RESUMO
OBJECTIVE: The objective of this study was to investigate whether histamine H4 receptor (H4 R) antagonists could prevent experimental periodontitis (EP)-induced histological, functional and inflammatory alterations in submandibular gland (SMG), periodontal bone and gingiva. METHODS: Bilateral EP was induced for 2 weeks in anaesthetized male rats. The effect of systemic and local administration of H4 R antagonists (JNJ7777120, JNJ10191584) on histopathology and functionality of SMG, bone loss and gingival inflammation was evaluated. RESULTS: The subcutaneous administration of JNJ7777120 prevented periodontitis-induced SMG histological injury, reducing vacuolization and apoptosis and additionally reversed the increased prostaglandin E2 (PGE2) levels in SMG while it partially reversed the methacholine-induced salivation reduction produced by periodontitis. JNJ7777120 attenuated bone loss and the increased PGE2 levels and inflammatory infiltration in gingival tissue of rats with periodontitis. Finally, local administration of JNJ7777120 and JNJ10191584 was also beneficial for improving periodontal parameters. CONCLUSIONS: H4 receptor antagonists are able to ameliorate periodontitis-induced injury on SMG, gingival tissue and bone structure, suggesting that pharmacological targeting of H4 R could be an attractive strategy to improve periodontal health.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Indóis/farmacologia , Doenças Periodontais/prevenção & controle , Piperazinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/patologia , Processo Alveolar/efeitos dos fármacos , Processo Alveolar/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Gengiva/química , Gengiva/efeitos dos fármacos , Gengiva/patologia , Masculino , Cloreto de Metacolina/farmacologia , Terapia de Alvo Molecular , Doenças Periodontais/patologia , Periodontite/tratamento farmacológico , Periodontite/patologia , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos , Receptores Histamínicos H4 , Glândula Submandibular/efeitos dos fármacos , Glândula Submandibular/patologiaRESUMO
OBJECTIVES: Searching for more effective and selective therapies for head and neck cancer, we demonstrated the therapeutic effect of boron neutron capture therapy (BNCT) to treat oral cancer and inhibit long-term tumor development from field-cancerized tissue in the hamster cheek pouch model. However, BNCT-induced mucositis in field-cancerized tissue was dose limiting. In a clinical scenario, oral mucositis affects patients' treatment and quality of life. Our aim was to evaluate different radioprotectors, seeking to reduce the incidence of BNCT-induced severe mucositis in field-cancerized tissue. MATERIALS AND METHODS: Cancerized pouches treated with BNCT mediated by boronophenylalanine at 5 Gy were treated as follows: control: saline solution; Hishigh : histamine 5 mg kg(-1) ; Hislow : histamine 1 mg kg(-1) ; and JNJ7777120: 10 mg kg(-1). RESULTS: Hislow reduced the incidence of severe mucositis in field-cancerized tissue to 17% vs CONTROL: 55%; Hishigh : 67%; JNJ7777120: 57%. Hislow was non-toxic and did not compromise the long-term therapeutic effect of BNCT or alter gross boron concentration. CONCLUSION: Histamine reduces BNCT-induced mucositis in experimental oral precancer without jeopardizing therapeutic efficacy. The fact that both histamine and boronophenylalanine are approved for use in humans bridges the gap between experimental work and potential clinical application to reduce BNCT-induced radiotoxicity in patients with head and neck cancer.
Assuntos
Terapia por Captura de Nêutron de Boro/efeitos adversos , Histamina/uso terapêutico , Neoplasias Bucais/radioterapia , Lesões Pré-Cancerosas/radioterapia , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Estomatite/prevenção & controle , Animais , Cricetinae , Modelos Animais de Doenças , Indóis/uso terapêutico , Piperazinas/uso terapêutico , Lesões Experimentais por Radiação/etiologia , Estomatite/etiologiaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Doxorrubicina/efeitos adversos , Histamina/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citoproteção , Doxorrubicina/administração & dosagem , Coração/efeitos dos fármacos , Histamina/administração & dosagem , Humanos , Camundongos , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
The aim of this study was to improve knowledge about histamine radioprotective potential investigating its effect on reducing ionising radiation-induced injury and genotoxic damage on the rat small intestine and uterus. Forty 10-week-old male and 40 female Sprague-Dawley rats were divided into 4 groups. Histamine and histamine-5Gy groups received a daily subcutaneous histamine injection (0.1 mg/kg) starting 24 h before irradiation. Histamine-5Gy and untreated-5Gy groups were irradiated with a dose of whole-body Cesium-137 irradiation. Three days after irradiation animals were sacrificed and tissues were removed, fixed, and stained with haematoxylin and eosin, and histological characteristics were evaluated. Proliferation, apoptosis and oxidative DNA markers were studied by immunohistochemistry, while micronucleus assay was performed to evaluate chromosomal damage. Histamine treatment reduced radiation-induced mucosal atrophy, oedema and vascular damage produced by ionising radiation, increasing the number of crypts per circumference (239 ± 12 vs 160 ± 10; P<0.01). This effect was associated with a reduction of radiation-induced intestinal crypts apoptosis. Additionally, histamine decreased the frequency of micronuclei formation and also significantly attenuated 8-OHdG immunoreactivity, a marker of DNA oxidative damage. Furthermore, radiation induced flattening of the endometrial surface, depletion of deep glands and reduced mitosis, effects that were completely blocked by histamine treatment. The expression of a proliferation marker in uterine luminal and glandular cells was markedly stimulated in histamine treated and irradiated rats. The obtained evidences indicate that histamine is a potential candidate as a safe radioprotective agent that might increase the therapeutic index of radiotherapy for intra-abdominal and pelvic cancers. However, its efficacy needs to be carefully investigated in prospective clinical trials.