Effect of salicylates on the toxicity of GABA-lytics in mice

Golovko, A. I.; Sofronov, G. A.; Klyuntina, T. V.

doi:10.1007/bf02443698

Cited by 4 publications

(4 citation statements)

References 7 publications

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“…Previous studies have indicated that during the development of allergen-induced airway responses, activation of PI3K/Akt leads to an increase in IL-13 that in turn, activates the airway epithelial cell (AEC) GABAergic system which acts in autocrine and paracrine fashions to enhance mucus hypersecretion of AECs resulting to airway obstruction (Corry & Kheradmand, 2007;Lu & Inman, 2009). In another study, it has been found that aspirin is involved in the detoxification of GABA-lytic picrotoxin (PT), an antagonist for the GABA A receptor chloride channels (Golovko et al, 1995). The inhibition of picrotoxin by aspirin restores GABA activity.…”

Section: Introductionmentioning

confidence: 99%

Association of SLC6A12 variants with aspirin‐intolerant asthma in a Korean population

Pasaje

Kim

Park

et al. 2010

Annals of Human Genetics

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SummaryAspirin-intolerant asthma (AIA) occurs from asthma exacerbation after exposure to aspirin. However, the underlying mechanisms of AIA occurrence are still unclear. The critical role of the solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in GABAergic transmission, which is associated with mucus production in asthma, makes it a candidate gene for AIA association study. Eight single nucleotide polymorphisms (SNPs) in SLC6A12 were genotyped in 163 aspirin-intolerant asthma (AIA) and 429 aspirin-tolerant asthma (ATA) patients of Korean ethnicity. Associations between polymorphisms of SLC6A12 and AIA were analysed using multivariate logistic analysis. Results showed that two polymorphisms and a haplotype in SLC6A12, rs499368 (P = 0.005; P corr = 0.03), rs557881 (nonsynonymous C10R, P = 0.007; P corr = 0.04), and SLC6A12_BL1_ht1 (P = 0.009; P corr = 0.05) respectively, were significantly associated with AIA after multiple testing corrections. In addition, SNPs of SLC6A12 were significantly associated with the fall rate of FEV 1 by aspirin provocation suggesting that SLC6A12 could affect reversibility of lung function abnormalities in AIA patients. Although these results are preliminary and future replications are needed to confirm these findings, this study showed evidence of association between variants in SLC6A12 and AIA occurrence among asthmatics in a Korean population.

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Section: Introductionmentioning

confidence: 99%

Association of SLC6A12 variants with aspirin‐intolerant asthma in a Korean population

Pasaje

Kim

Park

et al. 2010

Annals of Human Genetics

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“…However, a good number of the patients with AERD were recruited from the outpatient clinics of the experienced pulmonologists in Japan. Interestingly, aspirin has been shown to be involved in the detoxification of GABAlytic picrotoxin, an antagonist for GABA type A receptor [28]. The inhibition of picrptoxin by aspirin restores GABA activity, suggesting such interactions with aspirin might be present in pathobiology of AERD.…”

Section: Discussionmentioning

confidence: 99%

Solute Carrier Family 6 Member 12 Gene Polymorphisms in Japanese Patients with Aspirin-Exacerbated Respiratory Disease

Kurosawa¹,

Yukawa²

2015

J Allergy Ther

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Background: Betaine/gamma-aminobutyric acid (GABA) signaling pathway in the airway epithelium has been revealed to play a critical role in bronchial asthma. To elucidate any genetic influence of the GABAergic in aspirinexacerbated respiratory disease (AERD), we investigated the association of solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in Japanese patients with AERD.Methods: DNA specimens were obtained from 103 AERD patients, 300 patients with aspirin-tolerant asthma (ATA) and 100 normal controls. Allelic discrimination assay for two single nucleotides polymorphisms in SLC6A12 gene (rs499368 and rs557881) was carried out. Results:The minor allele frequencies in SLC6A12 intron 2 A>T genotype (rs49936) were higher in AERD patients than in normal controls, and that in SLC6A12 exon 4 T>C genotype (rs557881) were higher in AERD patients than in ATA patients and normal controls. The frequencies of the combined TC/CC genotype group of SLC6A12 exon 4 T>C were higher than those of the TT genotype in AERD patients compared with those in ATA patients (P=0.021; odds ratio, 1.724; 95% confidence interval, 1.087-2.732). In male patients with AERD, frequencies of the TC/CC genotype group were higher than those of the TT genotype compared with male patients with ATA (P = 0.010; odds ratio, 3.177; 95% confidence interval, 1.311-7.699). Forced expiratory volume in one second (percentage predicted) in AERD patients with the TC/CC genotype group of the SLC6A12 exon 4 T>C gene was lower than that in the patients with the TT genotype (P=0.039). Conclusion:This is the first Japanese study to investigate the SLC6A12 intron 2 A>T and SLC6A12 exon 4 T>C genotype polymorphisms in patients with AERD. Our findings suggest that the association between SLC6A12 intron 2 A>T and exon 4 T>C gene sequence variations might be implicated in the development of AERD in a Japanese population.

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“…So, modification of cysteine and replacing the guanidine group with a urea linkage in the side chain of arginine could be a risk factor for aspirin hypersensitivity in asthmatics. Interestingly, it has been reported that the extraneuronal GABAergic system might to be implicated in the mechanisms of AERD [108], and aspirin has been shown to be involved in the detoxification of GABAlytic picrotoxin, an antagonist for GABA type A receptor [112]. The inhibition of picrotoxin by aspirin restores GABA activity, suggesting such interactions with aspirin might be present in AERD patients.…”

Section: Solute Carrier Family 6 Member 12 (Slc6a12) Genesmentioning

confidence: 99%

Hypothetical Mechanism of Aspirin-Exacerbated Respiratory Disease Based on Recent Investigations of Gene Polymorphisms in Japanese Patients

Kurosawa¹,

Sutoh²,

Yukawa³

et al. 2015

J Allergy Ther

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Aspirin-exacerbated respiratory disease (AERD) is characterized by severe asthmatic attack after taking aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs). The typical patient with AERD is an adult who develops refractory chronic rhinitis in the third or fourth decade of life. Natural history and clinical features of AERD indicates that during the evaluation of chronic rhinitis persistent bronchial asthma develops, and finally after exposure to NSAID acute respiratory reactions begin to occur. The inhibitory action of aspirin and/or NSAIDs on cyclooxygenase activity may cause diversion to the 5-lipoxygenase pathway, which leads to the overproduction of cysteinyl leukotrienes (LTs). Thus, a general consensus exists that increased levels of cysteinyl LTs are key inflammatory mediators in AERD. As aspirin intolerance is found in a specific population, genetic predisposition has been considered as a crucial determinant. Investigations on candidate genes have been concentrated especially on cysteinyl LTs-related genes, however conflicting results have been reported. So, future areas of investigations need to focus on comprehensive approaches towards other genetic biomarkers. We've recently reported possible presence of other gene polymorphisms in Japanese patients with AERD. The natural history and clinical characteristics of AERD indicate that the respiratory mucosal inflammatory process in AERD begins and continues in the absence of ongoing or even intermittent exposure to NSAIDs. So, in this review, we propose a hypothetical progress of AERD over time based on mainly the results of our investigations, and present a schematically sketching the course of NSAIDs-triggered hypersensitivity with genes, such as asthma-associated genes, that may initiate susceptibility to AERD, and that may accelerate pathogenesis and induce onset of AERD. The findings of our studies were based on small-sized samples from a Japanese population, and future validation studies in independent populations are required to provide reassurance about our hypothesis.

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Effect of salicylates on the toxicity of GABA-lytics in mice

Cited by 4 publications

References 7 publications

Association of SLC6A12 variants with aspirin‐intolerant asthma in a Korean population

Association of SLC6A12 variants with aspirin‐intolerant asthma in a Korean population

Solute Carrier Family 6 Member 12 Gene Polymorphisms in Japanese Patients with Aspirin-Exacerbated Respiratory Disease

Hypothetical Mechanism of Aspirin-Exacerbated Respiratory Disease Based on Recent Investigations of Gene Polymorphisms in Japanese Patients

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