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Subacute toxicity of crotoxin at neuromuscular junction: functional, structural and molecular aspects.


Living organisms produce a wide variety of molecules characterized by specificity and selectivity to cellular and molecular targets which are important requirements for the development of new drugs. Several classes of drugs used in therapy as prototypes had natural molecules, especially originating from plants and microorganisms. The bioprospection of aquatic and terrestrial animal poisons have revealed a large number of molecules of therapeutic, diagnostic and investigational values. In Brazil, among snake toxins with potential therapeutic value, there is the Crotoxin (CTX), the main toxin of the venom of the snake Crotalus durissus terrificus (South American rattlesnake), which corresponds to about 65% of the protein content of the crude venom. This protein has potent neurotoxic activity consequent blocking the pre-synaptic and post neuromuscular transmission. Despite its toxicity, the CTX has therapeutic potential due to its immunomodulatory, anti-inflammatory, antimicrobial, anti-tumor and anti-nociceptive activities. However, to ensure possible therapeutic applicability of CTX or novel drugs derived from this protein, it is fundamental to the characterization of its toxic activities after repeated administrations. So, considering that the neuromuscular synapse is a dynamic structure, this project has as main objective to evaluate the consequences of sub-acute administration of low doses of CTX on the structure and function of the neuromuscular junction and skeletal muscle. To achieve these goals will be used an association of experimental approaches, such as miographic (to estimate the safety margin of neuromuscular transmission), morphological (optical, electron and confocal microscopy), biochemistry (dosage of creatine kinase), and molecular biology (gene and protein expression of nicotinic receptor). Additionally will be evaluated kidney function and general characteristics of animals, such as weight gain, mobility and presence of bleeding. (AU)