Vinpocetine: instructions for use

Indications and contraindications for Vinpocetine therapy

The instructions contain the following recommendations for the use of the drug:

chronic, acute circulatory failure in the brain;
encephalopathy arising from trauma;
vascular damage to the brain with memory impairment, cephalalgia, dizziness;
VSD during menopause;
decreased hearing acuity of toxic, vascular etiology;
non-inflammatory diseases of the inner ear, etc.

Vinpocetine is contraindicated in patients:

after acute hemorrhagic stroke;
with ischemic heart disease, arrhythmia;
intolerance to the component composition;
underage.

During therapeutic procedures, Vinpocetine in some cases provokes adverse reactions. The main symptoms are presented:

increased heart rate, unstable blood pressure;
changes in ECG, hot flashes;
extraordinary contractions of the heart muscle;
attacks of cephalgia with dizziness, insomnia;
heartburn, nausea, dry oral mucosa;
allergies with redness, obsessive itching, dermatological rash.

Side effects of the drug are determined by the active work of the sweat glands and a state of general weakness. The occurrence of unusual symptoms requires visiting a doctor and changing the drug.

Cerebrovascular diseases associated with hypoxic-ischemic damage are divided into acute and chronic cerebrovascular accidents (CVA). In the structure of cerebrovascular pathology, the chronic form is most common. It is characterized by slowly progressive multifocal or diffuse cerebral obstruction due to the accumulation of ischemic and secondary degenerative changes in the brain.

In contrast to acute cerebrovascular disorders associated with the pathology of large extra- and intracranial arteries, chronic forms of cerebrovascular accident are caused by damage to small cerebral arteries (microangiopathy), most often due to a combination of arterial hypertension and atherosclerotic lesions of cerebral vessels [1, 2].

Other causes include senile arteriosclerosis, hereditary and inflammatory angiopathy, amyloid angiopathy, heart rhythm disturbances, persistent migraines, dysproteinemia, arterial hypotension, hereditary diseases, smoking and alcohol abuse.

Ischemic heart disease with chronic heart failure, severe heart rhythm disturbances, diabetes mellitus and malignant neoplasms play an important role in the development and progression of cerebrovascular insufficiency in elderly patients. It should be taken into account that the presence of atherosclerosis, especially with cerebral microangiopathy, is a necessary condition that increases the risk of developing cerebral ischemia [3, 4].

Atherosclerosis is a chronic inflammatory process that affects both large and medium-sized arteries, including cerebral ones [5]. The accumulation of lipids in the arterial walls activates a series of inflammatory reactions, resulting in the stimulation of endothelial cells, which in turn attract T lymphocytes and monocytes, which turn into macrophages and ingest oxidized low-density lipoproteins (LDL), transforming into foam cells. The result is a complex structure that includes the accumulation of subendothelial lipids, an increase in the amount of extracellular matrix proteins and a diversity of immune system cell populations, which ultimately leads to the formation of a so-called plaque. In the inflammatory microenvironment, vascular smooth muscle cells migrate and proliferate to form the plaque cap. Damage to the surface of an atherosclerotic plaque attracts platelets and promotes the accumulation of coagulating proteins on its surface, resulting in the formation of a blood clot. Further development of this process in the vessels of the brain can lead to thrombotic stroke. The movement of the embolus leads to the formation of an embolic stroke and ischemic damage to the brain tissue in the area of the affected artery [5–7]. The pathophysiology of ischemic stroke has been studied for many years. It is known that with the development of hypoxia, the Krebs cycle is disrupted, as a result of which the formation of glucose decreases. A decrease in glucose and oxygen concentrations causes the development of excitotoxicity and calcium overload, which leads to damage and depolarization of neuronal membranes, and subsequent release of glutamate, as well as the development of oxidative stress as a result of hypoxia. All of these factors lead to cell death at the epicenter of ischemic damage [8]. Developing inflammation contributes to damage to the blood-brain barrier (BBB), which leads to further damage to brain tissue. Increasing oxidative stress leads to the formation of reactive oxygen species, which intensively interact with molecular compounds that form neuronal and intracellular membranes, namely with unsaturated fatty acids. The breakdown of unsaturated fatty acids leads to the formation of new reactive oxygen species and the development of the process of lipid peroxidation (LPO). LPO activates inflammatory cells, which is accompanied by the release of a number of cytokines, which together cause cellular damage in the infarct and peri-infarct areas [9]. Damaged brain tissue releases inflammatory mediators that pass through the BBB and cause a sustained inflammatory response in the affected area [10]. As a result, microglial cells, which are the main immune cells in the central nervous system, are activated, followed by the release of neurotransmitters that interact with neurons, thereby contributing to the development of post-ischemic inflammation. In addition, activated microglia and BBB-penetrating macrophages promote tissue repair by removing dead cells [11]. Thus, post-ischemic inflammation is involved in the reconstruction and restoration of brain tissue [12].

It should be noted that the main protein complex in the inflammatory response is the transcription factor - nuclear factor kappa-bi (NF-kB), which is triggered by a number of inflammatory molecules, such as interleukins - IL-6, IL-8 and tumor necrosis factor alpha (TNF-α). NF-kB initiates the expression of inflammatory cytokines and regulators of apoptosis. The NF-kB pathway includes: NF-kB inhibitor of kB (IκB) and IκB kinase (IKK). The formation of oxidized LDL in atherosclerosis is associated with the expression of the corresponding NF-kB genes [13]. In addition to the activation of endothelial cells and pathogenic proteins, the accumulation and proliferation of vascular smooth muscle cells is also regulated by NF-κB. The role of the NF-κB pathway in ischemic stroke is a complex phenomenon and has not yet been fully explored.

Clinical studies have shown that despite the emergence of new drug and non-drug treatment methods, mortality from cerebrovascular diseases remains high. The role and advisability of using vasoactive and neurometabolic drugs in the treatment of various forms of cerebrovascular accident continues to be discussed. In Russian practice, drugs such as apovincamic acid ethyl ester (vinpocetine) and 2-ethyl-6-methyl-3-hydroxypyridine succinate (EGPS) have been used for a long time (Fig. 1).

Rice. 1. Chemical structure and mechanism of action of EGPS and ethyl ester of apovincaminic acid.

Properties and mechanisms of action of vinpocetine and EGPS

Vinpocetine is an ethyl ester of apovincamic acid, a derivative of vincamine, an alkaloid from plants of the genus Vinca ( Vinca minor L

.). The first mention of the effectiveness of the use of vinca alkaloids for NMC and age-related changes appeared in the 50s of the last century. In the mid-70s, apovincamic acid ethyl ester (Cavinton) was proposed (Hungary) for the treatment of NMC. It has been used to improve cerebral circulation and cognitive function for many years, and is also used in many countries as a dietary supplement to prevent cerebrovascular disorders and symptoms associated with aging [14, 15]. The main mechanism of action of vinpocetine on blood circulation in the brain is an antivasoconstrictor effect due to blocking vascular noradrenergic reactions [16, 17]. The effects of increased utilization of glucose, oxygen and increased synthesis of adenosine triphosphate (ATP) in brain tissue were noted [18], as well as a decrease in platelet aggregation, which is associated with an increase in the formation of intracellular cyclic adenosine monophosphate (cAMP), which mediates the molecular effects of prostacyclin on platelets (see Fig. 1).

It should be noted that vinpocetine inhibits phosphodiesterase type 1 (PDE1), which leads to an increase in cAMP and cyclic guanosine monophosphate (cGMP), thereby initiating the expression of genes associated with cellular adaptation [19]. An increase in the content of cyclic nucleotides causes relaxation of myofibrils, dilation of blood vessels and an increase in the volumetric velocity of blood flow in ischemic tissues [20]. Since cGMP is a post-receptor second messenger for many CNS mediators (acetylcholine, catecholamines, serotonin and norepinephrine), an increase in its concentration has a direct cholinergic effect, stimulates the circulation of catecholamines in brain tissue, enhances the effects of norepinephrine in the area of cortical neurons, causing adenosine-like effects that lie in based on the nootropic properties of vinpocetine. Of particular interest is the drug’s ability to block the activity of voltage-dependent sodium channels, which is associated with its antiepileptic effect [21].

Vinpocetine is known to have high affinity for the 18-kDa translocator protein, which is a biomarker of activated microglia, and also inhibits microglial proliferation by blocking the transcription factor AP-1 (activating protein-1) of the NF-kB pathway. It also inhibits the release of inflammatory factors [22]. Suppression of the release of proinflammatory molecules due to inhibition of the IKK/NF-kB pathway after TNF-α activation occurs [23], as well as inhibition of differentiation of oligodendroglial progenitor cells, which has a direct negative effect on the remyelination process [24]. By preventing the phosphorylation of IKK, vinpocetine inhibits NF-kB, as a result, its translocation into the nucleus does not occur and adhesion molecules and cytokines such as IL-1, IL-2, IL-6 and TNF-α are not formed, and chemotaxis molecules are not activated (Fig. 2) [25, 26].

Rice. 2. The effect of apovincamic acid ethyl ester in slowing the progression of cerebral ischemia by inhibiting IKK/NF-kB. DAMPS - distress-associated molecular patterns, HMGB1 - high mobility group box 1 proteins, TLR4 - Toll-like receptor.

The expression of vascular cell adhesion molecules (L-, E- and P-selectin molecules) is inhibited due to a decrease in the synthesis of NF-kB in endothelial cells. This helps protect the BBB and reduce the penetration of leukocytes from the bloodstream. Vinpocetine restores the functioning of sensory sodium channels in neurons and reduces intracellular Ca2+ accumulation, which can lead to neuronal swelling and damage. Damaged neurons secrete molecular moieties (DAMPS) that activate microglial cells and macrophages through the Toll-like receptor. Vinpocetine interferes with this process by inhibiting the release of an inflammatory cytokine. At the same time, vinpocetine does not affect the activation of microglia, but inhibits its proliferation through transcription factors (NF-kB and activator protein-1), which regulate genes responsible for the innate and acquired immune response and play an important role in T-cell differentiation. Activated neutrophils secrete myeloperoxidase (MPO), which crosses the endothelium by transcytosis.

Y. Cai et al. [27] found that vinpocetine specifically inhibits platelet-derived growth factor-activated phosphorylation of extracellular regulated protein kinases (ERK1 and ERK2), thereby inhibiting platelet-derived growth factor-induced proliferation and migration of vascular smooth muscle cells. In addition, vinpocetine significantly inhibits the intracellular formation of reactive oxygen species induced by platelet-derived growth factor, and also reduces the activity of MPO produced by leukocytes, which reduces the production of hypohalic acids, mainly hypochlorous acid (HOCl/-OCl), which oxidizes lipoproteins (see Fig. 2) [27, 28]. It has been experimentally shown that apovincamic acid ethyl ester increases collagen content and significantly increases the density of the fibrous cap, thereby stabilizing the atherosclerotic plaque [26].

EGPS is a pyridine derivative (pyridoxine, vitamin B6). The main property of this drug is the restoration of biochemical processes in the Krebs cycle, increasing the activity of oxidative phosphorylation processes and the intensity of ATP synthesis, which contributes to the normal functioning of the electron transport chain of mitochondria, increasing the resistance of neurons to hypoxia. Activating succinate dehydrogenase oxidation and restoring the activity of the key redox enzyme of the mitochondrial respiratory chain - cytochrome oxidase (Fig. 3) [29]. It is noted that EGPS increases the content of polar fractions of lipids, such as phosphatidylserine and phosphatidylinositol in the cell membrane, as well as phosphatidylethanolamine, phosphatidylcholine and total phospholipids, which also contributes to moderate activation of superoxide dismutase (SOD), while reducing the cholesterol/phospholipid ratio, and also reduces viscosity lipid layer and increases the fluidity of the membrane (see Fig. 1, 3). It also suppresses the LPO process in cell membranes, increases the resistance of lipoprotein complexes to the LPO process, which helps restore the activity of the endogenous antioxidant system (see Fig. 1). Decreased production of reactive oxygen species reduces leukocyte activity and prevents initiation of the NF-kB pathway [30, 31].

Rice. 3. Mechanism of action of EGPS. EGPS stabilizes cell biomembranes and activates the energy-synthesizing functions of mitochondria. Suppresses the lipid peroxidation process in cell membranes and restores the activity of the endogenous antioxidant system, which reduces the formation of oxidized forms of lipids (oxPL).

Occurring changes in the functional activity of biological membranes under the influence of EGPS lead to conformational changes in protein macromolecules on synaptic membranes, as a result of which this drug has a modulating effect on the activity of membrane-bound enzymes, ion channels and receptor complexes, in particular benzodiazepine, GABA, acetylcholine, which enhances their ability to binding to ligands, thereby increasing the activity of neurotransmitters and the activation of synaptic processes (anxiolytic effect) [32, 33]. The listed properties of EGPS form a wide range of pharmacological effects at three levels - neuronal, vascular and metabolic.

Combined action of apovincamic acid ethyl ester and EGPS

It can be stated that the mechanisms of action of EGPS and ethyl ester of apovincamic acid, although they have a fairly similar direction, but realize neuroprotective and nootropic effects through various links in the pathogenesis of cerebrovascular brain damage. The mechanism of action of vinpocetine is associated with blocking phosphodiesterase, which, due to an increase in the content of cAMP and cGMP, leads to dilation of blood vessels, as well as a decrease in platelet aggregation, blood viscosity and, as a consequence, an increase in the volumetric velocity of blood flow in the ischemic zone. The cholinergic effect of vinpocetine determines its nootropic effect, which is also associated with an increase in the concentration of cGMP. This mechanism of action of apovincamic acid ethyl ester on the neurotransmitter systems of the brain determines the nootropic effectiveness of this drug. Developing ischemia promotes hyperactivation of glutamate receptors, which leads to a massive release of Na+ and Ca2+ ions. An increase in the concentration of intracellular Na+ and Ca2+ in neurons promotes cell swelling and further damage. An increase in Ca2+ concentration activates Ca2+-dependent enzymes, which leads to the development of oxidative stress. EGPS and vinpocetine block the activity of voltage-dependent sodium channels (Na+ channels), thus preventing the accumulation of Ca2+ in cells, and, therefore, reduce the development of the lipid peroxidation process, and consequently, neuronal damage. It should be noted that the antioxidant effect of EGPS is associated with its membrane-stabilizing properties and effects on the energy-synthesizing functions of mitochondria, receptor complexes and synaptic transmission. Both compounds (vinpocetine and EGPS) affect the mediator balance disturbed during the ischemic cascade by influencing benzodiazepine receptors, while EGPS also affects GABAergic receptors, widely represented in the synapses of cortical neurons of the frontal lobes, hippocampus and reticular formation, reducing excitotoxicity. They have an anti-inflammatory effect by modulating the activity of cytokine and chemokinergic intracellular systems. However, the effect of vinpocetine is realized primarily by influencing microcirculation and mediator processes, while EGPS affects the maintenance of physiological functional status at the cellular level. Studies conducted on models of cerebral ischemia showed that the combined use of another antioxidant, α-tocopherol, in combination with vinpocetine led to a mutual enhancement of the effects of inhibition of lipid peroxidation products in the membranes of brain neurons (see Fig. 1).

The conducted studies show that the main mechanisms of action of vinpocetine and EGPS, although they have a similar focus, implement neuroprotective and nootropic effects through different links in the pathogenesis of ischemic brain damage. The complementary effect of vinpocetine and EGPS indicates an increase in their therapeutic effectiveness when used together, and the use of this rational combination in clinical practice can be considered justified.

The authors declare no conflict of interest.

Methods of therapy and dosage from the instructions for Vinpocetine

Tablets for oral administration are prescribed at 5-10 mg, up to 3 times a day. The therapeutic regimen depends on the type of current disease and the severity of the clinical picture.

In an injection solution, the drug is administered intravenously, the maximum single dose does not exceed 20 mg. Injections are used in acute conditions; if therapy in the first days did not cause unusual reactions in the body, then the initial volume is increased for 3-4 days to 1 mg per kilogram of weight. The duration of treatment is 2 weeks.

Accidental increase in the dosage recommended by the instructions provokes the appearance of side effects in the form of allergies, heart rhythm disturbances, sleep problems, headaches and dizziness. To suppress clinical manifestations, the patient's stomach is washed and one of the available sorbents is given: Smecta, activated carbon (1 tablet for every 10 kg of weight). Subsequently, symptomatic therapy is carried out.