Institut de Neurociències (INc) - UAB Barcelona

Tetanus toxin fragment may treat depression, Parkinson's disease and ALS

Tetanus toxin fragment may treat depression, Parkinson's disease and ALS

Researchers at the Institute describe the mechanism through which a non-toxic derivative of the tetanus neurotoxin (Hc-TeTx) may serve to treat depression and neurodegenerative diseases, as has already been demonstrated in animal models.

13/07/2021

Depression has been treated traditionally with inhibitors of serotonin reuptake in the central nervous system. These drugs do not come without side effects, such as lack of immediate therapeutic action, the need for daily doses and the danger of becoming addicted to some of these drugs. That is why scientists continue to work on new therapies to treat depression.

In 2019, an international group of researchers co-led by Dr Yousef Tizabe from the Howard University College of Medicine in Washington, D.C., and Professor José Aguilera from the Department of Biochemistry and Molecular Biology and the Institut de Neurociències at the Universitat Autònoma de Barcelona (UAB), observed that a non-toxic derivative of the tetanus neurotoxin (which causes tetanus infections) improved depression symptoms in rat animal models. “One intramuscular dosis of Hc-TeTx made depression symptoms disappear in less than 24 hours, and its effects lasted two weeks”, explains Aguilera. Based on these findings, scientists began to work on discovering the mechanism through which this substance produces these effects.

In a recent study coordinated by Professor Aguilera and conducted in collaboration with the research group led by Dr Thomas Scior of the Benemérita Universidad Autónoma de Puebla (BUAP) in Mexico, researchers demonstrated that Hc-TeTx is capable of inhibiting the transport of serotonin within the central nervous system, by binding to neurotrophin receptors, proteins that induce the survival of neurons. These results, published in the journal Molecules, suggest that the drug may not only serve in treating depression, but also be useful in treating neurodegenerative diseases, such as Parkinson’s disease or amyotrophic lateral sclerosis (ALS).

According to researchers, the advantages of introducing Hc-TeTx as a new drug are evident. A biweekly or monthly dosis would allow medical professionals to control the progress. Since it is a recombinant product, there would be no problems with drug safety, production or high costs. Furthermore, in neurodegenerative cases, Hc-TeTx would stop the development of the pathology and at the same time eliminate any disease-related depressions.

Researchers recently patented the therapeutic use of Hc-TeTx for the treatment of depression, Parkinson’s disease and amyotrophic lateral sclerosis, and are now looking for investors to be able to conduct clinical trials on humans. “This is an important advance in science, and even more so now when in addition to the high incidence in depression and alterations in behaviours, we see mental alterations as a result of COVID-19 and the negative environments of stress, self-isolation or fear”, Aguilera concludes.



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A potential therapeutic target to treat cerebral blood alterations

A potential therapeutic target to treat cerebral blood alterations

The arachnoid is one of the three meninges, or brain membranes, and is responsible for mechanically and immunologically protecting the brain and the spinal cord. It allows communication between the cerebrospinal fluid (which bathes the brain and the spinal cord) and the cerebral blood vessels, and controls several crucial physiological responses in the brain, such as supplying nutrients and eliminating toxic waste.

Researchers from the Laboratory of Cerebral and Peripheral Vascular Diseases, at the UAB Department of Pharmacology, Therapeutics and Toxicology, and the Institute discovered that the arachnoid is a very important source of sphingosine-1-phosphate (S1P), a lipid that had hitherto been found mainly in red blood cells. Researchers show for the first time that this fat, once released from the arachnoid, produces the necessary vasoconstriction in the cerebral blood vessels for the regulation of blood flow. In addition, this process facilitates the elimination of waste substances, by generating a vascular pulsation that would help expel them through the cerebrospinal fluid. The research, done on mice and human samples, has been published in the Journal of Cerebral Blood Flow and Metabolism.

The results of the study are not only relevant to understanding the physiological role of this substance in the brain blood vessels. They also suggest that in those pathological states that present the accumulation of toxic substances, such as Alzheimer’s disease, SP1 in the arachnoid could be altered. This would explain why beta-amyloid peptide clearance is reduced in Alzheimer’s patients, altering proper brain function and causing cognitive dysfunction and dementia.

"In the study, we saw there is a decrease in S1P deposits with age, and we believe this could be affecting the elimination of beta-amyloid peptide, promoting the development of the disease", explains Francesc Jiménez-Altayó, esearcher leading the study. Jiménez-Altayó concludes that the results of the study “situate SP1 located in the arachnoid as a potential therapeutic target to modulate cerebral blood flow, to treat cerebrovascular pathologies and those that run with toxic waste in the brain”.

Researchers from the Institute for Biomedical Research in Barcelona and the Eberhard Karls University in Tübingen also took part in the study.

The H2020 project QSPainRelief awarded by the European Commission

The H2020 project QSPainRelief awarded by the European Commission

The QSPainRelief project "Effective combinational treatment of chronic pain in individual patients by an innovative quantitative systems pharmacology pain relief approach", which includes the participation of Dr. Jesús Giraldo’s team (Institute for Neurosciences and Biostatistics Unit of the School of Medicine), has been funded from the European Commission.

This  project will attempt to solve a crucial problem since about 20% of Europeans suffer from chronic pain and current therapies are not effective in many cases. Around 60% of patients do not reach enough relief from traditional painkillers, which in turn can lead to several adverse effects.

The QSPainRelief project addresses the problem of chronic pain by identifying new drug combinations that are expected to increase analgesic efficacy while reducing side effects. To do this, quantitative systems pharmacology and computational modeling will be used. The best combinations will be validated in animal models and clinical studies.

The QSPainRelief project will receive more than € 6 million in funding for 5 years through the H2020 program. The project is a collaboration between 9 research institutions from 6 different countries, including the UAB, starting January 1, 2020.

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