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Background Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease that affects young adults. It is characterized by generating a chronic demyelinating autoimmune inflammation in the central nervous system. An experimental model for studying MS is the experimental autoimmune encephalomyelitis (EAE), induced by immunization with antigenic proteins from myelin. Aims The present study investigated the evolution of EAE in pregabalin treated animals up to the remission phase. Methods and results The results demonstrated a delay in the onset of the disease with statistical differences at the 10th and the 16th day after immunization. Additionally, the walking track test (CatWalk) was used to evaluate different parameters related to motor function. Although no difference between groups was obtained for the foot print pressure, the regularity index was improved post treatment, indicating a better motor coordination. The immunohistochemical analysis of putative synapse preservation and glial reactivity revealed that pregabalin treatment improved the overall morphology of the spinal cord. A preservation of circuits was depicted and the glial reaction was downregulated during the course of the disease. qRT-PCR data did not show immunomodulatory effects of pregabalin, indicating that the positive effects were restricted to the CNS environment. Conclusions Overall, the present data indicate that pregabalin is efficient for reducing the seriousness of EAE, delaying its course as well as reducing synaptic loss and astroglial reaction.

Orientador: Alexandre Leite Rodrigues de Oliveira Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: A esclerose múltipla se caracteriza por gerar uma inflamação esmielinizantecrônica e de caráter autoimune no sistema nervoso central, gerando uma série desinais e sintomas clínicos. Um modelo experimental para estudo da esclerosemúltipla é a encefalomielite autoimune experimental (EAE). Durante o curso da EAE, observa-se no SNC, perda de contatos sinápticos, bem como aumento da gliose reativa, envolvendo tanto astrócitos quanto células microgliais. Assim, a amenização dessas alterações, por tratamentos farmacológicos, pode ser útil no tratamento dos sintomas da EM. Neste sentido, o emprego da pregabalina, um ligante da proteína ?2-? associada a canais de cálcio voltagem-dependentes em neurônios, pode se constituir numa estratégia para o controle dos sintomas da doença. Assim, o presente estudo investigou o efeito da pregabalina sobre o curso da EAE, através da análise clínica de ratos Lewis imunizados com MBP e avaliação imunoistoquímica da medula espinal, utilizando marcadores para sinapses, astrogliose e reação microglial. Adicionalmente, através de RT-PCR, avaliou-se a expressão gênica de interleucinas pró e anti-inflamatórias, bem como a recuperação motora nos grupos placebo e tratado, foi avaliada pelo walking track test (CatWalk System). Os resultados demonstraram que o tratamento com pregabalina foi capaz de atrasar e amenizar os sinais clínicos e morfológicos da EAE, bem como reduzir a perda sináptica e a reação astroglial na medula espinal. Ainda, o tratamento resultou numa regulação positiva de genes anti-inflamatórios. De forma similar, a administração desse fármaco permitiu um mais rápido restabelecimento de parâmetros de marcha. Os resultados do presente estudo indicam que a pregabalina apresenta características neuroprotetoras e antiinflamatórias que refletem positivamente na amenização da doença, mostrando potencial para o uso clínico, em associação aos imunomoduladores atualmente empregados Abstract: The multiple sclerosis (MS) is an autoimmune disease and neurodegenerative that affects young adults. It is characterized by generating a chronic demyelinating autoimmune inflammation in the central nervous system. An experimental model for the study of multiple sclerosis is the experimental autoimmune encephalomyelitis (EAE), induced by immunization with antigenic proteins of myelin of the central nervous system, dissolved in adjuvants. The present study investigated the evolution of the disease in pregabalin treated animals up to the remission phase. The results demonstrated a delay on the onset of the disease with statistical differences at the 10th and the 16th day after immunization For the gait evaluation, the walking track test (CatWalk) was used to evaluate different parameters related to motor function. Although no difference between groups was obtained for the foot print pressure, the regularity index was improved post treatment, indicating a better motor coordination. The immunohistochemical analysis of synapse preservation and glial reactivity revealed that pregabalin treatment improved the overall morphology of the spinal cord. A preservation of circuits was depicted and astroglial reaction was downregulated during the course of the disease. RT-PCR data were in line with the immunolabeling observations and indicated a shift of the immune response towards an anti-inflammatory response. Overall, the present data indicate that pregabalin is efficient for reducing the seriousness of EAE, delaying its course as well as reducing synaptic loss and astroglial reaction Mestrado Clínica Médica Mestra em Clínica Médica

Snake bite envenoming, a serious public health problem in rural areas of tropical and subtropical countries, was included in 2007 as a neglected disease by the World Health Organization (WHO, 2007). Under this geographical perspective Africa, Asia, Oceania and Latin America are the most vulnerable countries to this kind of accident, but also shared by many developing countries (Harrison et al., 2009; Warrel, 2010). An excellent meta-analytic approach about the subject was described by Chippaux (2011), who analysed more than 3,000 references for estimating the burden of snakebites in sub-Saharan Africa. Brazil encloses both requirements, as a developing and a tropical country, and needs to strengthen measures against venomous snake accidents, since, according to Lima et al. (2009), it is the country with the major number of accidents (about 20,000 cases/year), followed by Peru (4,500), Venezuela (2,500-3,000), Colombia (2,675), Ecuador (1,200-1,400) and Argentina (1,150-1.250) (Warrel, 2004).

In geographically isolated populations where intensive medical care or serum therapy is not easily accessible snake envenomation is a major cause for concern. The aim of the present study was to test Camellia sinensis extracts, theaflavin and epigallocatechin (two of the main C. sinensis components) against the irreversible neuromuscular blockade induced by Crotalus durissus terrificus venom in mouse phrenic-nerve diaphragm preparations. A quantitative histological study was also performed. The venom (20µg/ml) completely decreased twitch tension after 70min and 5µg/ml venom abolished 50% of twitch amplitude after 60min. C. sinensis extract induced intense facilitatory effect in the preparation activity at 0.2mg/ml and slightly facilitatory effect at 0.05mg/ml. Both 0.05mg/ml C. sinensis extract and 0.05mg/ml commercial theaflavin maintained partial muscular activity in presence of 5µg/ml venom. The histological data confirms that Cs is able to protect the muscle from the myotoxic activity of the venom. Commercial epigallocatechin gallate did not show pre-synaptic nor post-synaptic activities. C. sinensis extract was able to protect the mouse phrenic-nerve diaphragm against the irreversible neuromuscular blockade induced by C. durissus terrificus venom.