Mexidol® -
the drug of choice
among doctors of Russia*
The mechanism of action
Mexidol® (ethylmethylhydroxypyridine succinate) is a reference original Russian drug, which consists of two related and functionally significant compounds - ethylmethylhydroxypyridine and succinate [1]. The mechanism of action of the drug Mexidol® is due to a combination of several pharmacological effects: antioxidant, antihyplance and membrane -stabilizing. Penetrating through the hematoencephalic barrier, Mexidol® enters the nerve cells and concentrates in mitochondria, which ensures its high pharmacological activity.
Mexidol® has an antioxidant effect
Due to the influence of the drug Mexidol®, the activity of free radical processes that cause damage to the cellular structures of the nervous system and other organs and tissues decreases on various links of oxidative stress pathogenesis.
Mexidol® has an antihypoxic effect
Mexidol® causes an increase in the compensatory activity of aerobic glycolysis and a decrease in the degree of inhibition of oxidative processes in the Crebs cycle during hypoxia by increasing the content of adenosinericfate (ATP), creatine phosphate and activation of energy synthetic functions of mitochondria, stabilization of cell membranes.
Mexidol® has a membranestabilizing effect
Mexidol® increases the stability and functional activity of cell membranes, modulates the activity of membrane enzymes, receptor complexes. All this contributes to the preservation of the structural and functional organization of biomembrane, the transport of neurotransmitters and the improvement of synaptic transmission.
Suppression of oxidative stress
Oxidative stress is one of the stages of the ischemic cascade that occurs against the background of a decrease in blood flow in organs and tissues. With the ischemic-hypoxic cascade of the depression of the synthesis of ATP (energy deficiency) is accompanied by the simultaneous activation of the release of highly reactive free radicals and active oxygen forms (AFC) with free valency [1]. Energy deposit and oxidative stress are the links of one pathological chain, since the primary energy deficiency complicates the full -fledged transformation of metabolites in the cycles of anaerobic and aerobic glycolysis. The nervous system is most sensitive to ischemia, therefore, in recent years, oxidative stress is also considered as one of the most significant factors in the pathogenesis of acute and chronic cerebrovascular pathology, traumatic brain injury, neurodegenerative diseases, such as Alzheimer's disease and other types of dementia, Parkinson's disease, and lateral amyotrophic sclerosis, epilepsy, multiple sclerosis and the development of aging [2]. 3-oxypyridine in Mexidol® provides direct antioxidant effects due to the neutralization of free radicals (superoxide anion radical, gydroxil radical), preventing damage to cellular structures. Mexidol®, not having a proxidant effect, increases the activity of endogenous antioxidant enzymes of superoxidsmouth, glutathioneperoxidase, thereby mobilizing the antioxidant protection of the body [3].
Stimulates the expression of the rare-sensitive transcription factor NRF2
An important component of the implementation of the antioxidant action of the drug Mexidol® in conditions of hypoxia is its effect on the transcription factor NRF2. It is known that the rare-sensitive transcription factor NF-E2-RELEETED FACTOR 2 (NRF2) reacts to a change in the ratio of restored and oxidized SH groups in proteins. Its expression increases with the development of oxidative stress, which helps to protect the cell from the effects of free radicals. It is proved that Mexidol® in the experimental conditions contributes to the activation of the synthesis of the transcription factor NRF2 and increases its expression in the cells of the frontal cortex of the animal brain [4]. Thus, the proven stimulation of the expression of the rare-sensitive transcription factor NRF2 Mexidol® is a manifestation of its powerful antioxidant action.
The ability to suppress glutamate exaytotoxicity
Ex -tootoxicity is a pathological process that leads to damage and death of nerve cells due to excessive stimulation with exciting neurotransmitters (such as glutamate). With ischemia, a violation of the respiratory chain is characteristic. When blocking the work of the Crebs cycle, pyruvate dehydrogenate complex, and the activation of anaerobic glycolysis, lactate is accumulated in the cytoplasm of cells and the development of acidosis (reduction of PH). Moreover, anaerobic glycolis is not able to provide the required amount of ATP for the normal functioning of the cell, which leads to the progression of ischemia. A decrease in ATP level and the accumulation of AFC leads to a violation of the ion channels and the destabilization of cytoplasmic membranes [5]. There is an accumulation in the extracellular space of exciting amino acids-in particular, glutamate, which activates the flow of extracellular calcium into the neuron, which leads to overloading cells with calcium, activation of proteolytic enzymes and the formation of neeronshipypic no-syntase. The latter stimulates the production of nitrogen oxide, from which an active form of nitrogen can form - peroxinitrite, which enhances damage to neurons due to the development of nitro -retreat stress and leads to an irreversible damage to neurons and their death. It was established that Mexidol® in vitro suppresses the development of glutamatached neurotoxicity, which breaks off the pathological cascade of reactions leading to the destruction of the cell.
The contribution of succinatoxydal oxidation
Hypoxia as a typical pathological process underlies the pathogenesis of a wide range of diseases. Therefore, the correction of metabolic disorders for hypoxia is an important task of pharmacotherapy. After 30 minutes of ischemia, the need for the most important organs in the succinate increases sharply, its level in the brain increases by 3.5 times. This is due to the fact that the succinate in the process of oxidation in the Crebs cycle supports the operation of the respiratory chain during hypoxia. The contribution of succinate oxidation to total breathing can reach 65–85%. The succinate in the preparation of Mexidol® during hypoxia supports the work II of the complex of the respiratory chain of mitochondria, which provides the formation of up to 80% of ATP with a decrease in oxygen concentration [6]. This is how the energy -angle potential of the drug Mexidol® is realized.
Influence on a transcription factor induced by hypoxia (HIF-1)
The transcription factor, induced by hypoxia (HIF-1), plays the most important meaning in the resistance of cells to hypoxia. HIF-1 is a heterodimeric protein containing two subunits. While the β-Subela is constitutive, the α-bomb in normal conditions is subjected to constant destruction (proteolysis), and in conditions of hypoxia is stabilized. The accumulation of HIF-1 during hypoxia leads to the activation of the transcription of some proteins that contribute to the survival of the cell. К ним относятся гликолитические ферменты (альдолаза, пируваткиназа, лактатдегидрогеназа и др.), мембранные транспортеры глюкозы и лактата, регуляторы биогенеза (PPARGC1A) и аутофагии митохондрий (BNIP3), эритропоэтин, фактор роста эндотелия сосудов VEGF и др. Показано, что Мексидол® при Acute hypoxic hypobaric hypoxia increases the amount of HIF α-Subens in the neurons of the cortex of the large hemispheres of the brain, which contributes to the antihypoxic effect of the drug [7].
Interaction with SUCRN1 succinate receptors and impact on the growth factor of vascular vessels VEGF
The results of recent studies have shown that the succinate is the Ligand of the G-Booped SUCRN1 receptors (previously known as GPR91) and performs the function of the primary messenger. It is assumed that the interaction of the succinate that is part of the drug Mexidol® also has an antihypoxic effect with succinate receptors, regulating the release of pro -angiogenic factors and allowing to limit the size of the heart attack, for example, after neonatal hypoxia/ischemia [8]. Acting through these receptors, succinate also increases the expression of one of the main pro -angiogenic factors -the growth factor of the vascular endothelium (VEGF) and angiopoietins -1 and -2 [7].
The ability to stimulate mitochondriogenesis
One of the aging hypotheses is a free radical hypothesis, according to which an excess of free radicals is a limiting determinant of life. According to V.P. Skulachev, aging is considered as “slow phenoptosis, which is launched using intramitochondrial active forms of oxygen,” and “if you build curves of dependence of the life expectancy of the body on the number of free radicals in mitochondria, then a certain pattern is clarified: the more free free are in the cell of free Radicals, the less we live. ” Thus, mitochondrial dysfunction is a key pathogenetic link in aging and various neurodegenerative diseases [9]. The drug Mexidol®, having antioxidant and anti -enial effects, as well as activating succinate receptors due to the presence of amber acid in its molecule, induces cerebral mitochondriogenesis and eliminates mitochondrial dysfunction. Thus, it affects key pathogenetic links in the development of disorders during aging and neurodegenerative diseases.
Membranoprotection
It is shown that with various pathologies, the processes of lipid peroxidation and other influences lead to a violation of the structural-functional state of the cell membrane. This leads to its depolarization, an increase in the viscosity of the lipid bilage and a change in the thresholds of the sensitivity of neurons. Mexidol® increases the content of the polar fractions of lipids (phosphatidylserin and phosphatidydilinositis) and reduces the ratio of cholesterol/phospholipids, which indicates its lipid regulatory properties; causes the movement of structural transitions to the area of low temperatures, i.e., the viscosity of the membrane decreases and their fluidity increases; Increases the ratio of lipid -white [10]. This is how the membraneprotective effect of the drug Mexidol® is realized.
Improves intersneuronal interaction by modulating the activity of GABA-A-receptors
With the development of hypoxia and oxidative stress, the cell membranes and intrambemblastic protein complexes, for example, receptors, are damaged, which can lead to the development of various pathological conditions. For example, damage to the GABA-A-receptor molecule can lead to anxiety. The drug Mexidol®, having antioxidant, antihypoxic and membranes, modulates and restores the work of membrane enzymes and receptor complexes, in particular GABA-A (γ-aminomatic acid)-benzodiazepine and acetylcholine [11].
Mexidol® development history
Mexidol® is a reference (original) Russian drug that has a powerful anti -ischemic effect, a unique development of leading scientists and clinicians, noted in 2003, a prestigious prize of the Government of the Russian Federation “For the creation and introduction of antioxidant drugs for the treatment and prevention of cerebrovascular diseases” [12] .
In 1956, Nikolai Nikolayevich Semenov, together with Siril Norman Khinshelwood, was awarded the Nobel Prize in Chemistry in the field of chemical reactions, in 1956. Understanding the mechanisms of the formation of free radicals served as the basis for creating the concept of combating tissue ischemia and the development of drugs that have antioxidant and anti -hyphymentarian activity.
In the early 1980s, in the State Research Institute of Pharmacology, the RAMS L. D. Smirnov and V.I. Kuzmin synthesize the 2-ETIL-6-methyl-3-hydroxypirinate molecule-this is a breakthrough in the history of domestic neuroprotection. Under the leadership of the Academician of the RAMS A.V. Waldman, the pharmacological effects of a new compound were revealed, the mechanism of action was studied, preclinical studies on toxicology, pharmacokinetics and pharmacodynamics were performed.
Ethylmethylhydroxypyridine succinate
Structural formula
EthylMethylhydroxypyridine Succinate
The history of recognition
of the Government of the Russian Federation
For the development and introduction of the drug Mexidol® in the clinical practice of a group of specialists in 2003, the Prize of the Government of the Russian Federation “For the creation and introduction of antioxidant drugs for the treatment and prevention of cerebrovascular diseases” [11].
Russian Pharma Awards Prize
Mexidol® took 1st place in the nomination "The drug of choice in the treatment of ischemic disorders caused by spasm of the vessels of the brain."
"Molecule of Life"
Mexidol® received the Molecule of Life, first established by the Russian Scientific Medical Society of therapists (RNOWN). The drug Mexidol® was the first laureate of the pharmaceutical award, established by the oldest and most representative professional medical society.
Mexidol® took 2nd place in the nomination "Russian brand in the retail market."
IQVIA Awards Prize
Mexidol® received the IQVIA Awards Award - "3rd place RX Retail Brand in Russia"
How to use Mexidol®?
Mexidol® is effectively used both in adults and in children from 6 years of age*. Information on indications for use, dosages, duration
of treatment, methods of administering the drug Mexidol® can be found here.
* In children from 6 years old, Mexidol® tablets covered with a film shell are used, 125 mg.
List of literature
- Voronina T. A. Pioneer of antioxidant neuroprotheres. 20 years in clinical practice. Breast cancer. 2016. No. 7. S. 434-438.
- Fedin A. I. Clinical aspects of pathogenetic therapy of brain ischemia. - M.: LLC "AST 345", 2022. - 32 p.: Il.
- Zhang L, Wang H. TarGeting the NF-E2-RELEETED FACTOR 2 Pathway: A Novel Strategy for Traumatic Breen Injury. Molecular Neurobiology. 2018; 55 (2): 1773-1785.
- Yakusheva E. N., Mylnikov P. Yu., Chernykh I.V., Schulkin A.V. The influence of Mexidol on the expression of the transcriptional factor NRF2 in the cortex of the large hemispheres of the brain in experimental ischemia. Journal of neurology and psychiatry named after S. S. Korsakova. 2018; 118 (5): 63-67.
- Schulkin A.V. The influence of Mexidol on the development of the phenomenon of exaytotoxic neurons in vitro. Journal of Neurology and Psychiatry, 2, 2012. S. 35-39.
- Schulkin A.V. Modern ideas about the antihypoxic and antioxidant effects of Mexidol // Journal of Neurology and Psychiatry, 12, 2018; Ext. 2. 87-93.
- Yakusheva E. N., Mylnikov P. Yu., Blacks I.V., Schulkin A.V. The influence of Mexidol on the expression of the factor induced by HIF-1α hypoxia, in the cerebral cortex of the brain of rats with ischemia // Journal of Neurology and Psychiatry , 10, 2017. S. 62-66.
- Prikhodko V.A., Selizarova N.O., the molecular mechanisms of the development of hypoxia and adaptation to it. Part II. Archive of pathology. 2021; 83 (3): 62-69.
- Kirova Yu. I., Shakova F.M., Germanova E. L., Romanova G.A., Voronina T. A. Influence of Mexidol on Cerebral Mitochondriogenesis at a young age and with aging // Journal of Neurology and Psychiatry named after S. S. Korsakova. 2020, vol. 120, No. 1, p. 55-62.
- Eremenko A.V. The role of membrane properties of 3-oxypyridine derivatives in the pharmacological effect // Author. Diss. cand. Biol. sciences. M., 1986. 24 p.
- Voronina T.A. Mexidol: the main neuropsychotropic effects and the mechanism of action // Pharmacate. N 6. 2009. S. 28-31.
- Decree of the Government of the Russian Federation of 18.02.2003 No. 112 “On the award of the Prizes of the Government of the Russian Federation in 2002 in the field of science and technology”.
Information is intended for medical and pharmaceutical workers. This information cannot serve as a replacement for a doctor’s consultation.
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