Batrachotoxin

Batrachotoxin (BTX) is an extremely potent cardiotoxic and neurotoxic steroidal alkaloid found in certain species of beetles, birds, and frogs. The name is from the Greek word βάτραχος, bátrachos, 'frog'. Structurally-related chemical compounds are often referred to collectively as batrachotoxins. It is an extremely poisonous alkaloid. In certain frogs this alkaloid is present mostly on the skin. Such frogs are among those used for poisoning darts. Batrachotoxin binds to and irreversibly opens the sodium channels of nerve cells and prevents them from closing, resulting in paralysis. No antidote is known. Batrachotoxin (BTX) is an extremely potent cardiotoxic and neurotoxic steroidal alkaloid found in certain species of beetles, birds, and frogs. The name is from the Greek word βάτραχος, bátrachos, 'frog'. Structurally-related chemical compounds are often referred to collectively as batrachotoxins. It is an extremely poisonous alkaloid. In certain frogs this alkaloid is present mostly on the skin. Such frogs are among those used for poisoning darts. Batrachotoxin binds to and irreversibly opens the sodium channels of nerve cells and prevents them from closing, resulting in paralysis. No antidote is known. It was named by scientists John W. Daly and Bernhard Witkop, who separated the potent toxic alkaloids fraction and determined its chemical properties. They isolated four major toxic steroidal alkaloids including batrachotoxin, isobatrachotoxin, pseudobatrachotoxin, and batrachotoxinin A. Due to the difficulty of handling such a potent toxin and the minuscule amount that could be collected, a comprehensive structure determination involved several difficulties. However, Takashi Tokuyama, who joined the investigation later, converted one of the congener compounds, batrachotoxinin A, to a crystalline derivative and its unique steroidal structure was solved with x-ray diffraction techniques (1968). When the mass spectrum and NMR spectrum of batrachotoxin and the batrachotoxinin A derivatives were compared, it was realized that the two shared the same steroidal structure and that batrachotoxin was batrachotoxinin A with a single extra pyrrole moiety attached. In fact, batrachotoxin was able to be partially hydrolyzed using sodium hydroxide into a material with identical TLC and color reactions as batrachotoxinin A. The structure of batrachotoxin was established in 1969 through chemical recombination of both fragments. Batrachotoxinin A was synthesized by Michio Kurosu, Lawrence R. Marcin, Timothy J. Grinsteiner, and Yoshito Kishi in 1998. According to experiments with rodents, batrachotoxin is one of the most potent alkaloids known: its subcutaneous LD50 in mice is  2 µg/kg. Meanwhile, its derivative, batrachotoxinin A, has a much lower toxicity with an LD50 of 1000 µg/kg. The toxin is released through colourless or milky secretions from glands located on the back and behind the ears of frogs from the genus Phyllobates. When one of these frogs is agitated, feels threatened or is in pain, the toxin is reflexively released through several canals. As a neurotoxin, it affects the nervous system. Neurological function depends on depolarization of nerve and muscle fibres due to increased sodium ion permeability of the excitable cell membrane. Lipid-soluble toxins such as batrachotoxin act directly on sodium ion channels involved in action potential generation and by modifying both their ion selectivity and voltage sensitivity. Batrachotoxin (BTX) irreversibly binds to the Na+ channels which causes a conformational change in the channels that forces the sodium channels to remain open. Batrachotoxin not only keeps voltage-gated sodium channels open, but it also reduces the single-channel conductance. In other words, the toxin binds to the sodium channel and keeps the membrane permeable to sodium ions in an all or none manner. This has a direct effect on the peripheral nervous system (PNS). Batrachotoxin in the PNS produces increased permeability (selective and irreversible) of the resting cell membrane to sodium ions, without changing potassium or calcium concentration. This influx of sodium depolarizes the formerly polarized cell membrane. Batrachotoxin also alters the ion selectivity of the ion channel by increasing the permeability of the channel toward larger cations. Voltage-sensitive sodium channels become persistently active at the resting membrane potential. Batrachotoxin kills by permanently blocking nerve signal transmission to the muscles.