title: A Transient Upregulation of Glutamine Synthetase in the Dentate Gyrus Is Involved in Epileptogenesis Induced by Amygdala Kindling in the Rat.
abstract: Reduction of glutamine synthetase (GS) function is closely related to established epilepsy, but little is known regarding its role in epileptogenesis. The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling model of epilepsy induced by daily electrical stimulation of basolateral amygdala in rats. Both expression and activity of GS in the ipsilateral dentate gyrus (DG) were upregulated when kindled seizures progressed to stage 4. A single dose of L-methionine sulfoximine (MSO, in 2 µl), a selective GS inhibitor, was administered into the ipsilateral DG on the third day following the first stage 3 seizure (just before GS was upregulated). It was found that low doses of MSO (5 or 10 µg) significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20 µg) aggravated kindled seizures. In animals that seizure acquisition had been successfully suppressed with 10 µg MSO, GS upregulation reoccurred when seizures re-progressed to stage 4 and re-administration of 10 µg MSO consistently reduced the seizures. GLN at a dose of 1.5 µg abolished the alleviative effect of 10 µg MSO and deleterious effect of 20 µg MSO on kindled seizures. Moreover, appropriate artificial microRNA interference (1 and 1.5×10(6) TU/2 µl) of GS expression in the ipsilateral DG also inhibited seizure progression. In addition, a transient increase of GS expression and activity in the cortex was also observed during epileptogenesis evoked by pentylenetetrazole kindling. These results strongly suggest that a transient and region-specific upregulation of GS function occurs when epilepsy develops into a certain stage and eventually promotes the process of epileptogenesis. Inhibition of GS to an adequate degree and at an appropriate timing may be a potential therapeutic approach to interrupting epileptogenesis.
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China ; Department of Pharmacology, Binzhou Medical University, Yantai, China.
authors.forename: Hong-Liu
authors.initials: HL
authors.lastname: Sun
authors.forename: Shi-Hong
authors.initials: SH
authors.lastname: Zhang
authors.forename: Kai
authors.initials: K
authors.lastname: Zhong
authors.forename: Zheng-Hao
authors.initials: ZH
authors.lastname: Xu
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Qi
authors.initials: Q
authors.lastname: Fang
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Deng-Chang
authors.initials: DC
authors.lastname: Wu
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Zhang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D018891:Dentate Gyrus / Q000201:enzymology* / Q000503:physiopathology; D004827:Epilepsy / Q000201:enzymology* / Q000503:physiopathology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D007696:Kindling, Neurologic; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D005974:Glutamate-Ammonia Ligase