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Previous issue date: 2012-12-18 === The objective of this study was to evaluate the influence of two models of metabolic disorders, cardiomyopathy and type 2 diabetes, on periapical lesions in rats, and to evaluate the possible benefits of treatment with the antioxidant compound tempol in these experimental models. Initially, to assess the effects of tempol in periapical lesions of rats with doxorubicin-induced cardiomyopathy, 40 Male Wistar rats were divided into four groups: (i) na?ve rats orally treated with saline solution (10 ml/kg) during 21 days after periapical lesion induction); (ii) na?ve rats treated with tempol (30 and 50 mg/kg, during 21 days after periapical lesion induction), by oral pathway; (iii) rats with doxorubicin-induced cardiomyopathy treated with saline solution by oral route (10 ml/kg, from day 3 to day 21 after initiating treatment with doxorubicin); and (iv) rats with doxorubicin-induced cardiomyopathy orally treated with tempol (30 and 50 mg/kg, , from day 3 to day 21 after initiating treatment with doxorubicin).Body weight was recorded throughout the experimental period. Periapical lesions were induced on the first right mandibular molar tooth. Following 21 days of apical periodontitis induction, the animals were euthanized, and the mandibles were collected for radiographic and histological analysis. Samples of livers and hearts were removed for determination of free radicals. The oral administration of tempol (50 mg/kg) was able to significantly prevent the establishment of periapical lesions in either control animals or in rats submitted to the model of doxorubicin-induced cardiomyopathy, according to radiographic and histological evaluation. Nevertheless, the protective effects of tempol were virtually greater in control animals, in comparison to doxorubicin-treated rats, as indicated by histological inflammatory assessment. This might be related to the increased production of free radicals under cardiomyopathy. Treatment with tempol was able to reverse significant weight loss induced by doxorubicin, although the reduction of catalase activity was not significantly altered in the liver or heart.Subsequently, we investigated the development of periapical lesions in rats with type 2 diabetes. In this part of the study, 20 Male Wistar rats were used; they received tap water (N= 5) or a 20%-glucose solution (N = 15) during nine weeks. At the sixth week, periapical lesions were induced on the first mandibular molars, and the animals were subdivided into four groups. The subgroup (i) was composed by non-diabetic rats orally receiving saline solution (10 ml/kg). Glucose-fed insulin resistant rats were divided into the following subgroups: (ii) saline-treated animals (10 ml/kg, by oral route); animals orally treated with tempol (iii) 50 mg/kg; or (iv) 100 mg/kg. The body weight was monitored thoroughly. Following 21 days of apical periodontitis induction, the animals were euthanized, and the mandibles were collected for radiographic and histological analysis. The livers were removed to determine free radicals and the blood plasma was used to measure insulin levels. Type-2 diabetic rats displayed a significant decrease of body weight gain and a slight increase of insulin levels, allied to reduced levels of the antioxidant components catalase and GSH; these alterations were virtually reversed by tempol (100 mg/kg).The extent and cellularity of periapical lesions in glucose-fed type 2 diabetic rats was similar to that seen in control rats. However, administration of tempol, even at a dose of 100 mg/kg, was no able to change the periapical lesions in diabetic rats, suggesting that systemic therapy with tempol was ineffective in rats submitted to a high-glucose diet. In conclusion, treatment with tempol showed beneficial systemic effects on apical periodontitis in both control animals and in rats with doxorubicin-elicited cardiomyopathy, at the dose of 50 mg/kg. However, despite affecting other parameters related to diabetes, tempol (for up to 100 mg/kg) failed to improve the outcome of endodontic lesions in type-2 diabetic animals. This data might be useful to support the treatment planning for patients with metabolic disorders looking for endodontic treatment. Other therapeutic strategies should be 16 evaluated in the same experimental models, including the use of intracanal dressings containing tempol, as well as the association with hypoglycemic agents, such as metformin === O objetivo deste estudo foi avaliar a influ?ncia de dois modelos de desordens metab?licas, cardiomiopatia e diabetes do tipo 2, no desenvolvimento de les?es periapicais em ratos, bem como, analisar o poss?vel benef?cio do tratamento com o composto antioxidante, tempol, nestes modelos. Inicialmente, para avaliar o efeito do tempol em les?es periapicais de ratos com cardiomiopatia induzida por doxorrubicina, foram utilizados 40 ratos divididos em quatro grupos: (1) ratos tratados com solu??o salina (10 ml/kg, durante 21 dias ap?s a indu??o da les?o periapical) por via oral; (2) ratos tratados com tempol (30 e 50 mg/kg, durante 21 dias ap?s a indu??o da les?o periapical) por via oral; (3) ratos com cardiomiopatia induzida por doxorrubicina, tratados com solu??o salina por via oral (10 ml/kg), e, (4) ratos com cardiomiopatia induzida por doxorrubicina, tratados com tempol (30 e 50 mg/kg, a partir do terceiro dia de tratamento com doxorrubicina, at? 21dias ap?s a indu??o da les?o periapical). O peso corporal foi registrado durante todo o per?odo experimental. As les?es periapicais foram induzidas no primeiro molar inferior direito.Ap?s 21 dias de indu??o de periodontite apical, os animais foram eutanasiados e as mand?bulas foram removidas para realiza??o das radiografias e an?lise histol?gica. Amostras do f?gado e do cora??o foram retiradas para determina??o dos radicais livres. A administra??o oral de tempol (50 mg/kg) foi eficaz em prevenir significativamente o estabelecimento de les?es periapicais em animais controle e, em ratos submetidos ao modelo de cardiomiopatia induzida por doxorrubicina, de acordo com os resultados observados no exame radiogr?fico e, corroborados pela analise histol?gica. No entanto, foi poss?vel observar que os efeitos protetores do tempol, foram virtualmente maiores nos animais controle, quando comparados com ratos tratados com doxorrubicina, como indicado pelas an?lises histol?gica e radiogr?fica. Este fato pode estar relacionado com a produ??o aumentada de radicais livres nos animais com cardiomiopatia.O tratamento com tempol foi capaz de reverter significativamente a perda de peso corporal 10 induzida pela doxorrubicina, embora a redu??o da atividade da catalase n?o tenha sido significativamente alterada no f?gado ou no cora??o. Posteriormente, foi investigado o desenvolvimento de les?es periapicais em ratos com diabetes do tipo 2. Nesta etapa, os animais receberam ?gua (N=5) ou uma solu??o de glicose a 20% (N=15) durante nove semanas. Ap?s a sexta semana, as les?es periapicais foram induzidas nos primeiros molares mandibulares e, os animais foram subdivididos em 4 grupos. O grupo (1) foi composto por ratos n?o diab?ticos, que receberam solu??o salina por via oral (10 ml/kg). Os ratos tratados com glicose foram divididos nos seguintes subgrupos: (2) animais tratados com solu??o salina (10 ml/kg por via oral); animais tratados por via oral com tempol (3) 50 mg/kg; ou (4) 100 mg/kg. O ganho de peso corporal foi monitorado durante toda a fase experimental. Ap?s 21 dias de indu??o de periodontite apical, os animais foram submetidos ? eutan?sia e, as mand?bulas foram removidas para a an?lise radiogr?fica e histol?gica. Amostras de f?gado foram retiradas para determina??o dos radicais livres e, o plasma sangu?neo foi utilizado para a determina??o dos n?veis de insulina.Os animais diab?ticos mostraram uma diminui??o significativa do ganho de peso e, um ligeiro aumento dos n?veis de insulina, com uma redu??o dos n?veis das enzimas antioxidantes, catalase e glutationa-S-transferase (GSH). Essas altera??es foram revertidas com a administra??o do tempol, na dose de 100 mg/kg. A extens?o e a celularidade das les?es periapicais dos ratos com diabetes tipo 2 foi semelhante ao observado nos ratos controle. Entretanto, a administra??o de tempol, mesmo na dose de 100 mg/kg, n?o foi capaz de alterar as les?es periapicais em ratos diab?ticos, sugerindo que a terapia sist?mica com tempol foi ineficaz em ratos submetidos ao consumo de altas concentra??es de glicose.Em conclus?o, o tratamento com antioxidante tempol apresentou efeitos sist?micos ben?ficos sobre a periodontite apical de animais com cardiomiopatia induzida por doxorrubicina e em ratos controle. Entretanto, apesar de afetar outros par?metros relacionados 11 com o diabetes, o tempol n?o foi eficiente em melhorar os resultados de les?es endod?nticas em animais com diabetes tipo 2. Estes dados podem ser ?teis para auxiliar no plano de tratamento de pacientes com desordens metab?licas que procuram por tratamento endod?ntico. Outras estrat?gias terap?uticas devem ser avaliadas nos mesmos modelos experimentais, incluindo a utiliza??o de curativos de demora contendo tempol, bem como, a associa??o com f?rmacos hipoglicemiantes, como a metformina
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