title: A sub-threshold dose of pilocarpine increases glutamine synthetase in reactive astrocytes and enhances the progression of amygdaloid-kindling epilepsy in rats.
abstract: The prognosis of patients exposed to a sub-threshold dose of a proconvulsant is difficult to establish. In this study, we investigated the effect of a single sub-threshold dose of the proconvulsant pilocarpine (PILO) on the progression of seizures that were subsequently induced by daily electrical stimulation (kindling) of the amygdaloid formation. Male Sprague–Dawley rats were each implanted with an electrode in the right basolateral amygdala and an indwelling cannula in the right ventricle. The animals were randomized into groups and were administered one of the following treatments: saline, PILO, saline+L-α-aminoadipic acid (L-AAA; one dosage tested), PILO+L-AAA, or PILO+L-methionine sulfoximine (three dosages tested). Amygdaloid stimulation and electroencephalography were performed once daily. We performed immunohistochemistry and western blot for glial fibrillary acidic protein and glutamine synthetase (GS). We also assayed the enzymic activity of GS in discrete brain regions. An intraperitoneal injection of a sub-threshold PILO dose enhanced the progression of amygdaloid-kindling seizures and was accompanied by an increase in reactive-astrocyte and GS (content and activity) in the hippocampus and piriform cortex. L-AAA and L-methionine sulfoximine, inhibitors of astrocytic and GS function, respectively, abolished the effect of PILO on amygdaloid-kindling seizures. We conclude that one sub-threshold dose of a proconvulsant may enhance the progression of subsequent epilepsy and astrocytic GS may play a role in this phenomenon. Thus, a future therapy for epilepsy could be inhibition of astrocytes and/or GS.
authors.affiliation: aSchool of Pharmaceutical Sciences, Binzhou Medical University, Yantai bInstitute of Radiation Medicine, Shandong Academy of Medical Sciences, Jinan, China.
authors.forename: Hong-Liu
authors.initials: HL
authors.lastname: Sun
authors.forename: Da-Ping
authors.initials: DP
authors.lastname: Deng
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Pan
authors.forename: Chao-Yun
authors.initials: CY
authors.lastname: Wang
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Zhang
authors.forename: Xiang-Ming
authors.initials: XM
authors.lastname: Chen
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Wang
authors.forename: Yu-Xia
authors.initials: YX
authors.lastname: Liu
authors.forename: Shu-Cui
authors.initials: SC
authors.lastname: Li
authors.forename: Xian-Yong
authors.initials: XY
authors.lastname: Bai
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
mesh_terms: D015074:2-Aminoadipic Acid / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D066272:Basolateral Nuclear Complex / Q000187:drug effects* / Q000201:enzymology; D002408:Catheters, Indwelling; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000378:metabolism; D018021:Lithium Chloride; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000633:toxicity*; D010862:Pilocarpine / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D013702:Temporal Lobe / Q000187:drug effects / Q000201:enzymology
chemical_list: D005904:Glial Fibrillary Acidic Protein; D018721:Muscarinic Agonists; D010862:Pilocarpine; D008717:Methionine Sulfoximine; D015074:2-Aminoadipic Acid; D005974:Glutamate-Ammonia Ligase; D018021:Lithium Chloride