The best antioxidants. Review of neuroprotectors: frequently prescribed and most common Antioxidant drugs in neurology list

Should neuroprotective drugs be used in clinical practice?

Kuznetsov A.N. National Medical and Surgical Center named after N.I. Pirogov, Moscow

The debate regarding the appropriateness of neuroprotective therapy is currently one of the most heated. Several dozen substances have demonstrated a neuroprotective effect in experimental studies, but none of them have confirmed their effectiveness and safety in clinical randomized controlled trials (RCTs). In this regard, in all modern clinical guidelines for the treatment of acute neurological diseases, neuroprotective therapy is not recommended for use. On the other hand, based on empirical experience, as well as within the framework of their own protocols in many medical institutions, and in Russia - in the vast majority of them, drugs with supposed neuroprotective activity are widely used. Why are neuroprotective agents that have proven their effectiveness in experimental studies not subsequently confirmed in clinical trials? Most experts agree that the reason is significant design flaws in the RCTs conducted:

• selection of an inadequate “therapeutic window”;
• lack of targeted patient selection;
• use of obviously insufficient dosages of the drug;
• selecting endpoints with low sensitivity and overestimating the magnitude of the possible effect.

Although experimental studies have used neuroprotective agents immediately after ischemic or traumatic injury (usually within 90 minutes), RCTs have enrolled patients within 24 to 48 hours of the acute event. In addition, when selecting patients with stroke, there was no upper and lower threshold for stroke severity, the subtype of ischemic stroke was not taken into account, and the presence or absence of recanalization of the affected artery was not taken into account, while in experimental studies, in almost all cases, neuroprotective therapy was carried out in conditions restored perfusion. This approach to selecting patients and choosing a “therapeutic window” was dictated by the desire to include as many patients as possible in the study, with deliberate disregard for extrapolating the results of experimental studies to the clinical situation, which ultimately led to negative results from RCTs. The use of dosages of drugs in RCTs that were much lower than in the experiment was aimed at minimizing side effects. Treatment efficacy was assessed using clinical endpoints, scales with insufficient clinical sensitivity (eg, Glasgow Coma Scale) were used, and the study design was modeled for a clinically significant effect. Differences of about 10-15% were assumed for the primary endpoints, that is, the effect obtained for thrombolytic therapy within a 3-hour “therapeutic window”, which was obviously an unrealistic result. Statistical calculations show that, using a single neuroprotective agent and clinical endpoints, an effect of 3-5% can be calculated by enrolling 3000-4000 patients using a 3-hour “therapeutic window” and using dosages similar to the experimental ones. An effect of 1-2% is realistically achievable. In any case, these should be large or very large studies in terms of the number of patients included. But in this case the question arises: who will be able to pay for such research? And even if an effect of 1-2% is achieved: who will pay for an expensive drug with minimal effect? Possible ways to overcome this situation are:

• use of surrogate endpoints;
• the use of several neuroprotective drugs with different points of application;
• use of combined thrombolytic and neuroprotective therapy.

Surrogate, that is, non-clinical, endpoints have recently become more and more widely used in RCTs. The most commonly used results are magnetic resonance neuroimaging, which can monitor the extent of damage and serve as a predictor of recovery. But the most promising seems to be the use of combined thrombolytic and neuroprotective therapy in the case of ischemic stroke. Recanalization of an occluded artery will ensure maximum delivery of a neuroprotective agent to the site of damage and, thus, approach the conditions for conducting experimental studies. On the other hand, neuroprotective therapy will help to expand the “therapeutic window” for thrombolysis, as well as reduce reperfusion injury. It should be noted that the experimental studies also had significant shortcomings that contributed to the negative results of the RCT:

• the “therapeutic window” was not precisely defined;
• the dose range that ensures maximum effectiveness and safety of the substance has not been precisely determined;
• the set of markers for the effectiveness of the substance has not been precisely defined.

The main groups of neuroprotective drugs are:

• calcium channel blockers;
• NMDA and AMPA receptor antagonists;
• glutamate release inhibitors;
• GABA receptor agonists;
• adenosine receptor agonists;
• membrane-stabilizing drugs;
• neurotrophic (growth) factors;
• nitric oxide inhibitors;
• antioxidants;
• anti-inflammatory drugs;
• other drugs.

The action of so-called calcium antagonists or calcium channel blockers (nimodipine (NimotopR) is the most well known in Russia) is aimed at one of the key mechanisms of cell death, both through the mechanism of necrosis and the mechanism of apoptosis - excessive calcium entry into the cell. Drugs in this group block voltage-gated calcium channels, but do not affect calcium channels controlled through receptors (NMDA, AMPA), so their effectiveness is limited. In addition, calcium antagonists have significant side effects, in particular vasodepressor effects. In this regard, numerous RCTs have had negative results. The effectiveness of nimodipine has been demonstrated only in relation to the prevention of vasospasm in subarachnoid hemorrhage. NMDA and AMPA receptor antagonists block receptor-gated calcium channels and thus interrupt the basal flow of calcium into the cell. Receptor activation occurs due to the release of excitotoxic amino acids (mainly glutamate). Substances with high affinity for NMDA receptors (for example, MK-801) showed in RCTs serious psychotomimetic and neurotoxic side effects, since they caused a complete blockade of the receptors, inhibiting their normal physiological activity. Promising drugs are drugs with low affinity for NMDA receptors (memantine, amantadine sulfate, magnesium sulfate and others). An additional important mechanism of action of memantine demonstrated experimentally is the inhibition of hyperphosphorylation of the tau protein and thus the process of neurodegeneration. Some other excitotoxic amino acids, in particular glycine, also cause activation of NMDA receptors, so glycine antagonists have been studied in RCTs, but have not yet confirmed their effectiveness. Currently, RCTs are ongoing to study the effectiveness and safety of AMPA receptor antagonists. The experiment demonstrated the effectiveness of substances that prevent the release of glutamate from presynaptic terminals (lubeluzole), but RCTs have not confirmed their effectiveness. RCTs are ongoing to study the effectiveness of new classes of neuroprotectors - GABA and adenosine receptor antagonists. Among drugs with membrane-stabilizing effects, the effectiveness and safety of cytidine diphosphocholine (cyticholine) is currently being studied in RCTs. A drug used in Russia with a similar mechanism of action is choline alphoscerate (GliatalinR). It should be noted that the effectiveness and safety of this drug have not been studied in RCTs. Great hopes are associated with the use of neurotrophic (growth) factors. One such drug, fibroblast growth factor, was studied in RCTs, but the results were negative. At the same time, the results of experimental studies show the effectiveness of such substances (in particular, the drug CerebrolysinR) in blocking both necrotic and apoptotic neuronal death by inhibiting the calcium-dependent protease calpain. Clinical studies of the neuroprotective activity of antioxidants are ongoing. RCTs of the drug ebselen are currently being conducted. In Russia, antioxidant drugs are used quite widely (MexidolR, CarnitineR and others), but their effectiveness and safety have not been studied in RCTs. Currently, an RCT study of the neuroprotective activity of piracetam, a drug that has been widely used in Russia for a long time, is being conducted. Nitric oxide inhibitors and anti-inflammatory drugs have not yet demonstrated their effectiveness and safety in RCTs. There is no doubt that new RCTs, the design of which will be carried out taking into account previously existing shortcomings, as well as the emergence of new, safer neuroprotective agents, will make it possible to prove the clinical effectiveness of neuroprotection. In this case, the high expectations that the medical community has regarding neuroprotective therapy, as well as the high costs that pharmaceutical companies incurred when creating drugs, will be justified. However, this takes time, so what to do now? The way out of this situation is the use of drugs with supposed neuroprotective activity and known symptomatic effects. Such drugs can also be considered as means that increase the effectiveness of early rehabilitation of patients with severe acute neurological pathology. Early rehabilitation, as is known, is one of the integral components of complex treatment of such patients. Among the drugs used in Russia:

• amantadine sulfate (PC-MerzR) has demonstrated its effectiveness in restoring motor functions; has an awakening effect;
• memantine (AkatinolR) has been shown to improve cognitive function in RCTs;
• CerebrolysinR promotes the restoration of cognitive functions;
• choline alfoscerate (GliatilinR) has an awakening effect;
• piracetam (PiracetamR, NootropilR, LucetamR) helps improve cognitive functions and has also shown its effectiveness in restoring impaired speech.

It should be noted that one of the areas where neuroprotective drugs can demonstrate their effectiveness is the prevention of neurological complications during surgical interventions that are aggressive to the nervous system (surgeries and manipulations on the heart and cerebral vessels, neurosurgical interventions). Today, when we are on the verge of creating Russian recommendations for the treatment of acute neurological diseases, there is a need to invite Russian specialists to a broad discussion regarding the advisability of using neuroprotective drugs.

Sources:

1. Fisher M., Brott T. Emerging therapies for acute ischemic stroke: New therapies on trial // Stroke.- 2003.- Vol. 34.- P. 359-361.
2. Grotta J. Neuroprotection is unlikely to be effective in humans using current trial designs // Stroke.- 2002.- Vol. 33.- P. 306-307.
3. Lees K. Neuroprotection is unlikely to be effective in humans using current trial designs: An opposing view // Stroke.- 2002.- Vol. 33.- P. 308-309.
4. Lees K., Hankey G., Hacke W. Design of future acute-stroke treatment trials // Lancet Neurol.- 2003.- Vol.2.- P. 54-61.
5. Tolias C., Bullock R. Critical appraisal of neuroprotection trials in head injury: What have we learned? // The Journal of the American Society for Experimental NeuroTherapeutics.- 2004.- Vol. 1.- P. 71-79.
6. Adams H., del Zoppo G., von Kummer R. Management of stroke: A practical guide for the prevention, evaluation, and treatment of acute stroke.- Professional Communications Inc., 2002.- 303 p.
7. Gusev E.I., Skvortsova V.I. Cerebral ischemia.- M.: Medicine, 2001.- 327 p.
8. Lipton S. Failures and successes of NMDA receptor antagonists: Molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults // The Journal of the American Society for Experimental NeuroTherapeutics.- 2004.- Vol. 1.- P. 101-110.
9. Li L., Sengupta A., Haque N., Grundke-Iqbal I., Iqbal K. Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration // FEBS Letters.- 2004.- Vol. 566.- P. 261-269.
10. Odinak M.M., Voznyuk I.A., Yanishevsky S.N. Cerebral ischemia: Neuroprotective therapy: Differentiated approach. - St. Petersburg, 2002. - 77 p.
11. Wronski R., Tompa P., Hutter-Paier B., Crailsheim K., Friedrich P., Windisch M. Inhibitory effect of a brain derived peptide preparation on the Ca-dependent protease, calpain // J. Neural. Transm.- 2000.- Vol. 107.- P. 145-157.

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Many people, especially those who often have to be treated in hospitals for chronic diseases, have noticed that, in addition to the main treatment, antihypoxic drugs and antioxidants are added, which at first glance are not directly related to their illness. And upon discharge, it is often recommended to purchase vitamins and antioxidant complexes from the pharmacy that will help the patient cope with his illness. Antioxidants are often recommended for pregnant women, teenagers, people with weakened immune systems, or people working in unfavorable or extreme conditions.

Hypoxic syndrome

A pathological process such as hypoxic syndrome, which occurs at the cellular level, although rarely found in its pure form, nevertheless often accompanies (complicates) many already serious conditions.

Insufficient oxygen supply to cells:

• Disturbs the energy balance;
• Activates free radical oxidation;
• Damages membranes of fats and proteins.

hypoxia using the example of a violation of the blood supply to the brain, the brain reacts most noticeably to a lack of oxygen

To restore optimal energy production by reducing oxygen consumption by tissues and normalizing its utilization, since the second half of the 20th century, drugs called antihypoxants, which are primarily indicated in the following cases:

1. Shock conditions;
2. Insufficiency of cardiac activity;
3. Collapse, coma;
4. During gestation and during childbirth - fetal hypoxia;
5. Anemic syndrome;
6. Severe poisoning and withdrawal symptoms;
7. Extensive surgical operations.

Thus, antihypoxants– medicinal substances that, according to their characteristics, have the ability to reduce or completely eliminate the symptoms of hypoxia.

Antihypoxants

Patients call many antihypoxants “vascular drugs” or drugs for the treatment of heart disease, since they are recognized as the best in the treatment of pathology of the cardiovascular system. In principle, all medications (vascular) also perform an antihypoxic function. For example, any person who is affected by problems with cerebral circulation or cardiac activity has probably more than once received medications such as:

• Vinpocetine And Cavinton, which are the same thing - preparations of plant origin (derivatives of the main vinca alkaloid - vincamine), they are considered the best in their group, because do not have a large set of contraindications and at the same time significantly improve blood circulation and metabolism in brain tissue;
• Piracetam– improves cerebral blood flow and metabolic processes in brain tissue, protects brain neurons from the damaging effects of hypoxia, has a positive effect on memory and attention, helps in learning, is used in neurology, psychiatry, addiction medicine, and pediatrics;
• Riboxin– normalizes metabolic processes in the heart muscle and reduces the manifestations of oxygen starvation of tissues;
• Mildronate (Meldonium)– is an analogue of a component present in every living cell of the human body (γ-butyrobetaine), normalizes metabolism and energy supply to tissues subjected to oxygen starvation. Recently, in the sports community, the drug was recognized as doping and became a reason for the disqualification of some talented Russian athletes;
• Cytochrome C– indicated for use in newborns (as a result of asphyxia), as well as for heart failure, bronchial asthma, (coronary heart disease);
• Inosine– activates enzymes of the tricarboxylic acid cycle (TCA cycle, Krebs cycle), maintains energy balance, has a positive effect on metabolic processes in the myocardium, increases the body’s endurance, stimulates the immune response;
• Trimetazidine– has a positive effect on cardiac muscle cells, optimizes their metabolic and functional abilities, helps normalize blood pressure, increases tolerance to stress (mental and physical);
• Fezam– a combination drug that provides a powerful antihypoxic effect.

Of course, the list of drugs is not limited to the above-mentioned drugs; it is quite wide, and, moreover, many of them have several dosage forms. For example, Vinpocetine is available in tablets (Vinpocetine, Vinpocetine forte, Vinpocetine-SAR), aerosols (Vinpocetine-AKOS), concentrates for the preparation of infusion solutions (Vinpocetine-AKOS, Vinpocetine-SAR, Vinpocetine-ESKOM) or Riboxin, produced in tablets (Riboxin -Ferein, Riboxin-Lect) and solutions for intravenous administration (Riboxin Bufus).

Medications with a pharmacological “antihypoxic” effect include Semax nasal drops, which, in addition to antihypoxic, provide an antioxidant and angioprotective effect, as well as Solcoseryl gel and ointment, which have a regenerating and wound-healing effect.

Meanwhile, many of the given list of drugs, although designated in some reference books as antihypoxic drugs, are not without antioxidant action, so do not be surprised if in other sources they are classified as antioxidants and antihypoxants.

Free radicals

People are now literate and patients have heard that there are certain free radicals that are very dangerous to human health and can trigger any pathological process. Free radicals are unstable particles (unstable), endowed with a free (unpaired) electron, the pair of which these particles strive to take from normal molecules, damaging a healthy cell. By giving away “its own,” the cell suffers and loses its ability to function physiologically. The saddest thing is that in such situations one thing clings to another, initiating a chain reaction that the body itself may not be able to stop due to the loss of protective forces.

However, it should be noted that a certain, very small amount of such radicals must be present in the body and perform a specific task, for example: helping to fight pathogens or preventing the formation of tumor cells.

Free radicals appear during biochemical reactions of food breakdown and oxygen utilization. The accumulation of excess free radicals leads to:

1. Cell damage and death;
2. Loss of immunity;
3. Premature aging of the body;
4. The occurrence of harmful mutations;
5. Development of the oncological process.

In conditions of weakened immune defense, free radicals begin to become especially active, sometimes causing irreparable harm to organs and systems.

One way to combat excess free radicals is to use antioxidants, just having in their molecule the missing free electron, by giving which these drugs neutralize the harmful effects of these unstable particles.

the antioxidant donates an electron to the free radical and neutralizes its action, preventing it from “taking” electrons from the body’s cells and destroying them

Antioxidants

The best antioxidants are natural, that is, those that contain vitamins and are easily found in available foods:

• Alpha tocopherol acetate – vitamin E(peanuts, corn, peas, asparagus);
• Ascorbic acid – vitamin C(citrus fruits, white cabbage, especially pickled cabbage, cranberries, sweet bell pepper);
• Beta-carotene – provitamin A(carrots, broccoli, spinach).

It is often recommended as an antioxidant agent that prevents aging of the body. selenium, which is found in garlic, pistachios, coconut. Selenium is one of the main natural antioxidants. It stimulates the immune system, actively fights free radicals, inhibits inflammatory reactions caused by viral and bacterial infections, prevents the development of tumor diseases, and participates in metabolic processes. Selenium solves many more useful problems, but it should be remembered that when used unreasonably by humans (use in large doses or intake of selenium from outside from other sources) such a valuable chemical element may become dangerous.

Picture: antioxidants in foods

In the pharmacy you can always see ready-made drugs labeled as antioxidant (multivitamin) complexes (for example, the widespread - Antioxicaps). In almost all cases, these products contain vitamins of various groups (E, A, C) and individual chemical elements: selenium (Antioxycaps with selenium), zinc (Antioxycaps with zinc), iron (Antioxycaps with iron), iodine (Antioxycaps with iodine).

There is no clear boundary between them

Obviously, antioxidants and antihypoxants can be quite difficult to differentiate, because they complement each other in the treatment of many pathological conditions. These drugs have similar goals: to help the body cope in critical situations, as well as prevent the development of undesirable consequences resulting from damage and death of cells (even if, at first glance, nothing threatens life yet), and together they are strength. By blocking free radical reactions, preventing fat peroxidation on cell membranes, ensuring normal tissue respiration, these drugs are quite effective preventive and at the same time independent medicines in relation to:

1. , myocardial infarction;
2. both ischemic and hemorrhagic types;
3. Cardialgia caused by hormonal imbalance;
4. Diseases associated with circulatory disorders in a particular region;
5. Vascular complications of diabetes mellitus;
6. Septic conditions;
7. Extensive burns, injuries, massive blood loss;
8. Professional activities related to extreme sports;
9. Chronic diseases of the respiratory system (bronchi, lungs).

In addition, antihypoxants and antioxidants, being part of any complex therapy, maintain cellular and humoral immunity at the proper level, preventing its decline and loss of the body’s defenses. In general, almost universal medicines that are good for all occasions.

Antioxidants, along with antihypoxants, take an active part in combating the consequences of hypoxia, and antihypoxants also do not remain aloof from free radical processes, therefore many drugs with such characteristics are classified as a general pharmaceutical group “Antihypoxic and antioxidant drugs”, for example:

• A common and quite popular drug Actovegin– it improves the nutrition and respiration of tissues, accelerates metabolic processes in them and promotes their regeneration;
• Sodium polydihydroxyphenylene thiosulfonate– has a pronounced antihypoxic effect, supporting optimal aerobic processes and tissue respiration (in cell mitochondria), increases resistance to psycho-emotional and physical stress;
• Ethylthiobenzimidazole hydrobromide– helps organs and tissues “survive” in conditions of oxygen starvation, has anti-asthenic, psycho- and immunostimulating effects, increases ability to work, attention, endurance;
• Emoxipin– inhibits free radical reactions of cell membranes, and thus protects them, activates antioxidant enzymes, and has a pronounced antihypoxic effect;
• Ethylmethylhydroxypyridine succinate– blocks free radical oxidation, protects cell membranes from damage and, at the same time, has a nootropic and pronounced antihypoxic effect;
• Probucol – having hypocholesterolemic properties, normalizes lipid metabolism, and at the same time “works” as an antioxidant.

The drugs that we described above can also be included in this group, that is, it is difficult to distinguish between a “pure antioxidant” or a “pure antihypoxant”.

One of the presenters will answer your question.

Currently answering questions: A. Olesya Valerievna, candidate of medical sciences, teacher at a medical university

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27.03.2015

Based on the results of the II Russian International Congress “Cerebrovascular Pathology and Stroke” (September 17-20, St. Petersburg, Russia)

The role of disturbances in the redox homeostasis of blood and nervous tissue in the pathogenesis of ischemic pathology of the brain and other neurological diseases is very often underestimated by practitioners. At the same time, interest in finding optimal ways of drug correction of oxidative stress does not fade among experimental and clinical researchers.
The 3rd Russian International Congress “Cerebrovascular Pathology and Stroke”, which took place on September 17-20 in St. Petersburg, confirmed the relevance of the topic of antioxidant neuroprotection.
A large number of reports by authoritative Russian scientists were devoted to it, the most interesting of which we present to your attention.

Doctor of Medical Sciences, Professor of the Department of Neurology and Neurosurgery of the Russian State Medical University Alla Borisovna Gekht (Moscow) in her report reviewed the experimental and clinical prerequisites for the use of one of the most studied antioxidants - α-lipoic (thioctic) acid - in the recovery period of cerebral stroke.
– Under physiological conditions, free radical processes are under the control of antioxidant systems and perform a number of vital functions: they participate in the regulation of vascular tone, cell growth, secretion of neurotransmitters, repair of nerve fibers, formation and conduction of nerve impulses, and are part of the memory mechanism and inflammatory response. Under physiological conditions, the process of free radical oxidation of lipids occurs at a low steady-state level, but the picture changes dramatically with excessive production of endogenous or supply of exogenous reactive oxygen species.
Recent studies in the field of pathobiochemistry of acute cerebrovascular accidents have made it possible to identify the main mechanisms of the neurotoxic action of free radicals formed under conditions of underoxidation of glucose during ischemia. These mechanisms are realized through complex cascades of mutually mediated reactions, leading to the acceleration of lipid peroxidation (LPO) of cell membranes and the formation of dysfunctional proteins. The consequences of hyperactivation of lipid peroxidation for nervous tissue include destruction of lysosomes, damage to cytoplasmic membranes, disruption of neurotransmission and, ultimately, death of neurons.
The destructive effects of free radical oxidation are countered by antioxidant defense mechanisms, each of which deserves special attention not only from a biochemist, but also from a clinician. The antioxidant protection system of body tissues can be divided into two levels – physiological and biochemical. The first includes mechanisms for regulating the flow of oxygen into the cell, which are implemented by reducing microcirculation in tissues with an increase in the partial pressure of oxygen in arterial blood (hyperoxic vasospasm). The biochemical level is realized by antioxidant factors themselves, which regulate the production of reactive oxygen species or neutralize them in cells, intercellular fluid and blood.
By origin, antioxidant factors can be enzymes (superoxide dismutase, catalase, glutathione peroxidase), proteins (ferritin, transferrin, ceruloplasmin, albumin), low molecular weight compounds (vitamins A, C, E, ubiquinone, carotenoids, acetylcysteine, α-lipoic acid, etc. .). The mechanisms for regulating oxidative activity also differ. Thus, superoxide dismutase inactivates the aggressive superoxide anion due to the presence in its structure of metals with variable valency - zinc, magnesium, copper. Catalase prevents the accumulation of hydrogen peroxide (H 2 O 2) in cells, which is formed during the aerobic oxidation of reduced flavoproteins. Enzymes of the glutathione system (glutathione peroxidase, -reductase, -transferase) are capable of decomposing lipid hydroperoxides and H 2 O 2, reducing hydroperoxides, and replenishing the pool of reduced glutathione.
Today we will talk about one of the most important components of the body’s antioxidant defense – α-lipoic acid. Its antioxidant properties and ability to modulate the work of other antioxidant systems have been known for a long time. Various studies have shown that α-lipoic acid indirectly restores vitamins C and E (Lakatos B. et al., 1999), increases the level of intracellular glutathione (Busse E., Zimmer G. and et al., 1992), as well as coenzyme Q 10 (Kagan V. and et al., 1990), interacts with glutathione, α-tocopherol, inhibits the acute phase of inflammation and reduces the manifestations of pain (Weicher C.H., Ulrich H., 1989). Experiments on animals show how important the level of endogenous production of this substance is for the development of the nervous tissue of the embryo. A study by Yi and Maeda (2005) demonstrated that mice heterozygous for the gene lacking α-lipoic acid synthase had significantly reduced glutathione levels in red blood cells (a sign of weakened endogenous antioxidant defenses), and homozygous mice died on the 9th day of embryogenesis.
The possibilities of using α-lipoic acid drugs in the treatment of ischemic brain lesions have been well established in experimental models. A recently completed experiment by M. Wayne et al. confirmed the ability of this antioxidant to reduce infarct volume and improve neurological functioning in mice subjected to transient focal ischemia in the middle cerebral artery territory.
In the work of O. Gonzalez-Perez et al. (2002) α-lipoic acid in combination with vitamin E was used in two therapeutic regimens - prophylactic administration and intensive treatment in a model of thromboembolic cerebral infarction in rats. The effect of antioxidants on neurological deficits, glial reactivity and neuronal remodeling in the ischemic penumbra zone was studied. The results of the experiment demonstrated the undeniable advantage of the preventive administration of the studied antioxidants in terms of the degree of improvement in neurological functions, and the suppression of astrocytic and microglial reactivity was noted both with the prophylactic use of α-lipoic acid with vitamin E, and in the intensive therapy of already developed ischemic brain damage.
After encouraging experimental results opened the way for α-lipoic acid to the clinic, many studies were conducted to study the capabilities of this antioxidant in the treatment of acute cerebrovascular accidents. At our clinic, α-lipoic acid in the form of the drug Berlition produced by Berlin Chemie was studied as an antioxidant for the adjuvant treatment of patients in the recovery period of stroke.
For this category of patients, Berlition was prescribed for 16 weeks orally at a dose of 300 mg 2 times a day or intravenously at a daily dose of 600 mg, followed by switching to oral administration. For placebo control, a group of patients who did not receive antioxidant therapy was recruited. The patients' condition was assessed using the B. Lindmark scale, which fairly fully reflects the degree of neurological dysfunction in stroke. As a result, in patients who received Berlition along with traditional treatment for stroke, after 16 weeks of observation, the increase in points on the rating scale was significantly and significantly higher compared to the placebo group, and the result was comparable in the groups of oral and combined use of the drug, which is very important, since as in real clinical practice, the convenience of the therapeutic regimen plays a significant role. Pharmacoeconomic analysis of the study demonstrated that the cost of one point increase on the Lindmark B scale was significantly lower in the groups of patients receiving Berlition.
The possibility of using drugs with antioxidant properties in the combination of cerebral stroke and diabetes mellitus (DM) deserves special attention. It is known that diabetes significantly complicates the course of stroke. There is also no doubt about the need to prescribe α-lipoic acid drugs for diabetic neuropathy. A reliable evidence base regarding the effect of α-lipoic acid on the course of stroke in patients with diabetes has not been accumulated, but today, undoubtedly, this is one of the promising areas of scientific research in the field of practical application of antioxidant therapy.

Doctor of Medical Sciences, Professor Ella Yurievna Solovyova (Department of Neurology, Faculty of Advanced Training for Physicians, Russian State Medical University, Moscow) presented a report on the topic of correction of oxidative stress in patients with chronic cerebral ischemia.
– An imbalance between the production of free radicals and antioxidant control mechanisms is usually referred to as “oxidative stress.” The list of pathological conditions and diseases in which oxidative stress of the vascular endothelium and nervous tissue plays a key role includes hypoxia, inflammation, atherosclerosis, arterial hypertension, vascular dementia, diabetes mellitus, Alzheimer's disease, parkinsonism and even neuroses.
There are several known reasons for the high sensitivity of brain tissue to oxidative stress. Making up only 2% of the total body weight, the brain utilizes 20-25% of the oxygen the body receives. Conversion of just 0.1% of this amount into superoxide anion turns out to be extremely toxic to neurons. The second reason is the high content of polyunsaturated fatty acids in the brain tissue, a substrate for LPO. There are 1.5 times more phospholipids in the brain than in the liver, and 3-4 times more than in the heart.
The LPO reactions occurring in the brain and other tissues are not fundamentally different from each other, but their intensity in nervous tissue is much higher than in any other tissue. In addition, brain tissue contains a high concentration of metal ions with variable valency, which are necessary for the functioning of enzymes and dopamine receptors. And all this along with an experimentally proven low level of activity of antioxidant factors. Thus, according to Halliwell and Getteridge (1999), the activity of glutathione peroxidase in brain tissue is reduced by more than 2 times, and catalase by hundreds of times compared to the liver.
Chronic cerebral ischemia should be considered if regional cerebral blood flow decreases from 55 ml per 100 g of brain matter per minute (physiological norm) to 45-30 ml. Conventionally, there are two ways of LPO activation in the pathogenesis of chronic cerebrovascular diseases. The first is associated with the actual ischemia of brain tissue and microcirculation disorders, and the second is caused by damage to the cardiovascular system as a whole with atherosclerosis and arterial hypertension, which almost always accompany (and are important risk factors for) cerebrovascular pathology.
Most authors distinguish three stages of LPO activation in chronic cerebral ischemia. If at the first stage there is intensive production of reactive oxygen species along with the mobilization of antioxidant systems, then later stages are characterized by the depletion of protective mechanisms, oxidative modification of the lipid and protein composition of cell membranes, DNA destruction and activation of apoptosis.
When choosing a drug for antioxidant therapy in complex treatment regimens for chronic cerebrovascular accidents, it should be remembered that a universal molecule capable of blocking all pathways of formation of reactive oxygen species and inhibiting all lipid peroxidation reactions does not exist. Numerous experimental and clinical studies indicate the need for the combined use of several antioxidants with different mechanisms of action, which have the properties of mutually potentiating each other’s effects.
According to the mechanism of action, drugs with antioxidant properties are divided into primary (true) ones, which prevent the formation of new free radicals (these are mainly enzymes that work at the cellular level), and secondary ones, which are capable of capturing already formed radicals. There are few known drugs based on antioxidant enzymes (primary antioxidants). These are mainly substances of natural origin, obtained from bacteria, plants, and animal organs. Some of them are at the stage of preclinical trials, for others the path to neurological practice remains closed. Among the objective reasons for the clinical unpopularity of enzyme preparations, the high risk of side effects, rapid inactivation of enzymes, their high molecular weight and inability to penetrate the blood-brain barrier should be noted.
There is no generally accepted classification of secondary antioxidants. A wide variety of synthetic drugs with claimed antioxidant properties can be divided into two classes based on the solubility of the molecules - hydrophobic, or fat-soluble, acting inside the cell membrane (for example, α-tocopherol, ubiquinone, β-carotene), and hydrophilic, or water-soluble, acting at the boundary separation of aqueous and lipid environments (ascorbic acid, carnosine, acetylcysteine). Every year, the voluminous list of synthetic antioxidants is replenished with new drugs, each of which has its own pharmacodynamic characteristics. Thus, fat-soluble drugs - α-tocopherol acetate, probucol, β-carotene - are characterized by delayed action, their maximum antioxidant effect appears 18-24 hours after entering the body, while water-soluble ascorbic acid begins to act much faster, but in the most rational way is its purpose in combination with vitamin E.
A prominent representative of synthetic antioxidants, capable of penetrating the BBB and working both as part of the cell membrane and in the cell cytoplasm, is α-lipoic acid, the powerful antioxidant potential of which is due to the presence of two thiol groups in the molecule. α-Lipoic acid is able to bind free radical molecules and free tissue iron, preventing its participation in the formation of reactive oxygen species (Fenton reaction). In addition, α-lipoic acid provides support for the work of other antioxidant systems (glutathione, ubiquinone); participates in the metabolic cycles of vitamins C and E; is a cofactor for the oxidative decarboxylation of pyruvic and ketoglutaric acids in the mitochondrial matrix, playing an important role in the energy supply of the cell; helps eliminate metabolic acidosis, facilitating the conversion of lactic acid into pyruvic acid.
Thus, the therapeutic potential of α-lipoic acid in chronic cerebral ischemia is realized through its influence on the energy metabolism of neurons and the reduction of oxidative stress in nervous tissue.
According to many authors, α-lipoic acid is a promising drug for the treatment and prevention of neurological diseases, the pathogenesis of which involves free radical processes (Holmquist L. et al., 2006).
In our study, conducted at the clinical base of the Department of Neurology of the Federal University of the Russian State Medical University in 2006, patients with chronic cerebral ischemia were prescribed the drug α-lipoic acid Berlition, the regimen of which included intravenous drip administration in a daily dose of 300 units during the first 10 days with subsequent transition for oral administration (300 mg of the drug 2 times a day, course 2 weeks). The dynamics of free radical processes during antioxidant therapy were assessed by the concentration of primary (hydroperoxides, diene ketones, diene conjugates) and secondary (malondialdehyde) lipid peroxidation products, carbonyl products of blood plasma, as well as by determining the potential binding capacity of albumin. It should be noted that all patients who took part in the study had a high initial intensity of lipid peroxidation, but at the end of the course of treatment, the levels of secondary lipid peroxidation products in the Berlition group were significantly lower than in the control group. In addition, with the use of Berlition, positive dynamics in the oxidative stability of proteins was noted.
A promising direction in the development of new antioxidant drugs is associated with the synthesis of molecules that have specified properties to influence certain parts of the pathogenesis of oxidative stress, but for their use in widespread clinical practice it is necessary to ensure the possibility of routine laboratory assessment of the state of redox homeostasis of the body.

Vladimir Borisovich Chentsov, head of the resuscitation and intensive care department of infectious diseases clinical hospital No. 2 in Moscow, candidate of medical sciences, shared his clinical experience of using antioxidants in complex intensive therapy of severe bacterial meningitis.
– Between 2003 and 2006, 801 patients were admitted to our department with a diagnosis of purulent meningitis, although additional examination did not confirm the preliminary diagnosis in 135 of them. This is one of the most difficult categories of patients, requiring quick decision-making and adequate resuscitation measures from the first minutes after hospitalization.
Basic treatment of severe purulent meningitis includes mechanical ventilation, empirical or etiotropic antibiotic therapy, actions aimed at combating cerebral edema and preventing increased intracranial pressure, correction of water-salt and acid-base status, infusion, anticonvulsant, nootropic and neuroprotective therapy , adequate patient care and prevention of complications. Antioxidant therapy is of no small importance for this pathology, which, along with resuscitation measures, we begin to carry out from the first day of the patient’s stay in the hospital.
In our practice, we use for this purpose the intravenous administration of vitamins E and C in daily doses of 3 ml of a 30% solution and 60 ml of a 5% solution, respectively, Berlition - 600 mg / day, Actovegin in a dose of 250 ml / day, as well as the drug mexidol succinic acid (from the third day 600 mg intravenously with a gradual transition to a dose of 200 mg). Such high doses are due to the need to quickly restore the redox balance in conditions of critical inhibition of endogenous antioxidant systems during acute meningoinfection. At a dose of 3 g per day, vitamin C promotes the regeneration of the antioxidant activity of α-tocopherol. α-Lipoic acid maintains the active state of ubiquinone and glutathione, components of the antioxidant coenzyme Q. Different antioxidants have different points of application in a complex multi-level system of control over oxidative processes. Some of them act in the cytoplasm, others in the nucleus, others in cell membranes, and others in the blood plasma or as part of lipoprotein complexes. α-Lipoic acid occupies a special place in the body's antioxidant defense, since it exhibits its activity in all environments and is also able to penetrate the blood-brain barrier, which is especially important in neurological practice.
An important criterion for the effectiveness of antioxidant therapy is the dynamics of the activity of endogenous antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) in red blood cells or other cells available for study, as well as the content of low molecular weight antioxidants (ascorbic acid, tocopherol, etc.) in plasma. Assessment of the intensity of free radical reactions based on the concentration in the blood of primary, secondary and intermediate lipid peroxidation products (diene conjugates, malondialdehyde), reactive oxygen species can also be used to monitor redox homeostasis. Most of the listed laboratory parameters are available for determination in our clinic, which allows us to monitor the antioxidant therapy regimen and, if necessary, adjust it in accordance with detected changes.
It remains to add that the above scheme of antioxidant therapy, along with timely initiation of basic treatment, can significantly reduce mortality in severe bacterial meningitis.

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Neuroprotectors are a group of drugs that provide the protective function of the nervous system from adverse factors. Neuroprotectors include substances that ensure the functioning of the metabolic system, help maintain the integrity of nerve cells, protect them from death and improve oxygen supply. With their help, brain structures can quickly adapt to negative changes caused by pathological conditions such as senile dementia, Parkinson's syndrome and other neurological diseases.

Classification of drugs

Depending on the mechanism of action and composition, the following groups of neuroprotective drugs are distinguished:

1. Nootropics – improve the functioning of the metabolic system and are used in the treatment of neurological and mental disorders.
2. Antioxidants are designed to fight free radicals that appear under the influence of adverse factors.
3. Vasoactive (vascular) drugs – reduce vascular permeability, help improve blood circulation:

• anticoagulants – reduce blood viscosity;
• angioprotectors – increase blood microcirculation in the walls of blood vessels, thereby reducing their permeability;
• myotropes – help increase vascular tone and blood flow through the vessels;
• drugs that affect metabolism (calcium channel blockers);
• psychostimulants – provide nutrition to the brain.

1. Combination drugs – combine several properties (for example, vasoactive and antioxidant).
2. Adaptogens are neuroprotective drugs of plant origin.

The described neuroprotectors, depending on the diagnosis and state of health, can be combined during administration, while the range of drugs, as well as the treatment regimen, must be determined by the doctor.

Nootropic drugs

Nootropics are drugs that activate the interaction between nerve cells in the brain. Their action is aimed at:

• improving memory, concentration and thought processes;
• relieving nervous overexcitation;
• elimination of depressive mood;
• increasing the body's resistance to negative factors;
• improving blood supply to the brain;
• prevention of epileptic seizures and manifestations of Parkinson's syndrome.

Cerebrolysin

The hydrolyzate isolated from the pig brain quickly penetrates the brain cells through the blood and prevents the development of tissue necrosis caused by pathological conditions such as stroke, Alzheimer's disease, dementia, encephalitis, etc. In case of circulatory failure in the acute period due to stroke, brain infections, traumatic brain injuries, the drug is prescribed intravenously by drip infusion, dissolving it in special infusion solutions. In a state of sluggish circulatory disorders, Cerebrolysin is administered intramuscularly, without allowing it to be mixed in the syringe with substances that affect the functioning of the heart and vitamins.

Piracetam

The drug helps to increase the concentration of adenosine triphosphoric acid (ATP) in brain cells, which in turn has a positive effect on the functioning of the vascular system, restoration of cognitive, cerebral and metabolic functions. The action of the drug is aimed at protecting brain cells from damage caused by oxygen deprivation, intoxication, injury, and exposure to electric current.

Cerakson

Citicoline, which is the main active ingredient of the drug, has a beneficial effect on the membranes of brain tissue, protecting them from damage caused by traumatic brain injuries and strokes. It increases the speed of energy impulses between nerve cells, helps restore memory, concentration, awareness and thinking. Cerakson promotes a speedy recovery from post-traumatic and post-stroke coma, as well as a reduction in the severity of neurological symptoms characteristic of pathological conditions.

Antioxidants

The action of antioxidant drugs is aimed at neutralizing free radicals that have a negative effect on nerve cells and the body as a whole. Pharmaceuticals are prescribed if the body is exposed to such unfavorable factors as poor climate and ecology, work in harmful conditions, disruption of the metabolic and endocrine system, heart and vascular diseases. Taking them can increase the resistance of brain tissue to hypoxia, maintain energy balance, reduce the impact of long-term alcohol intoxication on nerve cells, and prevent the development of senile dementia.

Glycine

An amino acid that regulates metabolic processes in the central nervous system. A drug with a sedative and anti-stress effect is prescribed for increased nervous excitability, emotional exhaustion, neuroses, vegetative-vascular dystonia, and ischemic stroke. The cumulative effect of taking Glycine allows you to improve blood circulation, reduce the manifestations of psycho-emotional fatigue, and increase performance.

Mexidol

A powerful antioxidant used for acute attacks of impaired blood supply to the brain - epileptic seizures. The drug is also indicated for use in cases of decreased performance, loss of strength, nervous overexcitation, neuroses, alcohol intoxication, atherosclerotic disorders, and slowed down thinking processes characteristic of senile dementia.

Glutamic acid

A dicarboxylic amino acid that stimulates the functioning of the metabolic system and the interconnection of neurons in brain structures. It ensures the resistance of brain tissue to oxygen deficiency and protects them from intoxications of various types - alcohol, chemicals, medications. The drug in combination with other antipsychotics is prescribed for mental disorders - psychosis, epilepsy, schizophrenia, as well as brain infections - encephalitis, meningitis. In childhood, glutamic acid is used to treat cerebral palsy, Down's disease, and polio.

Vascular drugs (vasoactive)

Pharmacological agents that have a beneficial effect on blood vessels and hematopoietic function are prescribed to improve blood supply to brain tissue and metabolic processes between neurons. Depending on the mechanism of action, they are divided into several types:

• myotropic antispasmodics – improve vascular tone and blood flow through them to brain structures;
• drugs that improve metabolism between nerve cells;
• angioprotectors;
• drugs that nourish nerve cells;
• anticoagulants.

Cinnarizine

Myotropic antispasmodic with vasodilating properties. Under its action, blood fluidity is normalized, blood circulation improves, the resistance of nerve cells to oxygen starvation increases, and the bioelectrical exchange between them is activated. The drug relieves vasospasm and the symptoms accompanying this condition (,). It is prescribed for ischemic stroke, senile dementia, memory loss, Meniere's disease.

Vinpocetine (Cavinton)

The drug, which has antiplatelet, antihypoxic and vasodilating properties, accelerates metabolism in brain tissue, improves blood flow and oxygen delivery to them. Thanks to this, its use is effective in the acute stage of stroke, as well as in the progression of senile dementia. Taking Vinpocetine helps reduce the impact of neurological symptoms, improve memory, increase concentration and intellectual abilities.

Acetylsalicylic acid

An anti-inflammatory drug with antiplatelet properties. Taking it in large quantities helps suppress the biosynthesis process in platelets, due to which the blood clotting process slows down. Preparations containing acetylsalicylic acid are used in the post-stroke period to prevent the formation of blood clots.

Heparin

An anticoagulant with an effect aimed at preventing and treating diseases associated with the formation of blood clots - thrombophlebitis, thrombosis. The drug thins the blood and is administered intravenously in individual dosages. Contraindications to its use are bleeding disorders, the postoperative period, and gastrointestinal ulcers.

Combination drugs

Neuroprotectors of combined action have several properties that enhance each other, which makes it possible to achieve faster and more effective results in treatment by taking low doses of active substances.

Fezam

A drug based on Cinnarizine and Piracetam is prescribed to dilate blood vessels, increase the resistance of brain tissue and nerve cells to a lack of oxygen, and stimulate blood flow to areas of the brain that have been subject to ischemia. Phezam is also used to restore memory and thinking, improve emotional mood, eliminate intoxication syndrome and loss of strength.

Thiocetam

The drug is based on two main pharmaceutical agents - Thiotriazolin and Piracetam. Indications for the use of Thiocetam are cerebrovascular accidents and disorders caused by them, vascular diseases, brain, heart and liver diseases, as well as viral infections. Taking the drug helps strengthen the immune system and increase the resistance of brain cells to hypoxia.

Orocetam

A combined nootropic drug based on Piracetam and orotic acid improves liver function and its detoxification functions, accelerates the exchange of impulses between nerve cells. Thanks to these properties, Orocetam is effectively used for severe brain intoxication caused by infectious diseases and viruses, as well as alcohol and chemical poisoning.

Adaptogens

Herbal preparations that increase the body's resistance to harmful and pathological influences are called adaptogens. Substances in herbal remedies help adapt to stress and sudden climate change. They are effectively used during the recovery period for the treatment of infectious diseases of the brain, and intracranial injuries.

Ginseng tincture

The herbal product has a beneficial effect on the nervous, vascular and metabolic systems. It is prescribed as an adjuvant therapy for patients weakened by the disease, as well as in the presence of signs of physical and nervous exhaustion. Taking the infusion helps lower blood sugar, increase blood pressure during hypotension, improve metabolism, and eliminate bouts of vomiting.

Ginkgo Biloba

The drug contains plant substances such as eleutherococcus and gotu kola. It is prescribed for intracranial hypertension, decreased brain function, nervous fatigue, vascular and endocrine diseases, and decreased transmission of impulses between nerve cells.

Apilak

A biostimulant based on dried royal jelly of bees is prescribed for low blood pressure, loss of strength, eating disorders, mental and neurological disorders. Apilak is not recommended for use in cases of adrenal dysfunction, as well as hypersensitivity or intolerance to bee products.

Indications and contraindications for the use of neuroprotectors

The action of neuroprotectors is aimed at improving metabolic processes between brain cells and their adaptation to changes caused by circulatory disorders. Their use is indicated for the following pathological conditions:

Taking neuroprotectors is contraindicated in the following cases:

• hypersensitivity to substances included in the drug;
• inflammatory and infectious processes occurring in the kidneys and liver;
• when taking other sedatives and antidepressants;
• heart failure;
• pregnancy and lactation period.

Is something bothering you? Illness or life situation?

Neuroprotective drugs should also be discontinued if the patient experiences side effects after taking them - nausea, vomiting, allergic rash, increased breathing and heart rate, nervous overexcitation.

Currently, cerebrovascular pathology ranks second among the main causes of mortality, second only to heart disease and already ahead of mortality from tumors of all locations. Cerebrovascular pathology is the leading cause of disability in the population and, therefore, represents one of the most important medical and social problems.

Today, about 9 million people worldwide suffer from cerebrovascular diseases. The leading role among these diseases is occupied by strokes, affecting from 5.6 to 6.6 million people annually and claiming 4.6 million lives. According to the World Health Organization, the incidence of stroke ranges from 1.5 to 7.4 per 1000 people. Thus, in the United States, a cerebral stroke occurs every 53 seconds.

In the Russian Federation and CIS countries, there is a progressive increase in the incidence of this pathology: approximately every 1.5 minutes, one of the Russians develops a stroke for the first time. The incidence of stroke in Russia is 450,000 cases per year: in Moscow alone, the number of acute strokes ranges from 100 to 120 cases per day. The overall mortality rate from stroke in 2001 was 1.28 per 1000 people (men - 1.15, women - 1.38). The mortality rate from stroke in our country is one of the highest in the world: in 2000, the standardized rate was 319.8 per 100,000 people. In terms of mortality rates, Russia ranks second, second only to Bulgaria. Mortality in the acute stage of all types of stroke is approximately 35%, increasing by another 12–15% by the end of the first year. Along with high mortality, the consequences of strokes are also socially significant - the development of disability with loss of ability to work. Disability after a stroke ranks first among all causes of primary disability, since less than 20% of survivors return to their previous social and work activities. In addition, enormous damage is caused to the economy, taking into account the costs of treatment, medical rehabilitation, and losses in production. In the USA, material costs for strokes range from 7.5 to 11.2 million dollars per year, costs per patient, taking into account the need for long-term treatment and social rehabilitation, range from 55 to 73 thousand dollars per year.

The ratio between ischemic and hemorrhagic stroke was previously 5:1. Registry data from 2001 showed that in Russia ischemic strokes amounted to 79.8%, intracerebral hemorrhages - 16.8%, subarachnoid hemorrhages - 3.4%.

In Russia, up to 100,000 new cases of cerebral hemorrhages are registered annually. The incidence of hemorrhagic stroke is higher in men, while the mortality rate is higher in women. According to a number of authors, mortality from cerebral hemorrhage varies from 38 to 93%, with 15–35% of patients dying within a month from the moment of illness, half of them die within the first three days. Only 10% of patients by the end of the first month and 20% after six months can care for themselves; 25–40% of patients have a moderate degree of disability, 35–55% have severe disability.

The epidemiological and demographic situation in the world regarding cerebrovascular pathology is currently characterized by the widespread prevalence of this type of pathology, the “aging” of the population and the increase in the frequency of progressive cerebrovascular diseases, the “rejuvenation” of strokes due to the increase in the number of extreme factors and impacts (A. A. Mikhailenko and co-authors, 1996; A. A. Skoromets, 1999). In a large number of people over the age of 50, the processes of so-called “normal aging” are quickly replaced by pathological changes associated primarily with insufficiency of cerebral blood flow due to atherosclerotic damage to the vessels supplying blood to the brain, with changes in the rheological properties of the blood, leading to dysregulation and decreased neurotransmitter activity. Clinically, these neurotransmitter and morphological dysregulations are manifested by severe symptom complexes of acute and/or chronic cerebral ischemia, requiring constant and effective correction.

The number of patients with symptoms of chronic cerebral ischemia in our country is growing as steadily as the number of patients with acute cerebrovascular accidents, amounting to at least 700 per 100,000 people. While our country currently has statistics on acute strokes, albeit not in full, there are no reliable statistics on the number of patients with chronic cerebral ischemia. These are mainly outpatient patients; visiting a clinic is often difficult for them; Often they are given complex diagnoses, while cerebrovascular pathology is not taken into account or is classified as a complication, which makes it difficult to obtain objective data. The shortage of qualified neurologists in outpatient clinics also often leads to incorrect interpretation of this diagnosis.

Pathomorphological disorders in patients with acute and chronic cerebral ischemia are based on a variety of pathogenetic factors, such as atherosclerosis, arterial hypertension, as well as their combinations, cardiac pathology, changes in the condition of the spine with compression of the vertebral arteries, hormonal disorders leading to changes in the coagulation system blood, other types of disorders of the hemostatic system and physicochemical properties of blood, leading to the formation of functional and morphological ischemic disorders.

The most common causes of the formation of clinical manifestations of cerebral ischemia are atherosclerotic stenotic and occlusive lesions of the main arteries of the head; heart diseases, which include primarily coronary heart disease with symptoms of atrial fibrillation and a high risk of microembolization into intracerebral vessels. Atherosclerosis is a systemic vascular disease that leads to infiltration of the intima of the arteries with cholesterol coming from the blood. In the development of atherosclerosis, hereditary predisposition and constitutional characteristics play a role. However, the main reason for the wide spread of atherosclerosis in recent years is the functional effects on the higher nervous activity of humans, which can be classified as negative manifestations of urbanization in the conditions of scientific and technological progress. They lead to long-term and systematic neuropsychic stress. The development of atherosclerosis is promoted by physical inactivity and hypokinesia (work without physical exertion, limited walking, passive rest), hypoxia (urban air pollution), increased exposure to external electromagnetic potential, the negative impact of noise and the pace of city life, insufficient sleep and excess calorie content of food (taking into account hypokinesia). The widespread use of smoking in recent years as a factor contributing to the development of vasospasms in various vascular systems is also of known importance. In this regard, in recent years there has been a “rejuvenation” of the population of patients with atherosclerosis and arterial hypertension, in particular, from 50 to 60% of cases of cerebral vascular diseases occur between the ages of 50 and 60 years. At the same time, cerebral atherosclerosis takes first place compared to arterial hypertension. Four of the factors noted above are of leading importance in the development of cerebral vascular pathology, in particular atherosclerosis: neuropsychic stress, hypokinesia, physical inactivity and excess calorie intake. As a result of their influence, overexcitation of the cerebral cortex and the hypothalamic-pituitary-adrenal system occurs, increased release of catecholamines, disruption of all types of metabolism, especially in the walls of blood vessels, and sometimes increased blood pressure.

The study of the causes of morbidity and mortality in vascular diseases of the nervous system has led to the identification of risk factors that play a contributing role in the development of cerebral vascular accidents. These factors include: arterial hypertension, vascular hypotension, obesity (overweight), hypercholesterolemia (especially in young and middle-aged people), smoking, alcohol abuse, family history, coronary atherosclerosis, diabetes mellitus, endocrine pathology, mineral metabolism disorders (cervical osteochondrosis), living in areas with sharp fluctuations in meteorological factors, work with high intellectual stress.

Hemorrhagic stroke, also characterized by a severe secondary ischemic cascade, most often occurs as a complication of arterial hypertension (60% of cases). The development of degenerative changes (lipohyalinosis, fibrinoid necrosis) in small perforating arteries of the brain and the formation of microaneurysms against the background of arterial hypertension are the most important prerequisites for the occurrence of hypertensive intracerebral hemorrhage, and hemorrhage develops more often in patients with severe or moderate arterial hypertension than in patients with “mild” » arterial hypertension. Pathogenetically, intracerebral hemorrhages develop due to rupture of a vessel or through diapedesis. The next most common etiological factor for cerebral hemorrhage is rupture of an arteriovenous malformation, hemorrhage from ruptured aneurysms (10–12% of cases). Occurring more often in old age, cerebral amyloid angiopathy, formed as a result of deposition of abnormal amyloid protein in the tunica media and adventitia of small cortical arteries and arterioles, contributes to the occurrence of miliary aneurysms and fibrinoid necrosis of the affected vessels, which can rupture when blood pressure rises, causing intracerebral hemorrhage in 10 % of cases. Such hematomas are often multiple. Long-term use of anticoagulants in 8–10% of cases leads to intracerebral hemorrhage, especially when hypocoagulation is achieved, i.e., a decrease in the prothrombin index to 40% or an increase in the international normalizing coefficient to 5. Brain tumors or brain metastases are complicated by hemorrhages in them in 6 -8% of cases. Up to 20% are other causes, such as hemophilia, thrombocytopenia, leukemia, hemorrhagic diathesis, arteritis, thrombosis of intracranial veins, alcohol and drug abuse, coagulopathy, vasculitis.

The mechanism of development of hypoxia, which is a discrepancy between tissue demand for oxygen and its delivery, is the same for any form of cerebrovascular pathology. It is associated primarily with impaired oxidation of substrates in body tissues as a result of difficulty or blockade of electron transport in the mitochondrial respiratory chain, which leads to damage to lysosome membranes with the release of utilitarian enzymes into the intercellular space.

Stress, or more precisely distress according to Selye’s theory, is a mechanism of nonspecific adaptation to the changing conditions of the organism’s environment.

At the initial stage of oxygen starvation in mitochondria, the rate of aerobic oxidation and oxidative phosphorylation decreases, which leads to a decrease in protein synthesis and gene expression, a decrease in the amount of adenosine triphosphate (ATP), an increase in adenosine diphosphate (ADP) and adenosine monophosphate (AMP); the ATP/ADP+AMP ratio decreases. With a further decrease in cerebral blood flow, the enzyme phosphofructokinase (PFK) is activated, anaerobic glycolysis is enhanced, and then a final transition to anaerobic respiration is noted, which adapts the cell to hypoxia, but glycogen reserves are depleted. This, in turn, entails the accumulation of under-oxidized lactate, a decrease in pyruvate with the development of lactic acidosis - up to the development of cerebral edema.

At the same time, the activity of lactate dehydrogenase increases and the activity of succinate dehydrogenase, which supplies electrons to the respiratory chain of mitochondria, decreases, which indicates a disruption in the processes of energy formation in the ischemic brain. Under such conditions, anaerobic glycolysis does not occur, which leads to severe energy deficiency. At the final level, destabilization of cell membranes occurs, disruption of the functioning of ion channels, damage to the potassium-sodium pump, potassium (an excitatory neurotransmitter) leaves the cell, which makes it less excitable, and sodium enters the cell in excess, followed by sodium along the osmotic gradient and enters the cell Excessive amounts of water leaving the interstitium accumulate, which leads to cell hyperhydration, cloudy swelling, and then balloon degeneration. The most important role in this process belongs to glutamate receptors.

Oxidative stress, closely associated with the ischemic cascade, occurs when glutamate receptors are excited and consists of excessive accumulation of free radicals, activation of lipid peroxidation and excessive intracellular accumulation of their products. The reactions of oxidative stress and the ischemic cascade interact and potentiate each other.

Free radicals (these are molecules with an unpaired electron) are highly reactive forms of oxygen, hydrogen peroxide, aldehydes formed under hypoxic conditions, with incomplete reduction of oxygen, changing the functional properties of a number of enzymes, carbohydrates, proteins, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), as a result the cell loses its functions, abnormal proteins appear and, in addition to the direct damaging effect, secondary destructive processes are stimulated. Oxygen for any cell, especially for a neuron, is the main energy acceptor in the mitochondrial respiratory chain. By binding to the iron atom of cytochrome oxidase, the oxygen molecule undergoes four-electron reduction to form water. The main stable form of oxygen is “triplet” oxygen, in the molecule of which both unpaired electrons are parallel and their valences (spins) are directed in the same direction. Oxygen, in the molecule of which the valences are directed in different directions, is called singlet, it is unstable and toxic for biological substances. Free radicals are unstable and tend to transform into stable compounds by pairing a free radical, tearing off an atom, most often hydrogen, from another compound and attaching it to itself.

Along with the processes of free radical oxidation, stable antioxidant radicals are produced in biological objects, which are capable of abstracting hydrogen atoms only from special molecules that have weakly bound hydrogen atoms. This class of chemical compounds is called antioxidants, since their mechanism of action is based on inhibition of free radical processes in tissues, which inhibits the development of destructive changes and inactivates oxidative stress reactions. Changes in the structure and function of substrates under conditions of ischemia and stress depend on the ratio of the activity of free radicals and antioxidants.

It should be noted that the pathophysiological mechanisms of the emergence and progression of oxidative stress in patients with any form of cerebrovascular pathology are the same and are characteristic of both patients with ischemic and hemorrhagic stroke and patients with chronic forms of cerebral circulatory failure. Chronic cerebral ischemia is a disease that progresses stepwise against the background of repeated episodes of dyscirculation, leading to an increase in brain hypoxia.

Treatment of cerebral stroke consists of general and specific methods. The first include measures to ensure adequate oxygenation, correction of blood pressure, relief of complications, possible seizures, monitoring the condition of vital organs, patient care measures, as well as the use of specific therapy methods that stimulate the protective mechanisms of brain tissue in conditions of acute ischemia and hypoxia . The same applies to the processes of correction of chronic forms of cerebral circulatory disorders.

One of the most promising methods of nonspecific therapy for cerebral stroke and chronic forms of cerebral circulatory disorders is currently the use of antioxidants, which are specific correctors of brain energy metabolism, acting specifically under conditions of ischemia and hypoxia.

The body has a physiological antioxidant system that maintains oxidative-antioxidant balance both in liquid media (blood, lymph, intracellular and intercellular fluid) and in the structural elements of the cell (plasmic, endoplasmic, mitochondrial, cell membranes). Enzymatic antioxidants include: superoxide dismutase, which inactivates the superoxide radical inside the cell; catalase, which decomposes intracellular hydrogen peroxide; glutathione dehydroascorbate reductase, some other peroxidases.

Non-enzymatic antioxidants include vitamins C, E, K, glucose, ubiquinones, phenylalanine, transferrin, haptoglobin, tryptophan, ceruloplasmin, carotenoids. Biological and chemically synthesized antioxidants are divided into fat-soluble and water-soluble. The former are localized where the target substrates for attack by free radicals and peroxides are located, the most vulnerable biological structures to peroxidation processes, which include primarily biological membranes, blood lipoproteins, and the main targets in them are unsaturated fatty acids. The most significant fat-soluble antioxidant is α-tocopherol; it interacts with the hydroxyl radical OH and has an inhibitory effect on singlet oxygen, preserving the activity of membrane-bound enzymes. α-tocopherol is not synthesized in the body; it belongs to the group of vitamins (vitamin E), is a universal fat-soluble antioxidant and natural immunomodulator, normalizing the indicators of cellular and humoral immunity. Among the water-soluble antioxidants, the most important are glutathione, which plays a key role in protecting cells from toxic oxygen intermediates, and the ascorbic acid system, which is especially important for the antioxidant protection of the brain. It should be noted that antioxidants supplied in food also take part in the fight against oxidative stress: minerals (selenium, magnesium, copper compounds), some amino acids, flavonoids (plant polyphenols). However, their role is reduced to a minimum if we take into account that the diet of a modern person is dominated by refined and technologically processed foods devoid of natural qualities (even if plant-based products predominate in the diet), which is the cause of chronic deficiency of antioxidants in the human body.

The most adequate synergist and almost ubiquitous companion of ascorbic acid is the system of phenolic compounds. It is found in all plant living organisms, accounting for 1–2% of biomass or more, and performs various biological functions.

The antioxidant properties of phenols are associated with the presence in their structure of weak phenolic hydroxyl groups, which easily give up their hydrogen atom when interacting with free radicals and act as free radical traps, turning into low-active phenoxyl radicals. The greatest diversity of chemical properties and biological activity is characterized by phenolic compounds with two or more hydroxyl groups in the benzene ring. Such classes of phenolic compounds form a buffer redox system under physiological conditions. The latest generation phenolic antioxidant is the drug Olifen, the molecule of which contains more than 10 phenolic hydroxyl groups that can bind a large number of free radicals.

Currently, α-tocopherol, ascorbic acid, methionine, cerulloplasmin, carotene, ubiquinone, and emoxypine are used in clinical practice. However, the disadvantage of these drugs is the need for long-term use (several weeks) to ultimately achieve a weak antioxidant and antihypoxic effect. This provided the basis for the search and study of new synthesized antioxidants.

In recent years, the effect of succinic acid, its salts and esters, which are universal intracellular metabolites, has been widely studied. Succinic acid, contained in all tissues and organs, is the product of the 5th and substrate of the 6th reaction of the tricarboxylic acid cycle. The oxidation of succinic acid in the 6th reaction is carried out using succinate dehydrogenase. Performing a catalytic function in relation to the Krebs cycle, succinic acid reduces the blood concentration of other products of the cycle - lactate, pyruvate, citrate, produced and accumulated in the early stages of hypoxia, and is thereby included in energy metabolism, directing the oxidation process along the most economical path. The phenomenon of rapid oxidation of succinic acid by succinate dehydrogenase, accompanied by ATP-dependent reduction of the pool of pyrimidine dinucleotides, is called monopolization of the respiratory chain. The biological significance of this phenomenon lies in the rapid resynthesis of ATP. The Roberts cycle, or the so-called γ-aminobutyrate shunt, functions in nervous tissue, during which succinic acid is formed from γ-aminobutyric acid (GABA) through the intermediate stage of succinic aldehyde. The formation of succinic acid is also possible under conditions of hypoxia and oxidative stress in the reaction of oxidative deamination of α-ketaglutaric acid in the liver. The antioxidant effect of succinic acid is associated with its effect on the transport of mediator amino acids, as well as with an increase in the content of aminobutyric acid in the brain due to the Roberts shunt. Succinic acid in the body normalizes the content of inflammatory mediators histamine and serotonin, increases microcirculation in organs and tissues, primarily in the brain, without affecting blood pressure and heart function. The antihypoxic effect of succinic acid is associated with the activation of succinate dehydrogenase oxidation and the restoration of the activity of cytochrome oxidase, the key redox enzyme of the respiratory chain.

Currently, derivatives of succinic acid are widely used - domestic drugs reamberin, cytoflavin, mexidol.

Mexidol is an antioxidant, membrane protector, antihypoxant with direct energizing action, inhibiting free radicals, reducing the activation of lipid peroxidation, increasing the activity of its own physiological antioxidant system, activating the energy-synthesizing functions of mitochondria and improving energy metabolism in the cell. Mexidol has a modulating effect on membrane-bound enzymes, ion channels, receptor complexes, including GABA and acetylcholine, improves synoptic transmission in brain structures, correcting disorders in microcirculatory systems. Mexidol acts under conditions of ischemia and hypoxia as a specific trap of free radicals, reducing their damaging effect on cerebral structures. The drug is prescribed in doses of 200 to 500 mg per day intravenously in saline or intramuscularly.

Detoxification 1.5% solution for infusion Reamberin, which contains succinic acid salt and microelements (magnesium chloride, potassium chloride, sodium chloride), has antioxidant, antihypoxic, energy-protective effects, reduces the production of free radicals, has a positive effect on aerobic processes during ischemia and hypoxia, restores the energy potential of the cell, utilizes fatty acids and glucose in the cells, normalizes the acid-base balance and gas composition of the blood. Reamberin is successfully used as an infusion solution in critical conditions associated with brain damage, as well as in any conditions caused by endo- and exotoxicosis (cerebral strokes, delirious and predelirious states, poisoning, infectious diseases, clinical manifestations of a systemic inflammatory reaction, liver failure , pancreatic necrosis, peritonitis). The standard dosage is up to 800 ml (400 ml 2 times) per day intravenously. The drug can serve as a basic infusion solution for the use of other medications.

Cytoflavin is a metabolic corrector and energy protector, antioxidant, antihypoxant, aimed at normalizing conditions accompanied by disruption of free radical homeostasis, having a pronounced anti-ischemic effect, reducing the intensity of lipid peroxidation, stimulating the antioxidant defense system. Cytoflavin is a balanced complex of two metabolites (succinic acid, riboxin) and two coenzymes of vitamins - riboflavin (B 2) and nicotinamide (PP). The active substances included in this complex preparation have a high level of influence on the metabolism of neuronal structures and act as effective correctors of its imbalance under conditions of ischemia, hypoxia and oxidative stress. Thus, riboflavin mononucleotide - a coenzyme that activates succinate dehydrogenase - a flavoprotein used to activate alternative NAD (Nicotinamide Adenine Dinucleotide)-dependent metabolic pathways, has a direct antihypoxic effect associated with an increase in the activity of flavin reductases and restoration of the level of ATP and creatine phosphate (macroergs). It has been proven that riboflavin penetrates the cell membrane regardless of pH. Its entry into the cell depends only on the magnitude of the transmembrane potential. Riboflavin stimulates the utilization of succinic acid by activating the mitochondrial transport system of dicarboxylic acids of the Krebs cycle through the shuttle (glycerol phosphate) pathway, and succinic acid, in turn, increases the transmembrane potential, increasing the transport of riboflavin across membranes. In addition, riboflavin increases the activity of dehydrogenases, preventing ischemic damage to nervous tissue, and inhibits lipid peroxidation in tissues provoked by iron ions Fe 2+.

Riboxin (inosine) has a pronounced antioxidant effect, which is realized by a complex of interconnected metabolic pathways, stimulating the activation of NAD synthesis in mitochondria from nicotinamide and stimulating anaerobic glycolysis with the formation of lactate and NAD. It is characterized by a neuroprotective effect in reperfusion syndrome, potentiating the vasodilating effect of adenosine and inhibiting the enzyme adenosine deaminase.

Nicotinamide is a neuroprotector, one of the fragments of NAD, which activates NAD-dependent cell enzymes, including the antioxidant systems of ubiquinone oxyreductases, which protect cell membranes from destruction by radical particles. Nicotinamide is a selective inhibitor of the enzyme poly-ADP-ribose synthetase, which is formed under ischemic conditions and leads to dysfunction of intracellular proteins with subsequent cell apoptosis.

Succinic acid, as an antioxidant, deactivates peroxidases in mitochondria and increases the activity of NAD-dependent enzymes. Nicotinamide and riboflavin, in turn, increase the pharmacological activity of succinic acid. The drug is administered in a dose of 10–20 ml per day intravenously by slow drip in saline solution or 5% glucose. In severe conditions associated with diffuse hypoxia, resuscitation measures, post-reperfusion syndrome, the dosage of the drug can be increased to 40 ml per day, intravenous slow drip administration (60 drops per minute) is indicated.

Numerous pilot and placebo-controlled studies have revealed the positive effect of including the above antioxidants (cytoflavin, reamberin and mexidol) in the complex therapy of patients with cerebral strokes and chronic forms of cerebrovascular disorders. Research in recent years has shown the feasibility of the complex use of these drugs in the treatment of cerebrovascular disorders, since mexidol and cytoflavin have different points of application and their combined use can help correct energy processes in brain tissue with simultaneous utilization of free radical oxidation products.

In addition, cytoflavin has been shown to be highly effective in the treatment of patients with intracerebral hemorrhages, characterized by a particularly high level of oxidative stress. A clear relationship between the effect of cytoflavin therapy and the size of intracerebral hematoma was revealed. When cytoflavin is included in the complex therapy of intracerebral hemorrhages, the most significant regression of disorders of consciousness is observed, especially pronounced in hematomas measuring 10–30 cm 3, a more rapid regression of focal neurological deficit, and a better functional outcome.

For all modern antioxidants, a clear dependence of the degree of effectiveness on the timing of initiation of therapy has been proven. The maximum clinical effect can be achieved when therapy is started within a period of 2 to 6 hours from the moment of cerebral catastrophe. A less striking but real clinical effect in the form of activation of consciousness and a decrease in focal neurological symptoms is observed when therapy is started within a period of up to 24 hours.

In patients with chronic ischemia, long-term planned therapy with antioxidants significantly corrects the quality of life and helps prevent the progression of functional and morphological cerebral disorders.

Early therapy with antioxidants is currently considered as a real pathogenetically determined method for correcting cerebral metabolism in cerebral vascular disorders.

S. A. Rumyantseva, Doctor of Medical Sciences, Professor

A. A. Kravchuk

E. V. Silina

RGMU, City Clinical Hospital No. 15, Moscow