Study Explores Therapeutic Potential of Hc-TeTx
A potential mechanism by which Hc-TeTx — a fragment of the tetanus toxin previously shown to have neuroprotective effects — enters the central nervous system (CNS) has been unraveled by researchers in Spain.
Hc-TeTx appears to mimic a neurotrophin called brain-derived neurotrophic factor (BDNF). Neurotrophins are proteins that promote the survival and function of neurons, and bind to its receptor, TrkB, inducing their survival. The findings highlight its potential usefulness in preventing neuron damage in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease.
The study, “Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin,” was published in the journal Molecules.
Recent studies have shown that Hc-TeTx, a non-toxic derivative of the tetanus neurotoxin, protects brain cells from death and improves depression symptoms in rat models.
“One intramuscular dosis of Hc-TeTx made depression symptoms disappear in less than 24 hours, and its effects lasted two weeks,” José Aguilera, PhD, said in a press release. Aguilera is professor at the Universitat Autònoma de Barcelona (UAB), in Spain, and the study’s senior author.
Researchers found that Hc-TeTx can inhibit the transport of serotonin in the CNS by binding to neurotrophin receptors. This is of particular interest since depression is treated conventionally with inhibitors of serotonin reuptake (absorption).
Based on these results, Aguilera and colleagues sought to discover the mechanism through which Hc-TeTx produces these neuroprotective effects.
Using computational simulations and structural analysis of neurotrophins, the binding site of Hc-TeTx in the TrkB receptor was identified and validated in the laboratory. The data showed that Hc-TeTx could bind and be internalized in motor neurons through its interaction with the receptor.
Further investigations showed that Hc-TeTx competes with the neurotrophin BDNF for binding and internalization in neurons.
Mice were injected with Hc-TeTx in the leg muscle and results revealed the presence of both Hc-TeTx and TrkB on the neuromuscular junction, which is the where the terminal end of a motor nerve and a muscle fiber connect. Hc-TeTx enters in motoneuron terminals by binding to TrkB.
“In the model we propose, TrkB would act as a receptor for [TeTx] at axonal terminals of motor neurons,” the researchers wrote.
“The identification of the receptor, or receptors, for [TeTx] is a key aspect for medical applications and toxicology, in addition to providing new strategies against tetanus,” the team added. “It will have an important impact on the developing of new therapies against neurodegenerative diseases, like Parkinson’s or ALS, by the utilization of Hc-[TeTx] as a vector for the delivery of therapeutic molecules to the CNS, or by using Hc-[TeTx] itself as a drug, taking advantage of its observed therapeutic properties.”
According to the scientists, there are many benefits in introducing Hc-TeTx as a new therapy, including the fact that recombinant proteins are considered safe and could be less expensive to develop. Hc-TeTx also might prevent the development of neurodegeneration and eliminate depression at the same time.
“This is an important advance in science,” said Aguilera.
The therapeutic use of Hc-TeTx for the treatment of depression, Parkinson’s, and ALS was patented recently, and the researchers now are seeking investors so they can conduct clinical trials to test its safety and effectiveness in people.