Luiz Ricardo Goulart1, Thiago Neves Vieira1, André L Lopes Saraiva1, Rafaela Mano Guimarães2, João Paulo Mesquita Luiz2, Larissa Garcia Pinto3, Veridiana de Melo Rodrigues Ávila1, Jair Pereira Cunha-Junior4, Peter Anthony McNaughton3, Thiago Mattar Cunha2, Juliano Ferreira5, Cassia Regina Silva6,7. 1. Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38408-100, Brazil. 2. Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil. 3. Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, SE1 1UL, UK. 4. Department of Immunology, Institute of Sciences Biomedical Sciences, Federal University of Uberlândia, Uberlândia, MG, 38405-318, Brazil. 5. Graduated Program in Pharmacology, Pharmacology Department, Federal University of Santa Catarina (UFSC), Florianopolis, SC, 88049-900, Brazil. 6. Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38408-100, Brazil. cassia.regina@ufu.br. 7. LABITOX, Post-Graduated Program in Genetics and Biochemistry, Biotechnology Institute, Federal University of Uberlândia, Av. Pará 1720-Campus Umuarama, Jardim Umuarama-Bloco 2E-Officeroom 224, Uberlândia, MG, 38408-100, Brazil. cassia.regina@ufu.br.
Abstract
BACKGROUND: There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (AT2R) antagonism in an acute gout attack mouse model. METHODS: Male wild-type (WT) C57BL/6 mice either with the AT2R antagonist, PD123319 (10 pmol/joint), or with vehicle injections, or AT2R KO mice, received intra-articular (IA) injection of monosodium urate (MSU) crystals (100 µg/joint), that induce the acute gout attack, and were tested for mechanical allodynia, thermal hyperalgesia, spontaneous nociception and ankle edema development at several times after the injections. To test an involvement of AT2R in joint pain, mice received an IA administration of angiotensin II (0.05-5 nmol/joint) with or without PD123319, and were also evaluated for pain and edema development. Ankle joint tissue samples from mice undergoing the above treatments were assessed for myeloperoxidase activity, IL-1β release, mRNA expression analyses and nitrite/nitrate levels, 4 h after injections. RESULTS: AT2R antagonism has robust antinociceptive effects on mechanical allodynia (44% reduction) and spontaneous nociception (56%), as well as anti-inflammatory effects preventing edema formation (45%), reducing myeloperoxidase activity (54%) and IL-1β levels (32%). Additionally, Agtr2tm1a mutant mice have largely reduced painful signs of gout. Angiotensin II administration causes pain and inflammation, which was prevented by AT2R antagonism, as observed in mechanical allodynia 4 h (100%), spontaneous nociception (46%), cold nociceptive response (54%), edema formation (83%), myeloperoxidase activity (48%), and IL-1β levels (89%). PD123319 treatment also reduces NO concentrations (74%) and AT2R mRNA levels in comparison with MSU untreated mice. CONCLUSION: Our findings show that AT2R activation contributes to acute pain in experimental mouse models of gout. Therefore, the antagonism of AT2R may be a potential therapeutic option to manage gout arthritis.
BACKGROUND: There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (AT2R) antagonism in an acute gout attack mouse model. METHODS: Male wild-type (WT) C57BL/6 mice either with the AT2R antagonist, PD123319 (10 pmol/joint), or with vehicle injections, or AT2R KO mice, received intra-articular (IA) injection of monosodium urate (MSU) crystals (100 µg/joint), that induce the acute gout attack, and were tested for mechanical allodynia, thermal hyperalgesia, spontaneous nociception and ankle edema development at several times after the injections. To test an involvement of AT2R in joint pain, mice received an IA administration of angiotensin II (0.05-5 nmol/joint) with or without PD123319, and were also evaluated for pain and edema development. Ankle joint tissue samples from mice undergoing the above treatments were assessed for myeloperoxidase activity, IL-1β release, mRNA expression analyses and nitrite/nitrate levels, 4 h after injections. RESULTS: AT2R antagonism has robust antinociceptive effects on mechanical allodynia (44% reduction) and spontaneous nociception (56%), as well as anti-inflammatory effects preventing edema formation (45%), reducing myeloperoxidase activity (54%) and IL-1β levels (32%). Additionally, Agtr2tm1a mutant mice have largely reduced painful signs of gout. Angiotensin II administration causes pain and inflammation, which was prevented by AT2R antagonism, as observed in mechanical allodynia 4 h (100%), spontaneous nociception (46%), cold nociceptive response (54%), edema formation (83%), myeloperoxidase activity (48%), and IL-1β levels (89%). PD123319 treatment also reduces NO concentrations (74%) and AT2R mRNA levels in comparison with MSU untreated mice. CONCLUSION: Our findings show that AT2R activation contributes to acute pain in experimental mouse models of gout. Therefore, the antagonism of AT2R may be a potential therapeutic option to manage gout arthritis.
Authors: Jose C Alves-Filho; Fabiane Sônego; Fabricio O Souto; Andressa Freitas; Waldiceu A Verri; Maria Auxiliadora-Martins; Anibal Basile-Filho; Andrew N McKenzie; Damo Xu; Fernando Q Cunha; Foo Y Liew Journal: Nat Med Date: 2010-05-16 Impact factor: 53.440
Authors: Nicola Dalbeth; Amanda Phipps-Green; Christopher Frampton; Tuhina Neogi; William J Taylor; Tony R Merriman Journal: Ann Rheum Dis Date: 2018-02-20 Impact factor: 19.103
Authors: T M Cunha; W A Verri; G G Vivancos; I F Moreira; S Reis; C A Parada; F Q Cunha; S H Ferreira Journal: Braz J Med Biol Res Date: 2004-03-03 Impact factor: 2.590