.LEV of 200mg/Kg/d and 300mg/Kg/d increased the SUVR of epileptic rats（P<0.01）compared to the Vehicle group.Immunohistochemical experiments found that the expression of SV2A increased,the number of neurons partially recovered,and the proliferation of gliocytes decreased in the treatment group.The SUV of18F-Syn Ves T-1 in the hippocampus was significantly positively correlated with the pathological SV2A in the hippocampus（r=0.7625,P<0.01）.The SUVR of 18F-Syn Ves T-1 in the hippocampus was significantly negatively correlated with the seizure duration（r=-0.8723,P<0.01）and the seizure frequency（r=-0.8425,P<0.01）.Conclusion:1.The expression of SV2A in normal rats remained basically stable.Compared with normal rats,SV2A in epilepsy rats was significantly decreased in the acute,subacute,and chronic phases,with the most significant in the subacute phase.Compared with the subacute phase,SV2A partially recovered in the chronic phase.2.18F-SynVesT-1 PET imaging could monitor the efficacy of LEV in the lithium-pilocarpine epilepsy model.And the 18F-SynVesT-1 PET imaging results were in good agreement with the behavioral changes and hippocampal pathology of SV2A in epileptic rats.This study provides an experimental basis for 18F-SynVesT-1 PET imaging to dynamically monitor the efficacy of LEV in the treatment of epilepsy patients. |
PDF Full Text Request