Dataset Information

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

ABSTRACT:

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 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.

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.

SUBMITTER: Hu WW

PROVIDER: S-EPMC6493495 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Hu Wei-Wei WW Fang Qi Q Xu Zheng-Hao ZH Yan Hai-Jing HJ He Ping P Zhong Kai K Fan Yan-Ying YY Yang Ying Y Zhang Xiang-Nan XN Zhang Chun-Yang CY Ohtsu Hiroshi H Xu Tian-Le TL Chen Zhong Z

CNS neuroscience & therapeutics 20120628 8

<h4>Aim</h4>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.<h4>Methods</h4>After drug withdrawal from a 2-week treatment with diphenhydramine or pyrilamine, seizure susceptibility was determined by amygdaloid kindling or pentylenetetrazol model; meanwhile, ...[more]

PMID: 22742831

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Project description:OBJECTIVE:Allergic rhinitis symptoms can be reduced by behaviorally conditioning antihistamine. It is unclear whether these findings extend to histamine-induced itch or work when participants are informed about the conditioning procedure (open-label conditioning). The current study aims to investigate the efficacy of (open-label) antipruritic behavioral conditioning for histamine-induced itch. METHODS:Healthy participants (n = 92; 84% female) were randomized to I) an open-label conditioned, II) closed-label conditioned, III) conditioned-not-evoked control, or IV) nonconditioned control group. A two-phase conditioning paradigm was used. During acquisition, a conditioned stimulus (CS; distinctively tasting beverage) was repeatedly paired with the H1-antihistamine levocetirizine (groups I-III). During evocation, the CS was paired with placebo (I, II), or instead of the CS, water was paired with placebo (III). The nonconditioned control group (IV) received CS with placebo in both phases. Itch after histamine iontophoresis and physiological data (i.e., spirometry, heart rate, skin conductance) were assessed. Combined conditioned and combined control groups were first compared, and analyses were repeated for separate groups. RESULTS:Marginally lower itch was reported in the combined conditioned compared with the control groups (F(1,88) = 2.10, p = .076, ?partial = 0.02); no differences between separate groups were found. No effects on physiological data were found, except for heart rate, which reduced significantly and consistently for control groups, and less consistently for conditioned groups (group by time interaction: F(7,80) = 2.35, p = .031, ?partial = 0.17). CONCLUSION:Limited support was found for the efficacy of antipruritic behavioral conditioning, regardless of whether participants were informed about the conditioning procedure. The application of open-label conditioning in patient populations should be further researched. TRIAL REGISTRATION:www.trialregister.nl; ID NTR5544.

Project description:Ciprofloxacin is the choice treatment for infections caused by Salmonella Typhi, however, reduced susceptibility to ciprofloxacin has been reported for this pathogen. Considering the decreased approbation of new antimicrobials and the crisis of resistance, one strategy to combat this problem is to find new targets that enhances the antimicrobial activity for approved antimicrobials. In search of mutants with increased susceptibility to ciprofloxacin; 3,216 EZ-Tn5 transposon mutants of S. Typhi were screened. S. Typhi zxx::EZ-Tn5 mutants susceptible to ciprofloxacin were confirmed by agar diffusion and MIC assays. The genes carrying EZ-Tn5 transposon insertions were sequenced. Null mutants of interrupted genes, as well as inducible genetic constructs, were produced using site-directed mutagenesis, to corroborate phenotypes. SDS-PAGE and Real-time PCR were used to evaluate the expression of proteins and genes, respectively. Five mutants with increased ciprofloxacin susceptibility were found in the screening. The first confirmed mutant was the glutamine synthetase-coding gene glnA. Analysis of outer membrane proteins revealed increased OmpF, a channel for the influx of ciprofloxacin and nalidixic acid, in the glnA mutant. Expression of ompF increased four times in the glnA null mutant compared to WT strain. To understand the relationship between the expression of glnA and ompF, a strain with the glnA gene under control of the tetracycline-inducible Ptet promoter was created, to modulate glnA expression. Induction of glnA decreased expression of ompF, at the same time that reduced susceptibility to ciprofloxacin. Expression of sRNA MicF, a negative regulator of OmpF was reduced to one-fourth in the glnA mutant, compared to WT strain. In addition, expression of glnL and glnG genes (encoding the two-component system NtrC/B that may positively regulate OmpF) were increased in the glnA mutant. Further studies indicate that deletion of glnG decreases susceptibility to CIP, while deletion of micF gene increases susceptibility CIP. Our findings indicate that glnA inactivation promotes ompF expression, that translates into increased OmpF protein, facilitating the entry of ciprofloxacin, thus increasing susceptibility to ciprofloxacin through 2 possible mechanisms.

Dataset Information

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

Aim

Methods

Results

Conclusions

Publications

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

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