Heterocycles against stroke
The new compound will help in recovery even a day after a stroke
RNF Press Service
Russian scientists have determined that some derivatives of N-heterocycles — rings of carbon and nitrogen atoms with additional chemical groups "hung" on them help to reduce inflammation in the brain during ischemic stroke. Experiments have shown that such compounds contribute to the resolution of pathological inflammation and allow rats to recover faster, even if treatment began only a day later. The results give hope that the proposed substances will help people after a stroke, especially when the critical "golden hours" for first aid are missed. The study, supported by a grant from the Russian Science Foundation (RNF), is published in the journal Molecules (Borozdenko et al., The Effect of a New N-hetero Cycle Derivative on Behavior and Inflammation against the Background of Ischemic Stroke).
According to the World Health Organization, ischemic stroke, which is also called a brain infarction, is one of the most common causes of death and disability. The disease occurs due to disorders of the blood supply to the brain: the formation of blood clots, the expansion of the lumen of the arteries, high blood pressure and, as a consequence, insufficient oxygen supply to the tissues. Depending on which part of the brain and how badly affected, there may be memory, mobility and speech disorders.
In case of tissue damage, acute inflammation occurs, normally stimulating recovery: due to the release of special signaling molecules, various "helpers" are attracted to the site of the defect, and after the inflammatory reaction is resolved, the tissue is restored to one degree or another. In the case of stroke, an important role is played by microglia — "nurse" cells that provide communication between neurons and their work, are involved in the development of the nervous system, and in case of any damage, they are able to perform the function of macrophages - to absorb potentially dangerous objects. At the same time, their excessive activity leads to chronic inflammation and diseases. Astrocytes are also involved in the response to post—stroke damage - they are also a kind of "babysitters" for neurons, ensuring the constancy of their environment, and in case of serious damage, they can even turn into their "wards". After a stroke, astrocytes can support chronic inflammation, which interferes with normal regeneration and contributes to the progressive death of nerve cells. Often a breakdown in one of the links leads to violations of the entire chain, and therefore it is important to reduce the excessive activity of defenders. This way you can help patients recover faster and avoid disability.
Earlier studies have shown that racetam-class chemicals accelerate the rehabilitation process after a stroke. For simplicity, these substances can be considered as derivatives of various N-heterocycles (nitrogen-carbon rings with side groupings). Scientists from the Russian National Research Medical University named after N. I. Pirogov (Moscow) and the National Medical Research Center of Psychiatry and Narcology named after V. P. Serbsky (Moscow) decided to find out whether it is possible to create a more effective medicine based on them. The authors synthesized a new compound with a long alkyl "tail" containing a polar group at the end, and conducted its preclinical tests. The alkyl "tail" not only has biological activity itself, but also increases the solubility of the substance, which also improves its assimilation.
Based on data obtained from a series of experiments (including on animals), the researchers suggested that the proposed modification would create a drug for faster recovery after a stroke. Previously, scientists have already considered the effect of inserting a fragment of taurine potassium salt (taurine is also used in therapy after brain damage). It has led to more effective recovery of motor functions and improved cognitive abilities in animals who have suffered a stroke.
During the experiment, the hypothesis was tested on live cells and laboratory rats. Lipopolysaccharide was added to the macrophage culture, which is part of the cell wall of gram—negative bacteria, and therefore is recognized by the body as a foreign agent - thus inflammation can be provoked. Then the authors added a new substance to the cells and analyzed the activity of genes and molecules responsible for the onset, development and resolution of this protective reaction. They found out that the drug changes the profiles of special cytokine signaling molecules. For example, its addition led to a tenfold increase in the content of interleukin-2 and interleukin-4, which suppress the excessive activity of immune cells, leading to the destruction of nerve tissues.
Next, the researchers studied the effect of the substance on laboratory rats who had suffered an ischemic stroke, and injected them with the drug a day after surgery. The results showed that the animals on therapy showed higher research and motor activity in behavioral tests than those who did not receive the drug.
The researchers estimated the number of astrocytes in different areas of the brain on immunohistochemical preparations of brain tissues. After a stroke, they can form a cluster, the so—called glial scar: on the one hand, it separates the affected area, preventing it from spreading, and on the other hand, it restricts access to those molecules and cells that could help recovery. That is why a small number of astrocytes at the site of a post—stroke defect is a good sign, and the drug has reduced their number by almost half. Perhaps this explains the detected behavioral differences in rats against the background of taking a new drug.
"There is a rule of the so—called "golden hours" - it is necessary to help the patient within six hours after a stroke, so that the consequences are minimal. In our country, there are a large number of localities remote from district centers, so it is not always possible to observe this rule — it was not by chance that we waited for a whole day before injecting medicine to our test subjects. The results obtained have shown the prospects for further research of N-heterocycle derivatives to create effective domestic drugs for the recovery of patients after a stroke," says Vadim Negrebetsky, Doctor of Chemical Sciences, Professor of the Russian Academy of Sciences, Director of the Research and Testing Center of the N. I. Pirogov RNIMU.
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