title: Altered glutamate metabolism contributes to antiepileptogenic effects in the progression from focal seizure to generalized seizure by low-frequency stimulation in the ventral hippocampus.
abstract: As a promising method for treating intractable epilepsy, the inhibitory effect of low-frequency stimulation (LFS) is well known, although its mechanisms remain unclear. Excessive levels of cerebral glutamate are considered a crucial factor for epilepsy. Therefore, we designed experiments to investigate the crucial parts of the glutamate cycle. We evaluated glutamine synthetase (GS, metabolizes glutamate), glutaminase (synthesizes glutamate), and glutamic acid decarboxylase (GAD, a γ-aminobutyric acid [GABA] synthetase) in different regions of the brain, including the dentate gyrus (DG), CA3, and CA1 subregions of the hippocampus, and the cortex, using western blots, immunohistochemistry, and enzyme activity assays. Additionally, the concentrations of glutamate, GABA, and glutamine (a product of GS) were measured using high-performance liquid chromatography (HPLC) in the same subregions. The results indicated that a transiently promoted glutamate cycle was closely involved in the progression from focal to generalized seizure. Low-frequency stimulation (LFS) delivered to the ventral hippocampus had an antiepileptogenic effect in rats exposed to amygdaloid-kindling stimulation. Simultaneously, LFS could partly reverse the effects of the promoted glutamate cycle, including increased GS function, accelerated glutamate-glutamine cycling, and an unbalanced glutamate/GABA ratio, all of which were induced by amygdaloid kindling in the DG when seizures progressed to stage 4. Moreover, glutamine treatment reversed the antiepileptic effect of LFS with regard to both epileptic severity and susceptibility. Our results suggest that the effects of LFS on the glutamate cycle may contribute to the antiepileptogenic role of LFS in the progression from focal to generalized seizure.
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
authors.forename: Hong-Liu
authors.initials: HL
authors.lastname: Sun
authors.affiliation: Institute of Radiation Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
authors.forename: Yu-Rong
authors.initials: YR
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Pan
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
authors.forename: Jun-Ru
authors.initials: JR
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
authors.forename: Xiang-Ming
authors.initials: XM
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
authors.forename: Yu-Xia
authors.initials: YX
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
authors.forename: Shu-Cui
authors.initials: SC
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China. Electronic address: byylwqy@163.com.
authors.forename: Qiao-Yun
authors.initials: QY
authors.lastname: Wang
authors.affiliation: Institute of Radiation Medicine, Shandong Academy of Medical Sciences, Jinan 250062, China. Electronic address: yanzhid@126.com.
authors.forename: Da-Ping
authors.initials: DP
authors.lastname: Deng
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology; D018891:Dentate Gyrus / Q000378:metabolism; D018450:Disease Progression; D004558:Electric Stimulation; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000378:metabolism* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005973:Glutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase
keywords: Amygdaloid kindling; Epileptogenesis; Glutamate cycle; Low-frequency stimulation