Save the Brain: neuropeptides and stem cells
Take care of your nervesElena Ukusova, STRF.ru
Effective peptide compounds are able to prevent such formidable diseases as stroke, Alzheimer's and Parkinson's diseases.
These compounds are being sought by the team of Igor Anatolyevich Grivennikov, Doctor of Biological Sciences, Professor, laureate of the Russian Government Prize, head of the Center for Cellular and Gene Technologies, teacher of the Center for Genomics, Biotechnology and Medicine, head of the Laboratory of Molecular Genetics of Somatic Cells of the Institute of Molecular Genetics of the Russian Academy of Sciences.
The study of the mechanisms of functioning of the cells of the nervous system and their regulating factors makes it possible to better understand the processes of neurodegeneration associated with such widespread diseases as Alzheimer's, Parkinson's, strokes and others. Employees of the Laboratory of Molecular Genetics of Somatic Cells of the Institute of Molecular Genetics of the Russian Academy of Sciences are engaged in the regulation of the functions of the nervous system, studying peptides – molecules formed in our body as a result of certain chemical transformations and capable of influencing various functions of the body. Interest in this topic at the IMG RAS originated many years ago: in the late 70s, at the initiative of Academician Yuri Ovchinnikov of the Russian Academy of Sciences and Academician Igor Ashmarin of the Russian Academy of Medical Sciences, the Neuropeptides program was launched in the Soviet Union, within which active work was carried out to study the effects of these molecules on the nervous system.
Scientific groundworkThe research of scientists on the regulation of the functions of the nervous system attracted the attention of the military: specialists working at airfields, submarines, engaged in missile guidance needed drugs that improve attention, have an anti-stress effect.
Mistakes by operators of strategically important objects lead to serious consequences, and the possibility of additional concentration of attention and memory would be of great importance. In 1978, specialists in the structure and synthesis of peptides of the IMG RAS under the leadership of Vladimir Nezavibatko and Nikolai Myasoedov began work on the creation of a drug with such properties.
It is known that all regulatory peptides degrade quite quickly. And a medical preparation based on these molecules needed to be made stable. Scientists have created several short analogues of regulatory peptides – fragments of adrenocorticotropic hormone, consisting of seven amino acids. Amino acid sequences have been modified so that synthesized peptides decompose in the body more slowly than natural ones. After long–term scientific research and necessary tests, a new drug "Semax" was introduced to the market - a highly effective means of correcting brain functions (including in the treatment of severe strokes), enhancing a number of cognitive processes, and treating ocular nerve dystrophy. Today, there are two dosage forms of this drug of different concentrations on sale: "Semax 0.1%", intended for the correction of various attention and memory disorders, some post-traumatic lesions of the nervous system, and "Semax 1%", intended for the treatment of severe forms of strokes.
Continuing the Battle with StrokeToday, this work continues in the laboratory of molecular genetics of somatic cells in two directions: as studies of somatic cells themselves, as well as stem cells.
– A lot has already been done in the fight against stroke, but it is unrealistic to finally defeat neurodegenerative diseases today, – says Igor Grivennikov. – There are several medications against this disease, but there are absolutely no effective ones. So there is a lot of work here, and we are working on this problem. There is a possibility that we will be able to find more effective peptide compounds that inhibit or prevent various neurodegenerative processes. Our laboratory is studying the mechanisms of action of analogues of regulatory peptides, and analogues not only of adrenocorticotropic hormone, but also of other classes of compounds. We are studying which structures of regulatory peptides can be active, looking for which amino acids should be included in the synthesized structure so that it is protected from the action of proteolytic enzymes – substances that break down proteins.
It was these studies that led in 2008 to the appeal of the laboratory staff to the federal target program "Research and development in priority areas of development of the scientific and technological complex of Russia for 2007-2012".
– We could synthesize and investigate peptides independently, and we did it, but we needed a system that would allow us to quickly select compounds of a certain type of activity, – explains Igor Anatolyevich. – Chemists synthesize a huge number of derivatives of various classes of compounds, not knowing which of them will eventually be able to treat a particular disease. It is clear that the primary selection is carried out on fairly simple systems; you need to try as many compounds as possible to choose promising ones, because when it comes to animal testing, and then on humans, tests will become more expensive, and hundreds or thousands of compounds cannot be brought to clinical trials. Therefore, the money allocated by the Federal Target Program allowed us to develop a fairly simple and effective system for screening compounds for the presence of neuroprotective activity. To do this, we used primary cultures of nerve and glial cells obtained from the mammalian brain (in our case, rats). Using these models, we analyzed which compounds increase the viability of cells in vitro. This made it possible to test a fairly large range of compounds and select promising ones. Next, we studied how the selected compounds affect the expression of certain genes, the growth of processes, axons and dendrites, the division of nerve cells, and so on. If in the course of these fundamental studies we noted that the tested compound also affects protein molecules, causing the expression of certain genes, we talked about this compound as promising in terms of further development of a drug based on it that can slow down neurodegenerative processes in a number of pathologies of the nervous system.
Our project within the framework of the federal target program of Rosnauki was small, with funding of only 7.8 million rubles for two years. We worked together with colleagues from the Faculty of Fundamental Medicine of the Lomonosov Moscow State University (a team led by Professor Vladimir Koshelev) and the Kazan Institute of Physics and Technology (a team led by Professor Khalil Gainutdinov). The project ends on November 30, and I believe that it was a success on the whole. As a result of our work, we received two patents: "A method for screening pharmacological compounds for neuroprotective activity" and "A method for evaluating the expression of neurotrophin genes".
Are nerve cells recovering?
The second direction, which the employees of the laboratory of molecular genetics of somatic cells are engaged in, is related to the study of the differentiation of embryonic stem cells. While research is being conducted on a mouse cell model, not a human one, nevertheless, it fully allows us to trace the variants of differentiation of mammalian cells.
– Embryonic stem cells are able to multiply indefinitely in the laboratory, while they do not lose the ability to differentiate into all organs and tissues of the body. If we talk about a person, then, as you know, by launching embryonic stem cells into a certain type of differentiation, they can be used for transplantation into affected organs. If the cells take root, there is a regenerative process. It can be expected that the affected or lost functions will somehow restore cells differentiated into neurons, although today everything is ambiguous. Despite the fact that in animal models we observe partial restoration of functions disrupted by strokes, the problem is very complicated, because unlike other organs – the liver, kidneys and even the heart – the brain cannot be transplanted: it will be another person. We can only try to fix the affected areas. When transplanting cells, it is important not only that they remain viable, but also establish the right connections with existing neurons. Only then can we talk about restoring brain functions. This is what our research is aimed at.
Quality of lifeFrom the topic of scientific research, we turn to the question of the quality of life.
The difference in the approaches of scientists of the Institute of Molecular Genetics of the Russian Academy of Sciences and foreign laboratories to the modification of analogues of regulatory peptides was outlined in the late 70s, at the very beginning of work on this problem.
– On the structures consisting of natural amino acids, both we and the West began to work at the same time, – says Igor Anatolyevich. – The school of Dutch scientists led by De Vida, who also dealt with analogues of regulatory peptides, was especially strong. Which way did the Europeans go? They also modified the sequence of these molecules, but introduced D-amino acids – compounds that are not found in the human body. Or specific substituents such as fatty acid residues, carbon chains of various lengths were used. This could lead to undesirable side effects, including the development of cancer. Our institute used only natural L-amino acids. With this approach, nothing foreign was introduced into the body, and when the medicine disintegrated, only ordinary amino acids remained, of which our body consists to a large extent. This is an ideal approach, which, as they like to say now, provides the right quality of life. It was already developing in full swing in our country, although today it is called differently and it is believed that such principles of work came from the West. In reality, Western civilization is very closed, it wants to take everything from all over the world, and in particular from us, but listens only to itself. She is, so to speak, brazen – in a good sense of the word.
Intellectuals or agrarians?
We are developing the theme of "Western arrogance"– They are engaged in expansion, – says Igor Anatolyevich.
– If people are told every day that they need to eat Snickers, they will eat it. What do we have on TV screens? Can you count, for example, how many percent of Western programs and films are shown to us? I once asked. Up to thirty percent of Western (in particular, American) films. I don't think there can be thirty percent of Russian broadcasts on American television. It is necessary to understand the reality: there is no cooperation between us and the West, which is often talked about; there is the use of our resources, any – natural, intellectual, other. They are not doing anything illegal, they are just pursuing their goals, and we should also pursue our own. Why are we trudging at the end, and will we always trudge? Because we don't produce a final product that can be consumed and sold.
To the question "What prevents us from producing the final product, and in what area could we succeed in this today?" Professor Grivennikov answers:
– It seems to me that we need to start with what has been done in Europe and America for a long time: with agriculture. Maybe these words will outrage someone (supposedly we don't do anything else), but when a person is full, he stops thinking about how to feed his family, and thinks about how to develop something else. In the meantime, in our conditions, we need to start again in the same circle. Moreover, the only place where it is now possible to establish, firstly, environmentally friendly production, and secondly, without genetically modified additives, is here.
This opinion, as it turned out, does not contradict the hope of seeing Russia as a strong intellectual country. According to Igor Grivennikov, a state order is needed for research similar to those conducted by his laboratory.
– There are figures showing that the annual global losses from various neurodegenerative diseases, stress, schizophrenia and other diseases of the nervous system amount to hundreds of billions of dollars. According to statistics, for example, about five hundred thousand strokes occur in Russia per year. A person became incapacitated, did not go to work – this is a big loss for the state. That is, we are talking about socially significant work, we have a respectable state task: to help people be healthy. Therefore, for research in such areas as oncology, strokes, neurodegenerative or cardiovascular diseases, there should be government orders. If a scientist always needs to look for money, it means that he degrades as a scientist and ceases to fully think about the experiment. The Ministry of Education and Science to a certain extent provides the order, but requires a more applied output. This is the right direction, but fundamental research also needs to be developed and supported.
Portal "Eternal youth" http://vechnayamolodost.ru09.11.2009