Chronic h1-antihistamine treatment increases seizure susceptibility after withdrawal by impairing glutamine synthetase.

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.
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.
Seizure susceptibility significantly increased in amygdaloid kindling and pentylenetetrazol model 10 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 days after diphenhydramine withdrawal. Moreover, the seizure susceptibility increased 10 days after diphenhydramine withdrawal in wild-type mice but not in histidine decarboxylase knockout mice, which lack histamine.
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.
AuthorsWei-Wei Hu, Qi Fang, Zheng-Hao Xu, Hai-Jing Yan, Ping He, Kai Zhong, Yan-Ying Fan, Ying Yang, Xiang-Nan Zhang, Chun-Yang Zhang, Hiroshi Ohtsu, Tian-Le Xu, Zhong Chen
JournalCNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 18 Issue 8 Pg. 683-90 (Aug 2012) ISSN: 1755-5949 [Electronic] England
PMID22742831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2012 Blackwell Publishing Ltd.
Chemical References
  • Convulsants
  • Histamine H1 Antagonists
  • Glutamine
  • Methionine Sulfoximine
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Histidine Decarboxylase
  • Glutamate-Ammonia Ligase
  • Pentylenetetrazole
  • Animals
  • Astrocytes (enzymology, physiology)
  • Blotting, Western
  • Chromatography, High Pressure Liquid
  • Convulsants
  • Electroshock
  • Glutamate-Ammonia Ligase (metabolism)
  • Glutamic Acid (metabolism)
  • Glutamine (metabolism)
  • Histamine H1 Antagonists (adverse effects)
  • Histidine Decarboxylase (deficiency, genetics)
  • Immunohistochemistry
  • Kindling, Neurologic
  • Male
  • Methionine Sulfoximine (pharmacology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pentylenetetrazole
  • Rats
  • Rats, Sprague-Dawley
  • Seizures (chemically induced, epidemiology, etiology)
  • Substance Withdrawal Syndrome (enzymology, epidemiology)
  • gamma-Aminobutyric Acid (metabolism)

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