Botulinum neurotoxins: mechanism of action

Botulinum neurotoxins are used clinically for conditions characterized by hyperexcitability of peripheral nerve terminals and hypersecretory syndromes. These neurotoxins are synthesized as precursor proteins with low activity, but their effects are mediated by the active form of the neurotoxin through a multistep mechanism. Following a high-affinity interaction with a protein receptor and polysialogangliosides on the synaptic membrane, botulinum neurotoxins enter the neuron and causes a sustained inhibition of synaptic transmission. The active neurotoxin is part of a high-molecular-weight complex that protects the neurotoxin from proteolytic degradation. Although complexing proteins do not affect diffusion of therapeutic neurotoxin, they may lead to the development of neutralizing antibodies that block responsiveness to it. Nerve terminal intoxication is reversible and its duration varies for different BoNT serotypes. Although it was previously assumed that botulinum neurotoxins exert effects only on the peripheral synapses, such as the neuromuscular junction, there is now substantial evidence that these neurotoxins affect neurotransmission at distal central nervous system sites as well.