Study On Mechanism Of Action Of Vagus Nerve Stimulation And Epileptogenic Foci Irradiation By X-knife On Eplieptic Rats

The incidence of epilepsy amounts to 5‰ in our country with 500,000 patients newly diagnosed every year. In about 30% patients, epilepsy can not be effectively controlled after standard anti-epilepsy drugs treatment. It is called incurable epilepsy and surgery may be considered. Epilepsy neurosurgery developed greatly with the popularization of microsurgery, the accurate localization of epileptogenic foci and the intra-operative EEG supervision. Temple lobe resection may result in satisfactory outcome in more than 70% patients. But surgery is not preferred because it is more costly, traumatic and hazardous. The condition of patients should be considered and it is difficult to be accepted. It is required to find new effective treatment with little injury. Recently stereotactic radiotherapy and VNS showed great potential in treating epilepsy. Yet their mechanism and efficiency are not clear.Objective:This research studied the efficiency and mechanism of VNS and X-knife radiotherapy in treating rats with epilepsy and explored the effectiveness of self-made minimal VNS for the application of home-made implantable VNS.Methods:Rat chronic chemical kindling model is established by PTZ intraperitoneal injection. The reliability of epilepsy model is verified by symptomology, EEG and SPECT. These models were given high, medium and low VNS stimuli or 18Gy, 12Gy and 6Gy X-knife epileptogenic foci radiotherapy individually. Their behavioral changes were observed. The alteration of both excitatory amino acids and inhibitory amino acids were detected after different stimuli or radiotherapy and on different time spots. GABA receptors, GS and c-fos protein were also detected by immunohistochemistry.ResultsThe reliability of PTZ kindling model is 81%. EEG showed obvious high clustered spikes and multi-spike slow waves. SPECT indicated that brain bloodflow increased by 22.4% after PTZ injection.With VNS stimulation, seizure attack decreased in Group B, and rebounded to normal level at 4d. GABA_AR α1 subunit was found to decreased remarkably in both Group A and B. In the cortex of frontal lobe, GABA increased quickly after high ormedium VNS stimuli, kept the high level for more than 24 hours, and dropped down after 1 week. GABAaR increased after high or medium VNS stimulation and kept for more than 1 week. Glutamic acid and GS did not show any change after VNS stimuli, indicating that glutamic acid is not significant in anti-epilepsy treatment with VNS. In epileptic rat model, c-fos increased remarkably by 40.29%, decreased significantly after high or medium VNS stimuli and ascended to normal level after 24 hours.Seizure attacks were not found in epilepsy model in 1 week after 12-14Gy radiotherapy with the augment of GAB A and GABAaR ccl subunit. GABA level did not change after 6Gy X-ray radiation. In our research, GABA and GABAAR al subunit were both up-regulated to maximum at 24h after radiation and kept at high level for more than 1 week. Especially GABAaR al subunit level did not change dramatically after it increased. After 12-24Gy radiation, Glu level increased at lh and lweek with significant difference between them. While it decreased at 24h with no remarkable difference. The ratio of Glu/GABA reached minimum at 24h. GS positive cell ratio increased dramatically after 12-24Gy radiation and kept for at least 1 week. And c-fos decreased in each group, while more significantly in 12-24Gy group than in 6Gy group. It was found that radiation had a temporary effect on c-fos expression and it can hardly inhibit the overexpression of c-fos protein caused by PTZ injection at 24h.Conclusion:Rat PTZ induced kindling model is reliable for epilepsy microsurgery research. Self-made medium (B-type) VNS may inhibit the seizure of epileptic rats in 24 hours. VNS mainly affects the quantity of GABA in the cortex of frontal lobe. C-fos may be involved in the forepart anti-epileptic effects of VNS. Medium stimulation is relatively wise for treatment. 12Gy epileptogenic foci X-knife radiation will reduce seizures in 1 week. It impacts the quantity of GABA and Glu in the cortex of frontal lobe, c-fos may play a part in the early-stage anti-epileptic effects of X-knife radiation and GABAAR and GS may be involved in the anti-epileptic effects of epileptogenic foci radiation. 12Gy epileptogenic foci X-knife radiation is recommended in the treatment of epileptic rat model.