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This thesis is focused on the study of glycosphingolipids in the rat liver in different types of cholestasis and the effect of oxidative stress on changes in the composition and localization of gangliosides. First, it was necessary to optimize the immunochemical detection of glycosphingolipids. GM1 ganglioside was selected as a representative of a large glycolipid family. We found that minimum water content in the fixing solution was a key condition for fixation of histological sections. Optimized method of GM1 detection was subsequently used in in vivo experiments. We have demonstrated that estrogen-induced cholestasis characterized by high concentrations of bile acids and increased oxidative stress caused changes in the synthesis and distribution of liver gangliosides. HMOX induction is associated with a reduction in oxidative stress level and accompanied by normalization in GSL content. In experiments with obstructive cholestasis, we found that changes in the distribution and synthesis of gangliosides were not strictly specific to a particular type of cholestasis. We assume that it represents a general mechanism of hepatoprotection. We also confirmed the important role of bilirubin, product of HMOX reaction, in protection of hepatocytes against oxidative damage caused by high concentrations of...

This thesis is focused on the study of glycosphingolipids in the rat liver in different types of cholestasis and the effect of oxidative stress on changes in the composition and localization of gangliosides. First, it was necessary to optimize the immunochemical detection of glycosphingolipids. GM1 ganglioside was selected as a representative of a large glycolipid family. We found that minimum water content in the fixing solution was a key condition for fixation of histological sections. Optimized method of GM1 detection was subsequently used in in vivo experiments. We have demonstrated that estrogen-induced cholestasis characterized by high concentrations of bile acids and increased oxidative stress caused changes in the synthesis and distribution of liver gangliosides. HMOX induction is associated with a reduction in oxidative stress level and accompanied by normalization in GSL content. In experiments with obstructive cholestasis, we found that changes in the distribution and synthesis of gangliosides were not strictly specific to a particular type of cholestasis. We assume that it represents a general mechanism of hepatoprotection. We also confirmed the important role of bilirubin, product of HMOX reaction, in protection of hepatocytes against oxidative damage caused by high concentrations of...

O objetivo deste trabalho foi avaliar os efeitos do monossialogangliosídio (GM1), da câmara de oxigenoterapia hiperbárica e de ambos no tratamento da lesão medular experimental em ratos. Trinta e dois ratos Wistar com lesão medular foram divididos em 4 grupos: um grupo recebeu o monossialogangliosídio (GM1), um segundo foi submetido à oxigenoterapia hiperbárica, um terceiro recebeu os dois tratamentos e um quarto não recebeu tratamento (controle). Não houve diferença significativa entre os grupos na análise histológica, em todas as variáveis (necrose, hemorragia, hiperemia e degeneração cística, p>0,06). Também não houve nenhuma diferença na comparação entre os lados direito e esquerdo nos testes funcionais (p>0,06 para todos). Não foram encontradas diferenças nos testes motores, na comparação entre os grupos após 2, 7 21 e 28 dias de lesão medular. Mas, na avaliação após 14 dias, o Grupo 3, o qual recebeu a terapia combinada, mostrou um escore BBB significantemente maior que os outros grupos (p=0,015). Na avaliação de 28 dias, houve uma tendência dos Grupos 1 (GM1) e 3 (terapia combinada) apresentarem um escore BBB maior que o do Grupo 4 (controle), embora sem significância estatística (p=0,057). Concluiu-se que, quanto aos índices motores, a utilização do GM-1 tem efeito benéfico, embora sem diferença estatisticamente significante e que o efeito benéfico do GM-1 é antecipado através da utilização concomitante da oxigênio terapia hiperbárica. / The objectives were to evaluate the effect of GM1 ganglioside, hyperbaric oxygen, and both in combination, in the treatment of experimental spinal cord lesions in rats. Thirty-two Wistar rats with spinal cord lesions were divided into four groups: one group received GM1 ganglioside, one was submitted to hyperbaric oxygen therapy, the third received both treatments, and the fourth received no treatment (control). There were no significant differences between the groups in the histological analysis, for any of the variables (necrosis, hemorrhage, hyperemia, cystic degeneration, p > 0.06). Neither were there any significant differences in the comparison of left and right sides in the functional tests (p > 0.06 for all). No significant differences were found in the locomotor ratings, in the comparison of groups at 2 days, 7 days, 21 days and 28 days after the surgical procedure. However, in the evaluation on day 14, Group 3, which received the combined therapy, showed a significantly higher BBB score than the other groups (p = 0.015). In the evaluation on day 28, there was a trend to Group 1 (GM1) and 3 (combined therapy) showed a higher BBB score than the group 4 (control), but with no significance (p=0,057). In conclusion, the is a benefit in the use of GM1 ganglioside, but with no significance and the therapeutic effect of GM1 in locomotor evaluation of rats submitted to spinal cord lesion is anticipated by hyperbaric oxygen therapy.

O objetivo deste trabalho foi avaliar os efeitos do monossialogangliosídio (GM1), da câmara de oxigenoterapia hiperbárica e de ambos no tratamento da lesão medular experimental em ratos. Trinta e dois ratos Wistar com lesão medular foram divididos em 4 grupos: um grupo recebeu o monossialogangliosídio (GM1), um segundo foi submetido à oxigenoterapia hiperbárica, um terceiro recebeu os dois tratamentos e um quarto não recebeu tratamento (controle). Não houve diferença significativa entre os grupos na análise histológica, em todas as variáveis (necrose, hemorragia, hiperemia e degeneração cística, p>0,06). Também não houve nenhuma diferença na comparação entre os lados direito e esquerdo nos testes funcionais (p>0,06 para todos). Não foram encontradas diferenças nos testes motores, na comparação entre os grupos após 2, 7 21 e 28 dias de lesão medular. Mas, na avaliação após 14 dias, o Grupo 3, o qual recebeu a terapia combinada, mostrou um escore BBB significantemente maior que os outros grupos (p=0,015). Na avaliação de 28 dias, houve uma tendência dos Grupos 1 (GM1) e 3 (terapia combinada) apresentarem um escore BBB maior que o do Grupo 4 (controle), embora sem significância estatística (p=0,057). Concluiu-se que, quanto aos índices motores, a utilização do GM-1 tem efeito benéfico, embora sem diferença estatisticamente significante e que o efeito benéfico do GM-1 é antecipado através da utilização concomitante da oxigênio terapia hiperbárica. / The objectives were to evaluate the effect of GM1 ganglioside, hyperbaric oxygen, and both in combination, in the treatment of experimental spinal cord lesions in rats. Thirty-two Wistar rats with spinal cord lesions were divided into four groups: one group received GM1 ganglioside, one was submitted to hyperbaric oxygen therapy, the third received both treatments, and the fourth received no treatment (control). There were no significant differences between the groups in the histological analysis, for any of the variables (necrosis, hemorrhage, hyperemia, cystic degeneration, p > 0.06). Neither were there any significant differences in the comparison of left and right sides in the functional tests (p > 0.06 for all). No significant differences were found in the locomotor ratings, in the comparison of groups at 2 days, 7 days, 21 days and 28 days after the surgical procedure. However, in the evaluation on day 14, Group 3, which received the combined therapy, showed a significantly higher BBB score than the other groups (p = 0.015). In the evaluation on day 28, there was a trend to Group 1 (GM1) and 3 (combined therapy) showed a higher BBB score than the group 4 (control), but with no significance (p=0,057). In conclusion, the is a benefit in the use of GM1 ganglioside, but with no significance and the therapeutic effect of GM1 in locomotor evaluation of rats submitted to spinal cord lesion is anticipated by hyperbaric oxygen therapy.

Objetivo: avaliar os efeitos do monossialogangliosídeo (GM1) administrado pela via de transdérmica por laser a baixa temperatura, após lesão medular experimental em ratos. Métodos: o estudo incluiu 40 ratos Wistar, machos, com idade entre 20 e 21 semanas, submetidos à lesão medular contusa pelo equipamento NYU Impactor, a altura de 25 mm, de acordo com o protocolo MASCIS. Foram formados 4 grupos de 10 animais. No grupo 1, os ratos receberam diariamente 0,2 ml de soro fisiológico, via intraperitoneal; no grupo 2, GM1 via intraperitoneal, na concentração 30 mg/kg por dia; no grupo 3, sessão diária de laser a baixa temperatura na topografia da lesão; no grupo 4 sessão diária de laser contendo GM1 na concentração de 30 mg/kg pela via transcutânea por Laser Ice. Todos os animais foram tratados por 42 dias. Foram avaliados por meio da escala de avaliação funcional Basso, Baettie e Bresnahan (BBB) em 7, 14, 21, 28, 35 e 42 dias após a lesão, pelo exame histopatológico e por potencial evocado motor após 42 dias da lesão. Resultados: os animais do grupo 4 apresentaram os escores da escala BBB superiores aos demais grupos até a quarta semana, sendo equiparado aos demais na sexta semana. Não houve diferença estatisticamente significante entre os grupos e as semanas. A avaliação histológica não demonstrou resultados com significância estatística. Os exames de potencial evocado motor demonstraram maior latência média no grupo 1, sem significância estatística. Conclusão: o emprego de GM1 associado a laser em baixa temperatura demonstra resultados funcionais superiores nas primeiras semanas, mas sem evidenciar diferença estatisticamente significante / Objective: To evaluate the effects of monossialoganglioside (GM1) administered transdermally, and laser at low temperature, in the functional and histological recovery of spinal cord injury in rats. Methods: Forty male Wistar rats, aged between 20 and 21 weeks, underwent spinal cord contusion at NYU Impactor, according to the MASCIS protocol. They were divided into four groups: in Group 1, rats received 0.2 ml of saline intraperitoneally daily; in Group 2, GM1 was administered intraperitoneally at a concentration 30 mg/kg per day; in Group 3, rats were treated with laser at low temperature on the skin, daily and in Group 4, the daily laser session also contained GM1. All the groups were treated for 42 days. The animals were evaluated by the Basso, Baettie and Bresnahan (BBB) functional scale on days 7, 14, 21, 28, 35 and 42 after injury, and by histopathology and motor evoked potentials after 42 days of injury. Results: The animals in Group 4 had higher BBB scores compared to the other groups, until the 4th week. There were no statistically significant differences between the groups, or in the comparisons over time, i.e. from one week to the next. Histological evaluation showed no statistically significant results, and no significant differences were found in the motor evoked potential tests either. Conclusion: GM1 associated with the use of low-temperature laser shows no superior functional, neurological or histological results in the treatment of spinal cord lesions in rats

Objetivo: avaliar os efeitos do monossialogangliosídeo (GM1) administrado pela via de transdérmica por laser a baixa temperatura, após lesão medular experimental em ratos. Métodos: o estudo incluiu 40 ratos Wistar, machos, com idade entre 20 e 21 semanas, submetidos à lesão medular contusa pelo equipamento NYU Impactor, a altura de 25 mm, de acordo com o protocolo MASCIS. Foram formados 4 grupos de 10 animais. No grupo 1, os ratos receberam diariamente 0,2 ml de soro fisiológico, via intraperitoneal; no grupo 2, GM1 via intraperitoneal, na concentração 30 mg/kg por dia; no grupo 3, sessão diária de laser a baixa temperatura na topografia da lesão; no grupo 4 sessão diária de laser contendo GM1 na concentração de 30 mg/kg pela via transcutânea por Laser Ice. Todos os animais foram tratados por 42 dias. Foram avaliados por meio da escala de avaliação funcional Basso, Baettie e Bresnahan (BBB) em 7, 14, 21, 28, 35 e 42 dias após a lesão, pelo exame histopatológico e por potencial evocado motor após 42 dias da lesão. Resultados: os animais do grupo 4 apresentaram os escores da escala BBB superiores aos demais grupos até a quarta semana, sendo equiparado aos demais na sexta semana. Não houve diferença estatisticamente significante entre os grupos e as semanas. A avaliação histológica não demonstrou resultados com significância estatística. Os exames de potencial evocado motor demonstraram maior latência média no grupo 1, sem significância estatística. Conclusão: o emprego de GM1 associado a laser em baixa temperatura demonstra resultados funcionais superiores nas primeiras semanas, mas sem evidenciar diferença estatisticamente significante / Objective: To evaluate the effects of monossialoganglioside (GM1) administered transdermally, and laser at low temperature, in the functional and histological recovery of spinal cord injury in rats. Methods: Forty male Wistar rats, aged between 20 and 21 weeks, underwent spinal cord contusion at NYU Impactor, according to the MASCIS protocol. They were divided into four groups: in Group 1, rats received 0.2 ml of saline intraperitoneally daily; in Group 2, GM1 was administered intraperitoneally at a concentration 30 mg/kg per day; in Group 3, rats were treated with laser at low temperature on the skin, daily and in Group 4, the daily laser session also contained GM1. All the groups were treated for 42 days. The animals were evaluated by the Basso, Baettie and Bresnahan (BBB) functional scale on days 7, 14, 21, 28, 35 and 42 after injury, and by histopathology and motor evoked potentials after 42 days of injury. Results: The animals in Group 4 had higher BBB scores compared to the other groups, until the 4th week. There were no statistically significant differences between the groups, or in the comparisons over time, i.e. from one week to the next. Histological evaluation showed no statistically significant results, and no significant differences were found in the motor evoked potential tests either. Conclusion: GM1 associated with the use of low-temperature laser shows no superior functional, neurological or histological results in the treatment of spinal cord lesions in rats

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Alzheimer’s Disease (AD) is a chronic progressive neurological condition, clinically characterized by memory deficits, cognitive and physical impairment, and personality changes. Traditionally, AD was considered a type of protein folding disorder. Here, the concept of AD as an autoimmune disease of the innate immune system was developed. After exploring evolutionary connections between the AD peptide β-amyloid (Aβ) and known antimicrobial peptides (AMPs), and elucidating the structural similarities between Aβ and AMPs, a mechanism of action for Aβ’s antimicrobial activity is proposed that is based on the compromise of bacterial membranes. Following these theoretical considerations, experimental evidence is presented for the production of Aβ by cells in response to infection, and for Aβ’s antibacterial and antiviral activity. Rooted in similarities of the cell membranes of neuronal and bacterial cells in terms of lipid composition and transmembrane potential, it is hypothesised that Aβ’s neurotoxicity is caused by its misguided attack on neurons as an AMP. In reversing the concept of Aβ as an AMP, the similarity of AMPs to Aβ is demonstrated in experiments revealing the neurotoxicity of two AMPs, LL 37, and cecropin A. To determine a mechanism for the progressive nature of AD, it was shown that, although apoptosis may be involved in AD, it is actually necrosis that is responsible for the propagation of neuronal cell death so characteristic of AD. With the Vicious Cycle of AD, a scheme was devised, integrating the results obtained here with data and research from other groups, which explains the chronic and progressive nature of AD as a result of Aβ’s physiological role as an AMP and innate immune system effector. Borne from Aβ’s activity as an AMP and its central role in the Vicious Cycle of AD, a question was investigated: do antibiotics, such as penicillin, that cause release of bacterial endotoxins due to their mechanism of action, trigger the Vicious Cycle of AD and thus lead to the development of AD? Preliminary evidence supporting this notion was presented.

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