Chronic H1-Antihistamine Treatment Increases Seizure Susceptibility After Withdrawal by Impairing Glutamine Synthetase
Chronic H1-Antihistamine Treatment Increases Seizure Susceptibility After Withdrawal by Impairing Glutamine Synthetase
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DOI：
10.1111/j.1755-5949.2012.00356.x
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发表时间：
2012-01-01
影响因子：
5.5
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Hu, Wei-Wei;Fang, Qi;Chen, Zhong
目的观察慢性H1抗组胺药治疗对非癫痫大鼠停药后癫痫易感性的影响，并进一步研究其与谷氨酸代谢和γ氨基丁酸（GABA）合成的关键酶谷氨酰胺合成酶（GS）的关系。方法苯海拉明或吡拉明治疗2周后停药，采用杏仁核点燃或戊四氮点燃模型检测癫痫易感性，同时检测GS表达或活性。用高效液相色谱法测定谷氨酰胺、谷氨酸和GABA含量。结果在杏仁核点燃和戊四氮模型中，癫痫易感性显著增加，与H1抗组胺药治疗2周停药后10天相似。同时，皮质或海马GS活性和表达下降，谷氨酰胺和GABA含量明显下降。甲硫氨酸亚砜亚胺对GS活性的抑制作用也足以增加易感性，而补充谷氨酰胺逆转了类似于苯海拉明停药后10天的高易感性。此外，癫痫发作的易感性增加10天后，类似于苯海拉明撤出野生型小鼠，但不是在组氨酸脱羧酶基因敲除小鼠，缺乏组胺。结论慢性H1抗组胺药治疗可使停药后的非癫痫啮齿类动物癫痫发作易感性持续增加，其机制可能与阻断组胺的作用而损害GS有关。
Aim To investigate the effect of chronic H1-antihistamine treatment on seizure susceptibility after drug withdrawal in nonepileptic rats and to further study its relation to glutamine synthetase (GS), which is the key enzyme for glutamate metabolism and gamma aminobutyric acid (GABA) synthesis. Methods After drug withdrawal from a 2-week treatment with diphenhydramine or pyrilamine, seizure susceptibility was determined by amygdaloid kindling or pentylenetetrazol model; meanwhile, the GS expression or activity was analyzed. The glutamine, glutamate, and GABA contents were measured by high-performance liquid chromatography. Results Seizure susceptibility significantly increased in amygdaloid kindling and pentylenetetrazol model 10 similar to days after drug withdrawal from a 2-week treatment with H1-antihistamines. Meanwhile, GS activity and expression in the cortex or hippocampus decreased simultaneously with a marked decline of glutamine and GABA content. Comparable inhibition of GS activity by methionine sulfoximine was also sufficient to increase the susceptibility, while supplementation with glutamine reversed the high susceptibility 10 similar to days after diphenhydramine withdrawal. Moreover, the seizure susceptibility increased 10 similar to days after diphenhydramine withdrawal in wild-type mice but not in histidine decarboxylase knockout mice, which lack histamine. Conclusions Chronic H1-antihistamine treatment produces long-lasting increase in seizure susceptibility in nonepileptic rodents after drug withdrawal and its mechanism involves impairment of GS through blocking the action of histamine.