Emprego terapêutico da tetrodotoxina em organismos animais / Therapeutic use of tetrodotoxin in animals

A Tetrodotoxina (TTX) é uma poderosa neurotoxina produzida por bactérias e é encontrada nos peixes da família Tetraodontidea, sendo estudada desde 1884. Essa toxina apresenta a capacidade de bloquear canais de sódio voltagem-dependentes graças a um grupo guanidina que se liga na abertura externa do canal. Graças a essa capacidade bloqueadora a Tetrodotoxina mostrou seu possível uso em novas terapias em diversas áreas. Os estudos compilados mostraram que a atividade farmacológica da TTX vem sendo extensivamente estudada e é visto seu emprego em terapias relacionadas a dores crônicas e neuropáticas, na diminuição da metástase em câncer, em terapias relacionadas a patologias nos sistemas muscular, esquelético e motor, além de seu uso nas terapias com sistema nervoso. Desta forma é possível concluir que essa toxina é promissora para novos tratamentos.

The Tetrodotoxin (TTX) is a powerful neurotoxin produced by bacteria and is found in a fish from Tetraodontidea family, which has been studied since 1884. This toxin has ability to block voltage-dependent sodium channels through guanidine group that binds to the outer opening of the channel. Thanks to this ability tetrodotoxin presents the possibility to be used as a new therapy in several areas. The studies showed that the pharmacological activity of TTX has been extensively studied and its use has been seen in therapy related to chronic pain and neuropathic, the reduction of metastasis in cancer, therapy related diseases in the muscular, skeletal, motor and nervous systems. This toxin has been showing as a promising tool to new treatments.

Molecular basis for hyperkalemic periodic paralysis.

At least one form of periodic paralysis is a direct consequence of a mutation in a skeletal muscle, voltage-sensitive sodium channel--it was observed that many individual with this disease developed low serum potassium levels during paralytic episodes. Some families had hyperkalemic paralysis with serum potassium levels of 6 or 7 mEg/L during paralytic crises. In both hypokalemic and hyperkalemic paralysis one of the precipitants is a period of rest after exertion. In hypokalemic periodic paralysis carbohydrates may initiate weakness. In both hyper- and hypokalemic forms, the disorder is inherited as an autosomal dominant trait. During hypokalemic and hyperkalemic paralysis, one might respectively anticipate muscle hyperpolarization or depolarization. Has been observed a potassium-related abnormality of sodium conductance in the pathogenesis at least of the hyperkalemic form of periodic paralysis. The fact that TTX reverses the physiological defect suggested the hypothesis that the primary problem might be a mutation in a TTX-sensitive sodium channel. The protein consists of some 2000 amino acids with characteristic intracytoplasmic and extracellular domains as well a four remarkably conserved membrane spanning domains, each composed of six transmembrane of a polymorphism of the human sodium channel with hyperkalemic paralysis. When multipoint analysis was used to test for coinheritance of the disease with both Na-2 and growth hormone polymorphisms, a lod score of 7 was obtained. That is, the ratio of the probability of linkage to non-linkage is 10 million to one. When extracellular potassium is increased to 10 mM, the affected myotubes demonstrate strikingly abnormal channel behavior characterized by prolonged open times or repetitive opens throughout the voltage step. Potassium implicate as a primary factor triggering an abnormal sodium channel gating mode and, as a result, aberrant sodium current behavior. It was estimated that, for the normal channel, the probability of entering a non-inactivating mode was very low and independent of potassium. On the other hand, for the abnormal channel the probability of entering an inactive mode rises up to 5-fold with hyperkalemic. Four mutations have recently been detected in individuals with cold-sensitive paramyotenia congenital. Two of the cause amino acid substitutions within the III-IV intracytoplasmic loop. It is striking that one substitutes a valine for a glycine. An analysis of the molecular biology of each mutation should illuminate not only the disease phenotype but also biophysical properties of specific sub-regions of this muscle sodium channel.