Neural link: the "switch" of excitation in the brain will help with incurable muscle disease

Scientists have found that a special substance that "turns off" brain receptors associated with overexcitation and death of nerve cells can help in the fight against a severe hereditary disease — type 1 spinocerebellar ataxia. This disease leads to loss of coordination, impaired speech and early disability of patients. In experiments on mice injected with the compound, recovery of motor activity was observed, which cannot be achieved with the help of modern drugs. This result can become the basis for the development of fundamentally new drugs, experts told Izvestia. However, they emphasize that the compound has yet to undergo a full cycle of preclinical and clinical trials and confirm its effectiveness in humans.

What is the danger of type 1 c pinocerebellar ataxia?

Researchers from the Krasnoyarsk State Medical University named after Professor V.F. Voino-Yasenetsky of the Ministry of Health of the Russian Federation and colleagues from other institutes studied a substance that prevents the deterioration of motor skills in severe muscle disease. This compound may potentially form the basis of safe and effective treatment strategies for spinocerebellar ataxia type 1 (SCA 1). This genetic disease is associated with the accumulation of improperly "folded" protein ataxin-1 in the cells of the cerebellum, the part of the brain responsible for coordination of movements and speech. Its mutated form is toxic to neurons, which leads to impaired gait, coordination of movements, and gradual loss of motor functions.

Photo: KrasSMU press service

According to the scientists, the drug memantine is used to treat neurodegenerative diseases associated with the ataxin-1 mutation. It is able to slow down the death of nerve cells, but it has a side effect: it disrupts certain important signaling pathways between neurons. As a result, unsteadiness of movement may increase in patients, which limits the possibility of its use in spinocerebellar ataxia. Therefore, scientists are looking for new drugs to combat this disease.

Experts investigated the substance Ro25-6981. Earlier work showed that it selectively blocks certain receptors for glutamate, a key signaling molecule on the surface of nerve cells. They are the ones that are massively activated in spinocerebellar ataxia, which leads to damage and death of neurons. Therefore, the authors suggested that blocking these receptors could reduce neurodegeneration caused by the disease.

In the experiments, the scientists used mice to which the gene responsible for the synthesis of mutant ataxin-1 was artificially injected into the cerebellum. The model animals developed characteristic symptoms: impaired coordination of movements and death of cerebellar cells.

Photo: KrasSMU press service

For four weeks, Ro25-6981 was injected daily into the abdominal cavity of some rodents. It turned out that the tested substance prevented the death of neurons and disruptions in the signaling pathways responsible for motor learning and brain plasticity. As a result, the animals improved mobility and coordination of movements.

— Unlike existing drugs for the treatment of neurodegenerative diseases, Ro25-6981 acts more pointwise and therefore does not disrupt the normal transmission of signals between neurons and does not lead to side effects. Due to this, it can be considered as the basis for a new approach to the treatment of CCA 1," said Anton Shuvaev, MD, Senior Researcher at KrasSMU.

In the future, experts plan to study in detail the effect of prolonged administration of Ro25-6981 on anxiety and memorization of new information.

High start: what diseases causes hypertension

Why is it important to monitor blood pressure and how to understand that it has increased

Prospects for creating a medicine

If we imagine that the cerebellar neurons are wiring in the control system of our movement, then in SCA 1, the toxic protein ataxin—1 creates a permanent "short circuit" in them, causing overexcitation, explained molecular biologist Arina Kholkina. The existing drug memantine "turns off" all the wiring in the "electrical panel" of the cerebellum — the neurons die more slowly, but the useful signals also go out, so the unsteadiness of gait does not go away, and may even increase.

— Scientists from Krasnoyarsk have taken a more jewelry-like path. The substance Ro25-6981 is not a switch, but a point fuse: it turns off only those receptors that "spark" in case of illness, and does not touch healthy signal transmission pathways. As a result, neuronal death stopped in the mice, and coordination improved. Something happened that rarely happens in neurodegenerative diseases — it didn't just stop getting worse, it got better," the specialist emphasized.

Usually, medications can only slow down the disease, meaning the patient weakens anyway, just more slowly. Here, the mice began to move more confidently — this is a very strong result of the research work. In addition, scientists have noticed that the animals have improved memory and decreased anxiety, said Arina Kholkina.

Photo: KrasSMU press service

Approaches to the treatment of hereditary ataxia are now actively developing. There are examples of small molecules that are being studied in rare neurodegenerative diseases, including ataxia, Albert Rizvanov, head of the Personalized Medicine Center of Excellence at Kazan (Volga Region) Federal University, told Izvestia. The field of gene therapy is developing in parallel.

— But for dominant diseases such as CCA 1, it is much more difficult to create a gene drug than for autosomal recessive diseases such as spinal muscular atrophy, where it is enough to deliver a working copy of the gene. There are two tasks to be solved here: first, safely suppress the synthesis of the toxic mutant protein, and then carefully restore the normal level of ataxin-1 by delivering a functional copy of the gene. This is exactly the approach we are developing at Kazan Federal University, and new data on the mechanisms of neuron damage help us to more accurately select targets and combinations of future therapies," said the scientist.

The study involved employees of the Siberian Federal University (Krasnoyarsk), the Institute of Biophysics of the Siberian Branch of the Russian Academy of Sciences (Krasnoyarsk), the Sirius Educational Center (Sochi), the Krasnoyarsk Regional Clinical Hospital and the University of Bristol (Great Britain). The results of the study, supported by a grant from the Russian Science Foundation in cooperation with the Krasnoyarsk Regional Science Foundation, are published in the journal Cell Death Discovery.