title: Protective effects of the flavonoid hesperidin methyl chalcone in inflammation and pain in mice: role of TRPV1, oxidative stress, cytokines and NF-κB.
abstract: Cytokines and reactive oxygen species are inflammatory mediators that lead to increased sensitivity to painful stimuli, and their inhibition represents a therapeutic approach in controlling acute and chronic pain. The water-soluble flavonone hesperidin methyl chalcone (HMC) is used in the treatment of venous diseases, but its bioactivity as anti-inflammatory and analgesic is poorly understood. The present study evaluated the protective effects of HMC in widely used mouse models of acute and prolonged inflammation and pain. Male Swiss mice were treated with HMC (3-100 or 30 mg/kg, intraperitoneally) or vehicle (saline) 1h before inflammatory stimuli. In overt pain-like behavior tests, HMC inhibited acetic acid- and phenyl-p-benzoquinone-induced writhing, and capsaicin-, Complete Freund's Adjuvant (CFA)- and formalin-induced paw flinching and licking. HMC also inhibited carrageenan-, capsaicin- and CFA-induced mechanical and thermal hyperalgesia. Mechanistically, HMC inhibited carrageenan-induced cytokine (TNF-α, IL-1β, IL-6, and IL-10) production, oxidative stress and NF-κB activation. Furthermore, HMC did not cause gastric or hepatic injury in a 7 days treatment protocol. Thus, this is the first report that HMC reduces inflammation and inflammatory pain by targeting TRPV1 (transient receptor potential vanilloid type 1) receptor activity, oxidative stress, cytokine production, and NF-κB activity, which suggests its potential applicability in inflammatory diseases.
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Pinho-Ribeiro
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Miriam S N
authors.initials: MS
authors.lastname: Hohmann
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Borghi
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Carla F S
authors.initials: CF
authors.lastname: Guazelli
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Marilia F
authors.initials: MF
authors.lastname: Manchope
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86038-350 Londrina, Paraná, Brazil.
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil. Electronic address: waldiceujr@yahoo.com.br.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006569:Hesperidin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D047188:Chalcones; D016207:Cytokines; D016328:NF-kappa B; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C033022:hesperidin methylchalcone; D006569:Hesperidin
keywords: Cytokine; Hesperidin methyl chalcone; Inflammation; Nuclear factor-κB; Oxidative stress; Pain