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Orientador: Valeria Helena Alves Cagnon Quitete / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-13T16:32:13Z (GMT). No. of bitstreams: 1 Pinto_LeslieCristina_M.pdf: 6161359 bytes, checksum: e53c13123d8d830910aa70a9f89b179c (MD5) Previous issue date: 2009 / Resumo: A distroglicana (DG) é uma importante proteína estrutural a qual está envolvida no desenvolvimento celular epitelial, formação de membrana basal e manutenção da integridade de diferentes tecidos. Estudos indicaram que a alteração na expressão da DG é um evento freqüente nas malignecências humanas e sugerem que esta molécula tem um papel importante no desenvolvimento de tumor. No câncer de próstata, verificou-se expressiva redução das distroglicanas, especialmente da _-DG, acarretando em progressão tumoral e ocorrência de metástases. Desta maneira, alterações na expressão das distroglicanas podem ser relevantes na patogênese das doenças prostáticas. Além disto, estas moléculas fazem parte de um complexo glicoproteíco e estão relacionadas a uma série de proteínas tais como, agrinas, lamininas e a distrofina. Devido à deficiência de distrofina, este complexo está desestruturado na distrofia muscular de Duchenne e, no camundongo mdx. Este trabalho teve como objetivos caracterizar a estrutura epitelial e estromal do lobo ventral da próstata do camundongo mdx, identificar a ocorrência de receptores para distroglicanas _ e _, IGF-1, laminina _-3, estabelecer correlações entre os processos de proliferação e morte celular e analisar a viabilidade do camundongo mdx como modelo experimental no estudo de patologias prostáticas. Um total de 30 animais (15 C57BL10 e 15 mdx) foi dividido em 2 grupos experimentais: controle e mdx. Amostras do lobo ventral da próstata foram coletadas para análises macroscópicas, imunohistoquímicas, microscopias de luz e eletrônica de transmissão e análises morfométricas. Dosagens sorológicas de estradiol e testosterona foram realizadas. Os resultados mostraram que os níveis séricos de testosterona foram significativamente diminuídos nos camundongos mdx em relação aos controles. Em contraste, os níveis séricos de estradiol do grupo mdx mostraram-se significativamente aumentados em relação ao controle. Acentuada atrofia celular, ocorrência de neoplasia intraepitelial prostática, hipertrofia estromal, presença de células inflamatórias e hipertrofia estromal foram evidenciadas nos animais mdx. A intensidade da reação de imunolocalização da distroglicana foi de fraca expressão em relação ao controle, assim como a da laminina. Já a imunolocalização do IGF foi intensa em relação ao controle. Conclui-se que os animais mdx apresentaram alterações significativas na integridade estrutural e molecular prostática, com sinais de aumento do processo proliferativo, comprometendo a homeostase glandular e o processo reprodutivo destes animais. / Abstract: The prostate is a fundamental accessory sex gland for the male reproductive process and the stroma-epithelium interaction has an important role in prostate structural maintenance and function. The basal membrane is an interaction link, offering mechanical and physiological support. Nowadays, different studies suggest that dystroglycan (DG), which is an adhesion protein, plays a role in different types of cancer development and progression, including that of the prostate. Thus, the aims of this work were to characterize structural, ultrastructural and proliferative features of the prostatic stroma and epithelium of mdx mice; to verify the immunolocalization of the _ and ß dystroglycan, IGF-I and laminin _3 receptors; and to relate those structural and molecular events to prostate pathogenesis as well as to verify the viability of this experimental model in prostate disease studies. Thirty male mice (mdx and C57BL10/Uni) were divided into two groups: control and mdx. Samples from the ventral prostate were collected for immunological, Western Blotting, transmission electron and light microscopies and morphometrical analyses. Estradiol and testosterone measurements were verified. The results showed diminished testosterone and increased estradiol levels in the mdx group. Atrophied cells, stromal hypertrophy and prostatic intraepithelial were verified in the mdx mice. Weak _ and ß dystroglycan and laminin _3 immunolocalization was verified in the mdx group. However, intense IGF-I receptor localization was identified in the mdx animals. Thus, it was concluded that mdx animals presented changes in the molecular and structural integrity and proliferation signals, leading to glandular pathogenesis, compromising prostate homeostasis and the reproductive process. Apart from this, the destructuring of the dystroglycandystrophin complex can be considered a trigger factor for prostate pathogenesis. It can also point towards that the steroid-hormone and IGF relationship can be an alternative towards new therapies to treat prostatic diseases. / Mestrado / Anatomia / Mestre em Biologia Celular e Estrutural

The main goal for my research was to challenge the long held belief that the mechanical properties of maturing dystrophic compared to control skeletal muscle membranes are weaker, leading to onset of Duchenne muscular dystrophy (DMD). We built on a previous report from our lab that suggested sarcolemmal membranes from dystrophic mice are not more susceptible to damage early in maturation (i.e., age 9-12 days) and determined if and when muscle mechanical properties change as the mice mature. Across four studies, I have helped define the role of dystrophin-deficient skeletal muscle membranes in the onset of DMD. A linear viscoelastic muscle model was used to determine passive stiffness and damping in control and dystrophic muscles from maturing mice aged 14-35 days. Results confirmed my hypothesis that there are no differences in passive mechanical properties between normal and dystrophic mice. Recognizing the limitations of the linear model, a nonlinear model was developed to determine the stiffness and damping of active and passive dystrophic muscles from maturing mice aged 21 and 35 days. The nonlinear model achieved a significantly better fit to experimental data than the linear model when muscles were stretched to 15% strain beyond resting length. Active and passive mechanical properties of dystrophic mice were not different than control at 14 and 28 days of age. The previously developed nonlinear model was used to determine a more complete time-course (14-100 days of age) of dystrophic muscle mechanical properties. There was no difference in passive stiffness between mdx and control muscles at each age. However, the mdx:utrn-/- muscles showed increased stiffness compared to control and mdx muscles at 21 and 28 days, suggesting a temporary change within the muscle that only occurs with a lack of both utrophin and dystrophin. Fast-twitch and slow-twitch muscle mechanical properties were compared in control and dystrophic mice aged 3, 5, and 9 weeks of age. Dystrophic and control slow-twitch muscles did not have different mechanical properties, suggesting that a lack of dystrophin does not affect slow-twitch muscles during maturation (3-5 weeks) or well after maturation (9 weeks). / Ph. D.

A Distrofia Muscular de Duchenne (DMD) é um tipo de miopatia grave, degenerativa e progressiva, geneticamente determinada e ligada ao cromossomo X. Além dos graves distúrbios cardiorrespiratórios e da motricidade, o paciente apresenta disfunções do sistema digestório, caracterizadas pelas desordens da motilidade. Entretanto, sabe-se que tais disfunções não ocorrem no camundongo MDX. O objetivo deste estudo foi estimar a densidade numérica por área da população total de neurônios (QA[T]) e dos neurônios nitrérgicos (QA[N]); assim como a área de secção transversal média do corpo celular destes neurônios (A[T] e A[N]) do plexo mioentérico esofágico e a largura média das fibras estriadas (L) das camadas musculares. Foram utilizados 40 camundongos machos da linhagem C57BL/10 nas idades de 4 e 10 semanas, distribuídos entre grupos experimentais (MDX4 e MDX10), e controles (C4 e C10). As estimativas foram analisadas em preparados de membrana dos esôfagos, e técnicas histoquímicas de NADH-diaforase (NADH-d) e NADPH-diaforase (NADPH-d) foram utilizadas para evidenciar toda a população de neurônios e os neurônios nitrérgicos, respectivamente. Os resultados mostraram que a QA[T] foi significativamente maior no grupo MDX10 em relação ao C10 (p<0.05); enquanto a QA[N] foi menor no grupo MDX4 em relação ao C4 (p<0.05). A A[T] foi menor no grupo MDX10 em relação ao MDX4 e ao C10 (p<0.05); enquanto que para a A[N] não houve diferença significativa entre os grupos controle e experimental, e tampouco entre os grupos de 4 e de 10 semanas. A variável L foi maior nos grupos MDX4 e MDX10 em relação aos seus respectivos controles de mesma idade (p<0.05). Concluímos que no plexo mioentérico esofágico de camundongos MDX existe uma redução dos neurônios mediadores do relaxamento, especialmente em animais jovens (MDX4), provavelmente porque o organismo tenta manter íntegra a função peristáltica do órgão. Esse fato pode explicar a adaptação e ausência de disfunções esofágicas durante quase toda a vida desses animais. / Duchenne Muscular Dystrophy (DMD) is the most common and the most severe muscular dystrophy of childhood. DMD is degenerative, progressive and a genetic X-linked disease. Besides the cardiomyopathy and the movement disorders, the patients have serious disfunctions in the alimentary system, characterized by motility disorders. However, it is known that such changes do not exist in MDX mice. The aim of this study was to estimate the neuronal numerical density/area of total (QA[T]) and nitregic neurons (QA[N]), the average cross-sectional area of total (A[T]) and nitregic (A[N]) neurons in myenteric plexus of the oesophagus and the average width of striped muscle of muscular layer (L). Forty C57BL/10 male mice were studied from four to ten weeks of age, divided into four groups: MDX mice formed the experimental groups (MDX4 and MDX10) and C57BL/10 male mice without the mutation formed the control groups (C4 and MDX10). Whole mounts preparations were obtained from the samples and histochemistry for NADH-diaphorase (NADH-d) and NADPH-diaphorase (NADPH-d) were used for morphometric evaluation. The results showed a significant increase of the QA[T] in the MDX10 than C10 (p<0.05), and a decrease of the QA[N] in MDX4 comparing to C4 (p<0.05). The A[T] decreased significantly in MDX10 comparing to both MDX4 and C10 (p<0.05), while no significant differences were observed among all the groups regarding the A[N]. The groups MDX4 and MDX10 showed a significant increase in L when compared to its controls at the same age (p<0.05). We conclude that in the myenteric plexus of the oesophagus in MDX mice there is a reduction of the inhibitory neurons, manly in the young animals (MDX4), probably to keep normal the peristaltic functions. Thus, it may explain the adaptation and the absence of oesophageal disfunction during almost the whole life in this animal model.

Atualmente, a espectroscopia de Ressonância Magnética Nuclear (RMN) in vitro tem sido extensivamente empregada para estudar tecidos biológicos, atuando como uma poderosa ferramenta de análise química. Em particular, a RMN de próton (1H) e de fósforo (31P) vem sendo utilizada para estudar o metabolismo muscular de animais portadores de deficiências genéticas, como os camundongos com distrofia muscular mdx, modelos para a distrofia muscular Duchenne (DMD). A DMD, que afeta humanos, é um distúrbio recessivo ligado ao cromossomo-X e ocorre em 1 para cada 3500 nascidos vivos do sexo masculino. A DMD é caracterizada pela ausência da proteína distrofina, o que provoca um processo progressivo e rápido de degeneração muscular. Atualmente, o acompanhamento da evolução da doença e de benefícios de tratamentos é feito através de biópsias do tecido muscular. Neste estudo foram realizadas medidas de RMN de 1H em amostras de diafragma e do músculo quadríceps femural de camundongos mdx e de controle com 3 e 6 meses de idade. Os resultados foram comparados com a análise histológica dos mesmos tecidos. O objetivo deste trabalho é monitorar o desenvolvimento normal dos músculos de animais de controle e o progresso da distrofia nos músculos de animais mdx, através da análise dos espectros de RMN. Foi possível identificar diferenças entre os grupos de animais a partir das integrais dos picos observados, mostrando que a distrofia acarreta alterações em diversas vias metabólicas nos camundongos mdx. Estes resultados formam a base para estudos da doença in vivo, para que então seja possível diferenciar músculos distróficos de músculos sadios e caracterizar diferentes estágios de evolução da doença de maneira não invasiva. / Currently, Nuclear Magnetic Resonance spectroscopy in vitro has been extensively used to study biological tissues, acting as a powerful tool for chemical analysis. In particular, NMR of proton (1H) and phosphorus (31P) has been used to study muscle metabolism in animals with genetic diseases, such as mice with muscular dystrophy mdx, models for Duchenne muscular dystrophy (DMD). The DMD, which affects humans, is a recessive disorder linked to X-chromosome and occurs in 1 each 3,500 live births male. The DMD is characterized by the absence of dystrophin protein, which causes a progressive and rapid degeneration. Currently, the monitoring of disease progression and benefits of treatments is made by biopsy of muscle tissue. In this study, 1H NMR spectrum were acquired from samples of diaphragm and quadriceps muscle of mdx and control mice 3 or 6 months-old. Results were compared with histological analysis of the same tissues. The objective of this study is to monitor the normal development of the muscles of control animals and the progress of dystrophy in the muscles of mdx animals by analyzing the NMR spectra. Differences were found between the groups of animals comparing the integrals of the observed peaks, showing that dystrophy leads to alterations in several methabolic pathways in the mdx mouse. These results form the basis for studies of the disease in vivo, so then it can be possible to distinguish dystrophic muscles from healthy muscles and characterize different stages of the disease noninvasively.

This series of experiments investigated dystrophin localization in the normal cerebellum and examined Purkinje neuron function in normal and dystrophin-deficient mice to better understand the physiological basis for cognitive deficits associated with Duchenne muscular dystrophy (DMD), a common genetic disorder among children. Cognitive impairments are consistently reported in DMD, yet precise mechanisms for their occurrence are unknown. Dystrophin protein, which is absent in DMD, is normally localized to muscles and specific neurons in the brain. Purkinje neurons are rich in dystrophin, specifically in somatic and dendritic membranes. Studies demonstrate perturbed cerebellar function in the absence of dystrophin, suggesting that DMD should be regarded as a cerebellar disorder in addition to being considered a neuromuscular disorder. However, theory and evidence are not generated from overlapping information: research investigating cerebellar involvement in DMD has focused on the vermal region, associated with motor function. The lateral region, implicated in cognition, has not been explicitly examined in DMD. The first experiment revisited the issue of dystrophin distribution in the mouse cerebellum using immunohistochemistry to investigate qualitative and quantitative differences between cerebellar regions. Both regions showed dystrophin localized to Purkinje neuron somatic and dendritic membranes, but dystrophin density was 30% greater in the lateral than the vermal region. The second experiment examined intrinsic electrophysiological properties of vermal and lateral Purkinje neurons from wild-type (WT) mice and from the mdx mouse model of DMD which lack dystrophin. Significant differences in action potential firing frequency, regularity, and shape were found between cerebellar regions. Purkinje neurons from mdx mouse cerebellum exhibited membrane hyperpolarization and irregular action potential firing, regardless of region. Spontaneous action potential firing frequency was reduced in Purkinje neurons from lateral cerebellum in mdx mice relative to controls, demonstrating that a loss of dystrophin causes a potent dysregulation of Purkinje neuron function in the region associated with cognition. This research extends our understanding of cerebellar pathology in DMD and its potential relevance to cognitive deficits in the disorder. Moreover, this research further supports the role of the cerebellum as a structure important for cognition and contributes to our understanding of dystrophin’s role in the brain.

This series of experiments investigated dystrophin localization in the normal cerebellum and examined Purkinje neuron function in normal and dystrophin-deficient mice to better understand the physiological basis for cognitive deficits associated with Duchenne muscular dystrophy (DMD), a common genetic disorder among children. Cognitive impairments are consistently reported in DMD, yet precise mechanisms for their occurrence are unknown. Dystrophin protein, which is absent in DMD, is normally localized to muscles and specific neurons in the brain. Purkinje neurons are rich in dystrophin, specifically in somatic and dendritic membranes. Studies demonstrate perturbed cerebellar function in the absence of dystrophin, suggesting that DMD should be regarded as a cerebellar disorder in addition to being considered a neuromuscular disorder. However, theory and evidence are not generated from overlapping information: research investigating cerebellar involvement in DMD has focused on the vermal region, associated with motor function. The lateral region, implicated in cognition, has not been explicitly examined in DMD. The first experiment revisited the issue of dystrophin distribution in the mouse cerebellum using immunohistochemistry to investigate qualitative and quantitative differences between cerebellar regions. Both regions showed dystrophin localized to Purkinje neuron somatic and dendritic membranes, but dystrophin density was 30% greater in the lateral than the vermal region. The second experiment examined intrinsic electrophysiological properties of vermal and lateral Purkinje neurons from wild-type (WT) mice and from the mdx mouse model of DMD which lack dystrophin. Significant differences in action potential firing frequency, regularity, and shape were found between cerebellar regions. Purkinje neurons from mdx mouse cerebellum exhibited membrane hyperpolarization and irregular action potential firing, regardless of region. Spontaneous action potential firing frequency was reduced in Purkinje neurons from lateral cerebellum in mdx mice relative to controls, demonstrating that a loss of dystrophin causes a potent dysregulation of Purkinje neuron function in the region associated with cognition. This research extends our understanding of cerebellar pathology in DMD and its potential relevance to cognitive deficits in the disorder. Moreover, this research further supports the role of the cerebellum as a structure important for cognition and contributes to our understanding of dystrophin’s role in the brain.

Atualmente, a espectroscopia de Ressonância Magnética Nuclear (RMN) in vitro tem sido extensivamente empregada para estudar tecidos biológicos, atuando como uma poderosa ferramenta de análise química. Em particular, a RMN de próton (1H) e de fósforo (31P) vem sendo utilizada para estudar o metabolismo muscular de animais portadores de deficiências genéticas, como os camundongos com distrofia muscular mdx, modelos para a distrofia muscular Duchenne (DMD). A DMD, que afeta humanos, é um distúrbio recessivo ligado ao cromossomo-X e ocorre em 1 para cada 3500 nascidos vivos do sexo masculino. A DMD é caracterizada pela ausência da proteína distrofina, o que provoca um processo progressivo e rápido de degeneração muscular. Atualmente, o acompanhamento da evolução da doença e de benefícios de tratamentos é feito através de biópsias do tecido muscular. Neste estudo foram realizadas medidas de RMN de 1H em amostras de diafragma e do músculo quadríceps femural de camundongos mdx e de controle com 3 e 6 meses de idade. Os resultados foram comparados com a análise histológica dos mesmos tecidos. O objetivo deste trabalho é monitorar o desenvolvimento normal dos músculos de animais de controle e o progresso da distrofia nos músculos de animais mdx, através da análise dos espectros de RMN. Foi possível identificar diferenças entre os grupos de animais a partir das integrais dos picos observados, mostrando que a distrofia acarreta alterações em diversas vias metabólicas nos camundongos mdx. Estes resultados formam a base para estudos da doença in vivo, para que então seja possível diferenciar músculos distróficos de músculos sadios e caracterizar diferentes estágios de evolução da doença de maneira não invasiva. / Currently, Nuclear Magnetic Resonance spectroscopy in vitro has been extensively used to study biological tissues, acting as a powerful tool for chemical analysis. In particular, NMR of proton (1H) and phosphorus (31P) has been used to study muscle metabolism in animals with genetic diseases, such as mice with muscular dystrophy mdx, models for Duchenne muscular dystrophy (DMD). The DMD, which affects humans, is a recessive disorder linked to X-chromosome and occurs in 1 each 3,500 live births male. The DMD is characterized by the absence of dystrophin protein, which causes a progressive and rapid degeneration. Currently, the monitoring of disease progression and benefits of treatments is made by biopsy of muscle tissue. In this study, 1H NMR spectrum were acquired from samples of diaphragm and quadriceps muscle of mdx and control mice 3 or 6 months-old. Results were compared with histological analysis of the same tissues. The objective of this study is to monitor the normal development of the muscles of control animals and the progress of dystrophy in the muscles of mdx animals by analyzing the NMR spectra. Differences were found between the groups of animals comparing the integrals of the observed peaks, showing that dystrophy leads to alterations in several methabolic pathways in the mdx mouse. These results form the basis for studies of the disease in vivo, so then it can be possible to distinguish dystrophic muscles from healthy muscles and characterize different stages of the disease noninvasively.

A Distrofia Muscular de Duchenne (DMD) é um tipo de miopatia grave, degenerativa e progressiva, geneticamente determinada e ligada ao cromossomo X. Além dos graves distúrbios cardiorrespiratórios e da motricidade, o paciente apresenta disfunções do sistema digestório, caracterizadas pelas desordens da motilidade. Entretanto, sabe-se que tais disfunções não ocorrem no camundongo MDX. O objetivo deste estudo foi estimar a densidade numérica por área da população total de neurônios (QA[T]) e dos neurônios nitrérgicos (QA[N]); assim como a área de secção transversal média do corpo celular destes neurônios (A[T] e A[N]) do plexo mioentérico esofágico e a largura média das fibras estriadas (L) das camadas musculares. Foram utilizados 40 camundongos machos da linhagem C57BL/10 nas idades de 4 e 10 semanas, distribuídos entre grupos experimentais (MDX4 e MDX10), e controles (C4 e C10). As estimativas foram analisadas em preparados de membrana dos esôfagos, e técnicas histoquímicas de NADH-diaforase (NADH-d) e NADPH-diaforase (NADPH-d) foram utilizadas para evidenciar toda a população de neurônios e os neurônios nitrérgicos, respectivamente. Os resultados mostraram que a QA[T] foi significativamente maior no grupo MDX10 em relação ao C10 (p<0.05); enquanto a QA[N] foi menor no grupo MDX4 em relação ao C4 (p<0.05). A A[T] foi menor no grupo MDX10 em relação ao MDX4 e ao C10 (p<0.05); enquanto que para a A[N] não houve diferença significativa entre os grupos controle e experimental, e tampouco entre os grupos de 4 e de 10 semanas. A variável L foi maior nos grupos MDX4 e MDX10 em relação aos seus respectivos controles de mesma idade (p<0.05). Concluímos que no plexo mioentérico esofágico de camundongos MDX existe uma redução dos neurônios mediadores do relaxamento, especialmente em animais jovens (MDX4), provavelmente porque o organismo tenta manter íntegra a função peristáltica do órgão. Esse fato pode explicar a adaptação e ausência de disfunções esofágicas durante quase toda a vida desses animais. / Duchenne Muscular Dystrophy (DMD) is the most common and the most severe muscular dystrophy of childhood. DMD is degenerative, progressive and a genetic X-linked disease. Besides the cardiomyopathy and the movement disorders, the patients have serious disfunctions in the alimentary system, characterized by motility disorders. However, it is known that such changes do not exist in MDX mice. The aim of this study was to estimate the neuronal numerical density/area of total (QA[T]) and nitregic neurons (QA[N]), the average cross-sectional area of total (A[T]) and nitregic (A[N]) neurons in myenteric plexus of the oesophagus and the average width of striped muscle of muscular layer (L). Forty C57BL/10 male mice were studied from four to ten weeks of age, divided into four groups: MDX mice formed the experimental groups (MDX4 and MDX10) and C57BL/10 male mice without the mutation formed the control groups (C4 and MDX10). Whole mounts preparations were obtained from the samples and histochemistry for NADH-diaphorase (NADH-d) and NADPH-diaphorase (NADPH-d) were used for morphometric evaluation. The results showed a significant increase of the QA[T] in the MDX10 than C10 (p<0.05), and a decrease of the QA[N] in MDX4 comparing to C4 (p<0.05). The A[T] decreased significantly in MDX10 comparing to both MDX4 and C10 (p<0.05), while no significant differences were observed among all the groups regarding the A[N]. The groups MDX4 and MDX10 showed a significant increase in L when compared to its controls at the same age (p<0.05). We conclude that in the myenteric plexus of the oesophagus in MDX mice there is a reduction of the inhibitory neurons, manly in the young animals (MDX4), probably to keep normal the peristaltic functions. Thus, it may explain the adaptation and the absence of oesophageal disfunction during almost the whole life in this animal model.

Orientador: Elaine Minatel / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-16T07:43:42Z (GMT). No. of bitstreams: 1 Pinto_RafaeldeSenziMoraes_M.pdf: 2983578 bytes, checksum: b55e02c59ba61404fd155a3c6e731521 (MD5) Previous issue date: 2010 / Resumo: Estudos recentes demonstram o envolvimento do estresse oxidativo nas distrofinopatias. Neste trabalho, verificamos se o uso do antioxidante N-acetilcisteína (NAC) no período que antecede a mionecrose diminui a degeneração muscular em camundongos mdx, modelo experimental da distrofia muscular de Duchenne. Quinze camundongos mdx com 14 dias de vida receberam por via intraperitoneal 150mg/kg de NAC diluído em salina por 14 dias. Quinze camundongos mdx receberam salina pela mesma via e período. Os músculos tibial anterior (TA), esternomastóide (STN) e diafragma (DIA) foram utilizados para quantificar (1) fibras em degeneração muscular (fibras positivas ao azul de Evans), (2) fibras regeneradas (fibras com núcleo central), (3) áreas de Inflamação/Regeneração e Regeneração, (4) conteúdo de fator de necrose tumoral-alfa (TNF-?) e do 4-hidroxinonenal (4-HNE), através da técnica de immunoblotting. Amostras de sangue foram utilizadas para quantificar o conteúdo da enzima creatina quinase (CK). NAC promoveu diminuição significativa na porcentagem de fibras em degeneração (marcadas pelo azul de Evans) em todos os músculos analisados, redução significativa de fibras com núcleo central no músculo TA e diminuição significativa na área de Inflamação/Regeneração nos músculos STN e DIA (p<0,05; Teste t de Student). Na análise por immunoblotting, observamos diminuição significativa do TNF-? no músculo DIA e do 4-HNE nos músculos STN e DIA dos camundongos mdx tratados com NAC (p<0,05; Teste t de Student). Diminuição significativa dos níveis de CK foi observada nos animais tratados com NAC (p<0,05; Teste t de Student). Em conjunto, estes resultados demonstram que o antioxidante NAC possa ser potencialmente útil para o tratamento farmacológico da distrofia muscular / Abstract: Recent studies strongly support the involvement of oxidative stress in dystrophinopathies. In the present study, we verified whether N-acetylcysteine (NAC) treatment before the cycles of muscle degeneration-regeneration decreases muscular degeneration in mdx mice. Mdx mice at 14 days of age received intraperitoneal injection of NAC (150mg/kg diluted with saline) daily, for 14 days. Control mdx mice received saline by the same via and for the same period of time. The tibialis anterior (TA), sternomastoid (STN) and diaphragm (DIA) muscles were used for the quantification of (1) necrotic fibers (labeled with Evans blue dye), (2) regenerated fibers with central nuclei, (3) inflammation/regeneration area, (4) tumor necrosis factor-alpha (TNF-?) and 4-hydroxynonenal (4-HNE) levels (immunoblotting analysis). The blood of these animals was drawn to evaluate serum CK activity by spectrophotometry. NAC-treated muscle showed a significant decrease in the percentage of Evans blue dye-positive fibers (p<0,05; Student's t Test). The number of fibers with central nuclei decreased in the TA muscle (p<0,05; Student's t Test). The area of inflammation-regeneration decreased in the STN and DIA muscles in the NAC treated group. Immunoblots showed a significant decrease in the levels of TNF-? levels in DIA muscle and of 4-HNE levels in STN e DIA muscles in NAC-treated mice (p<0.05; Student's ttest). NAC significantly decreased the blood levels of creatine kinase in NAC-treated mice (p<0.05; Student's t-test). These results suggest that antioxidants such as NAC could have therapeutic potential for dystrophinopathies / Mestrado / Anatomia / Mestre em Biologia Celular e Estrutural