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A vitamin E long-chain metabolite and the inspired drug candidate α-amplexichromanol relieve asthma features in an experimental model of allergen sensitization

Authors :
Ida Cerqua
Konstantin Neukirch
Michela Terlizzi
Elisabetta Granato
Elisabetta Caiazzo
Carla Cicala
Armando Ialenti
Raffaele Capasso
Oliver Werz
Rosalinda Sorrentino
Denis Seraphin
Jean-Jacques Helesbeux
Giuseppe Cirino
Andreas Koeberle
Fiorentina Roviezzo
Antonietta Rossi
Source :
Pharmacological Research, Vol 181, Iss , Pp 106250- (2022)
Publication Year :
2022
Publisher :
Elsevier, 2022.

Abstract

Benefits for vitamin E intake in diseases with inflammatory components have been described and related in part, to endogenously formed metabolites (long-chain metabolites, LCM). Here, we have evaluated the role of LCM in relieving asthma features. To this aim, the endogenous vitamin E metabolite α-13′-carboxychromanol (α-T-13′-COOH) that acts as potent 5-lipoxygenase inhibitor has been administered either intraperitoneally or by oral gavage to BALB/c mice sensitized by subcutaneous injection of ovalbumin (OVA). We also have taken advantage of the metabolically stable α-T-13′-COOH derivative α-amplexichromanol (α-AC). Intraperitoneal treatment with α-T-13'-COOH reduced OVA-induced airway hyperreactivity (AHR) as well as peri-bronchial inflammatory cell infiltration. α-AC was more efficacious than α-T-13'-COOH, as demonstrated by better control of AHR and in reducing subepithelial. Both compounds exerted their protective function by reducing pulmonary leukotriene C4 levels. Beneficial effects of α-AC were coupled to inhibition of the sensitization process, as indicated by a reduction of IgE plasma levels, lung mast cell infiltration and Th2 immune response. Metabololipidomics analysis revealed that α-AC raises the pulmonary levels of prostanoids, their degradation products, and 12/15-lipoxygenase metabolites. Following oral administration, the pharmacodynamically different profile in α-T-13′-COOH and α-AC was abrogated as demonstrated by a similar and improved efficacy in controlling asthma features as well as by metabololipidomics analysis. In conclusion, this study highlights a role for LCM and of vitamin E derivatives as pharmacologically active compounds that ameliorate asthmatic features and defines an important role for endogenous vitamin E metabolites in regulating immune response underlying the sensitization process.

Details

Language :
English
ISSN :
10961186
Volume :
181
Issue :
106250-
Database :
Directory of Open Access Journals
Journal :
Pharmacological Research
Publication Type :
Academic Journal
Accession number :
edsdoj.91b43354b4b5a972cc24aaddca0c7
Document Type :
article
Full Text :
https://doi.org/10.1016/j.phrs.2022.106250