Prospects for the use of perampanel in the treatment of epilepsy in patients with malignant gliomas of the brain

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INTRODUCTION

Malignant brain gliomas (MBGs) account for approximately 60%–80% among primary brain tumors and are characterized by an aggressive clinical course and high mortality [1–3]. More than 70% of MBGs are accompanied by epilepsy, the treatment of which is one of the most important challenges of modern neuro-oncology [2, 4, 5]. Epileptic seizures may be the first symptom of the tumor [6] or occur during its evolution after surgical treatment [7] or during chemoradiotherapy [8–10].

Glutamate and activation of α-amino3-hydroxy5-methyl4-isoxazolpropionic acid receptors (AMPA-glutamate receptors) play a pivotal role in the epileptogenesis and tumor progression in brain tumor-related epilepsy (BTRE) patients [11–13]. In this regard, perampanel (PER), an AMPA-receptor antagonist, a highly effective third-generation antiepileptic drug (AED) with a minimal range of side effects, is a promising candidate for the treatment of epilepsy in MBG patients [6, 14, 15].

The review was based on a comprehensive literature search conducted up to November 2023 across PubMed, Embase, and Cochrane Library databases using the keywords “злокачественные глиомы головного мозга” (“malignant brain gliomas”), “глиобластома” (“glioblastoma”), “эпилепсия” (“epilepsy”), “перампанел” (“perampanel”), and “противоопухолевая активность” (“anti-tumor activity”). The review was prepared in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) reporting guidelines [16].

MALIGNANT BRAIN GLIOMAS AND EPILEPSY

MBGs are tumors originating from glial or glial precursor cells and include astrocytoma, oligodendroglioma, ependymoma and other rare gliomas [2, 3]. In recent years, there has been an increase in the incidence of MBGs, which can be attributed to increased life expectancy and the use of new diagnostic methods. Additionally, there has been an increase in the incidence among younger patients [17–19].

MBG is characterized by a high risk of recurrence, high mortality (with a median survival of ≤24.5 months), and a significant decrease in the quality of life [12, 20]. The clinical presentation of MBG is primarily comprised of neurological disorders resulting from tumor progression, including headaches (50%), neurocognitive disorders (30%–40%), paresis and paralysis (10%–40%), seizures (20%–50%), etc. [21–23].

BTRE plays a special role in MBG patients, occurring in 35%–70% of cases, including 46%–95% of patients with low-grade gliomas (Grade I and Grade II) [24–26], 42%–71% of patients with Grade III gliomas, and 29%–60% of patients with Grade IV gliomas [21, 22, 27]. At the time of diagnosis, BTRE is detected in more than 40% of patients with MBG, with an even higher prevalence at later stages of the disease [13, 28]. BTRE contributes to cognitive and psychiatric disorders and reduces the patient quality of life [9, 29]. The BTRE severity is influenced by several factors, including tumor size, extent of tumor resection, residual tumor size, and a history of preoperative seizures [7, 30].

HIGH-GRADE MALIGNANT BRAIN GLIOMAS

Glioblastoma (GBM) is the most aggressive type of MBG with a median survival ranging from 12 to 25 months (a mean of 14.6 months) [12, 31, 32]. Epilepsy (glioblastoma-related epilepsy, GRE) occurs in 30%–62% of patients with GBM [23, 33, 34]. The studies report that GBM is less epileptogenic than lower-grade gliomas, which is likely attributed to the shorter life expectancy of GBM patients and the presence or absence of mutations in isocitrate dehydrogenase (IDH) 1/2 [5, 27, 35]. In 40%–45% of GBM patients, seizures are the first symptom [18, 36, 37], although they may occur at different stages of the disease [30, 38].

The treatment of MBG patients is surgery and chemoradiation therapy [22, 39]. Surgical excision of the tumor has been demonstrated to result in a reduction in tumor size, the rate of tumor growth, and the incidence of seizures, improves the patient condition, and increases the overall survival [7, 28, 40]. However, surgery and a history of preoperative seizures may increase the risk of BTRE in the postoperative period [28].

A number of authors have demonstrated a correlation between the tumor epileptogenic potential and its growth rate [39]. The BTRE/GRE recurrence in the postoperative period or after first-line anti-tumor therapy may be attributed to tumor progression [30, 41]. Thus, the occurrence of seizures within 30 days post-surgery is a predictor of unfavorable outcome in GBM patients [42].

TREATMENT OF BRAIN TUMOR-RELATED EPILEPSY

The occurrence of BTRE in MBG patients requires the use of AEDs for seizure control, management, and secondary prevention [29, 39]. Patients with untreated BTRE tend to have a lower overall survival [14, 39]. Typically, a single AED is sufficient for the treatment of BTRE. However, in approximately 30% of cases, the administration of two or more AEDs is necessary, which increases the risk of adverse drug reactions, drug interactions, and, in some cases, BTRE resistance to treatment, thereby further reducing the quality of life [14, 22, 39]. The elevated risk of epilepsy relapse often requires the prolonged use of AEDs in BTRE patients [39]. The choice of AEDs for each BTRE patient is individualized, based on a comprehensive assessment of efficacy, tolerability, dose regimen and titration, pharmacokinetics, comorbidities, and the potential for drug interactions [43].

The potential for drug interactions between AEDs and chemotherapeutics represents a significant concern, particularly in light of the potential for decreased efficacy of anti-tumor therapy and/or increased toxicity [44]. The preferred AEDs are those that have no significant drug interactions, do not affect the liver monooxygenase system (MOS) activity, and do not have hematotoxic or immunosuppressive effects [26, 39]. The use of AEDs for the treatment of BTRE should be accompanied by a low risk of neurotoxicity, since the majority of MBG patients present with some degree of cognitive disorders [39, 45].

Valproic acid (VPA), phenytoin (PHT), carbamazepine (CBZ), and levetiracetam (LEV) are commonly used to treat BTRE [26, 39, 46]. However, VPA is known to be associated with hepato- and neurotoxicity, the risk of bleeding, suppression of hematopoiesis in the bone marrow, hormonal imbalance, and liver MOS activity inhibition, which increases the risk of drug interaction [8, 43, 47]. PHT and CBZ have been demonstrated to induce liver MOS activity and cause a number of endocrine disorders, alter vitamin D metabolism, contributing to osteopenia, and are known to be engaged in significant drug interactions [8, 43, 47]. Both drugs are sodium channel blockers that have been associated with cardiotoxicity, rhythm disturbances, and QRS prolongation [32, 47]. Similarly to PHT, CBZ has a hepatotoxic potential, increases the risk of bleeding, and may cause urinary tract disorders. The use of PHT is associated with the risk of aesthetic defects [32, 39, 47].

In recent years, LEV and PER have been used for the treatment of BTRE, and their anti-tumor activity has been demonstrated [48]. However, the use of LEV is limited due to adverse drug reactions such as behavioral and thinking disorders, hostility, aggression, irritability, and psychotic disorders [49–51].

Glutamate and AMPA receptor activation play an important role in the BTRE occurrence, mediating both seizure activity and tumor progression [12, 13, 52]. In this regard, great interest is focused on PER, a third-generation AED, a selective non-competitive AMPA receptor antagonist [53–55].

PERAMPANEL IN EPILEPSY TREATMENT

PER inhibits glutamatergic transmission, reduces intracellular Ca²⁺, and suppresses abnormal brain pulsations in epileptogenic foci [13, 32, 39]. Administered once daily, PER has linear pharmacokinetics, high bioavailability (100%), and long half-life (105–130 h) [39]. At therapeutic doses, PER does not affect liver MOS activity, and at high doses it is a weak inducer of CYP2B6 and CYP3A4/5 [10, 43].

The lack of significant effects on liver MOS, uridine diphosphate-glucuronosyltransferases and P-glycoprotein activities contributes to the low risk of PER drug interaction [8]. PER is used for the treatment of focal and generalized epilepsy [56], including in combination therapy of drug-resistant epilepsy [21, 46, 57]. A pooled analysis of three large, placebo-controlled, phase III studies involving 1480 patients with drug-resistant epilepsy treated with AEDs that induce liver MOS activity [58, 59] showed that the addition of PER (at 4–12 mg) provided a two-fold reduction in seizures [60]. These findings suggest that AEDs, which induce liver MOS activity, reduce PER blood levels without altering its antiepileptic activity [61].

Sagar et al. [57] performed a retrospective multicenter study involving 387 patients with drug-resistant epilepsy. A ≥50% reduction in seizure frequency was observed in 41.3% of patients, while 14.7% of patients exhibited complete seizure freedom. The side effects included neuropsychiatric disorders (18.86%) followed by dizziness (13.7%) and drowsiness (5.68%).

The efficacy of PER often allows for the withdrawal of other AEDs, which improves patient’s cognitive functions and quality of life [54, 62]. An analysis of 9 studies including 241 epileptic patients demonstrated that PER has a neutral cognitive profile [63]. At doses <4 mg/day or ≥8 mg/day, PER did not affect or slightly decreased the psychomotor speed, respectively [10]. In contrast to most AEDs, PER does not affect intracardiac conduction and does not cause ataxia, tremor, diplopia, or nystagmus [32, 39, 47].

The most common adverse drug reactions associated with PER administration are dizziness and drowsiness; less common ones include irritability and anger [54, 62, 64]. Adverse drug reactions caused by PER are dose-dependent, which requires the initiation of therapy with low doses with a gradual dose increase until the clinical effect is achieved [64].

EXPERIMENTAL STUDIES OF PERAMPANEL EFFICACY IN EPILEPSY TREATMENT

The efficacy of PER for BTRE was first reported in 2016, when Cunningham et al. [65] showed that the addition of PER reduces interictal activity in peritumoral slices ex vivo [65]. In 2019, PER was revealed to suppress voltage-dependent Na⁺ currents in U87 glioma cells, which may contribute to the anticonvulsant effect of PER [66]. A number of studies have shown that AMPA receptor inhibition increases the tumor cell response to chemotherapy in lung cancer, astrocytoma, neuroblastoma, and rhabdomyosarcoma [12, 13]. This suggested that AEDs (AMPA receptor antagonists) might have anti-tumor effects [12, 13].

A study of the anti-tumor activity of LEV, VPA, CBZ, and PER on 4 low-passage GBM cell lines and 3 brain metastasis cell lines showed that only PER inhibited cell proliferation [67]. This was accompanied by a decrease in glucose uptake, extracellular glutamate levels, and an increase in both GLUL (glutamine synthetase/glutamate-ammonia ligase) activity and GLUL gene expression [67]. The findings led to the conclusion that PER has both anti-convulsant and anti-tumor activity [67].

Analysis of the effect of PER and its combination with temozolomide on the growth of human U87, A172, U138 GBM cell lines showed that PER exerted an anti-proliferative effect in all investigated cell lines by enhancing apoptosis processes, and also increased the expression of GluR2/3 subunits in U87 and U138 cell lines. In combination with temozolomide, however, a synergistic effect was found in U87 and A172 cell lines [68].

Tatsuoka et al. [48] studied the effect of PER on proliferation of 6 malignant glioma cell lines (A-172, AM-38, T-98G, U-138MG, U-251MG, and YH-13). The observed dose-dependent inhibitory effect of PER on the cell line viability was also attributed to the induction of apoptosis, which was enhanced in combination with temozolomide. In contrast, U-138MG cells with high levels of PAI-1 (plasminogen activator inhibitor1) expression were resistant to PER. PAI-1 is known to play an important role in the angiogenesis processes in tumor tissue and tumor progression. When tiplaxtinin, a PAI1 inhibitor, was combined with PER, the U138MG cell viability was reduced [48].

In 2022, Yagi et al. [37] studied the anti-tumor activity of PER, CBZ, VPA, and LEV on 6 malignant glioma cell lines (A-172, AM-38, T-98G, U-138MG, U-251MG and YH13) at doses used for BTRE treatment [37]. PER, VPA, CBZ and LEV were found to suppress cell proliferation in 6, 4, 3, and 2 cell lines, respectively. A study of the effects of AEDs in combination with temozolomide on T-98G and U-251MG cell lines revealed that PER inhibited tumor growth and migration in both cell lines, LEV inhibited tumor growth and migration in T-98G cells, and CBZ and VPA had no effect [37]. PER has been shown to decrease the expression of Rac1 and RhoA, which constitute the cytoskeleton that enables cell motility. The authors found decreased expression of N-cadherin, a mesenchymal marker, which is involved in cell migration. This was accompanied by decreased expression of matrix metalloproteinase2 and increased expression of E-cadherin, which enhances intercellular adhesion and reduces cell motility. This may explain the PER-induced suppression of tumor cell migration. The findings suggest that PER may have a positive effect on MBG outcomes [37].

Moreover, Lange et al. [69] experimentally established that PER, when added to chemoradiation therapy, can protect healthy peritumoral tissues by preserving the activity of their glutamatergic network.

In 2020, Mayer et al. [52], who studied the anti-convulsant and anti-tumor effects of PER in vitro, found that PER reduced glucose uptake without affecting the level of extracellular glutamate. To study the effects of PER in vivo, they created a GRE model: C6 glioma cells were orthotopically injected into the neocortex of Wistar rats. It was shown that PER eliminated abnormal electrical activity in the GRE rat model, while no effect of PER on tumor size or animal survival was found.

CLINICAL USE OF PERAMPANEL FOR EPILEPSY TREATMENT

In 2015, PER was used in combination therapy for partial seizures in a patient with GBM multiforme without IDH1 mutation and O6-methylguanine-DNA methyltransferase (MGMT) methylation [70]. The median overall survival in patients with this disease is 6.5 months. The administration of PER increased the median overall survival in the GBM patient by approximately one year, seizures did not recur, and the toxicity of temozolomide did not increase [70].

The use of PER in 12 patients with low- and high-grade MBG and drug-resistant epilepsy provided a response to therapy in 9 patients (75%), a 50% reduction in seizure frequency in 3 patients (25%), and seizure freedom in 6 patients (50%) [11]. In 6 patients (50%), the authors found improvement in cognitive functions, which may be attributed to a decrease in the number of AEDs used in combination with PER [11].

According to Izumoto et al. [71], PER provided seizure control in 10 patients (100%) with glioma and drug-resistant epilepsy, of whom 6 (60%) had complete seizure freedom. Magnetic resonance imaging revealed suppression of tumor growth and reduction of peritumoral edema, which correlated with plasma PER concentration.

Dunn-Pirio et al. [72] showed the efficacy of PER as an additional AED for focal seizure control in 6 (75%) of 8 BTRE patients, with 3 (37.5%) showing a seizure reduction and the other 3 (37.5%) showing an improved seizure control. The authors noted that 5 patients had tumors with IDH1 mutation and 2 had wild-type IDH1 tumors, and all patients had MGMT hypermethylation.

A retrospective analysis of data from 11 patients with glioma and epilepsy who received PER for 12 months as adjunctive therapy revealed a response to therapy in 9 patients (81.8%), with 5 patients (45.5%) experiencing complete seizure freedom, 4 patients (36.4%) experiencing a ≥50% reduction in seizures, and only 2 patients (18.2%) experiencing no change in seizure frequency [73].

Later, in 2020, Maschio et al. [74] studied the efficacy of PER (at a mean daily dose of 6.6 mg/day) in 26 BTRE patients, of whom 16 received chemotherapy and 11 received radiation therapy. The use of PER resulted in complete absence of seizures in 8 patients (30.8%) and a ≥ 50% reduction in seizures in 15 patients (57.7%). However, 4 patients (15.4%) reported adverse drug reactions, which required PER dose reduction in 2 patients and drug withdrawal in 2 patients. No neuropsychological changes were detected. The authors found no significant differences in seizure control in patients with or without IDH1 mutations and with or without MGMT methylation [74].

Chonan et al. [46] showed that the addition of low-dose PER (2–4 mg) to LEV (500–3,000 mg) in 18 GBM patients with uncontrolled seizures provided complete seizure freedom in 17 patients (94.4%).

According to the PERADET prospective observational study, which included 36 BTRE patients with uncontrolled focal seizures, the efficacy of PER (at 2–12 mg/day) was 90.4% (34 patients), with complete absence of seizures observed in 33.3% (12 patients) [15].

In 2021, Heugenhauser et al. [6] showed the efficacy of PER in 5 patients with refractory BTRE, 2 of whom had SMART (Stroke-like migraine attacks after radiation therapy) syndrome. The response rate was 80%, and 2 patients with SMART syndrome showed a ≥50% reduction in seizure frequency. Rossi et al. [55] analyzed 13 studies with a sample size ranging from 8 to 36 patients who received additional PER (at 4–7 mg/day) for BTRE. At 6–12-month follow-up, 75%–95% of patients showed seizure freedom or a ≥50% reduction in seizure frequency. However, 11%–52% of patients experienced dizziness, pruritus, anxiety, or irritability, and only 12.5% of patients had to discontinue PER due to adverse drug reactions. According to the authors, PER is an effective and safe drug for BTRE treatment [55].

POTENTIAL MECHANISMS OF PERAMPANEL EFFICACY IN EPILEPSY TREATMENT

A comprehensive study of BTRE pathogenesis allows identifying new treatment targets with a lower risk of adverse drug reactions and drug interactions, improving the efficacy of therapy and the quality of life [13]. The oncogenesis and epileptogenesis are complex, multifactorial, and interrelated processes [8, 75]. Glutamate and its effects on ion-metabotropic receptors, such as AMPA, kainate, and NMDA receptors (N-methyl-D-aspartate) play an important role in epileptogenesis and progression of tumor growth in GBM [12, 13, 76]. AMPA receptors, which provide rapid excitatory transmission in the central nervous system, were found in GBM cells [77–79]. Increased glutamate secretion in MBG is known to promote tumor progression, the onset of epilepsy, neurodegeneration, and cognitive disorders [80]. Thus, the increase in glutamate secretion in MBG is accompanied by an increase in the expression and activation of AMPA receptors, enhancing seizure activity and neuronal excitotoxicity [15, 21, 80]. AMPA receptor activation increases the release of brain-derived neurotrophic factor (BDNF) and the number of synapses between peritumoral neurons and glioma cells, which contributes to tumor progression [12, 13, 80]. The latter is associated with activation of neuroligin 3 (NLGN3), which increases β3 integrin expression and GBM cell sensitivity to chemotherapy-induced apoptosis [22]. The expression of epidermal growth factor receptor (EGFR), fibroblast growth factor (FGFR), and vascular endothelial growth factor (VEGFR) increases, which is accompanied by the progression of tumor growth and invasiveness [10, 22]. The formation of AMPA-receptor-dependent neuron-glioma synapses leads to their electrochemical interaction and the formation of single neural circuits, contributing to the progression of tumor growth [79]. This is confirmed by intraoperative electrocorticography demonstrating increased excitability of the glioma-infiltrated cerebral cortex [79]. In vitro and in vivo studies have shown that AMPA receptor inhibition and/or mutations provide epilepsy control, suppress calcium-related tumor invasion and GBM growth [22, 78, 80].

Of note, glutamate is released by GBM cells via the cystine/glutamate transporter, solute carrier family 7 member 11 (SLC7A11, or xCT) [21, 75, 81], the expression of which is often increased in GBM cells [82, 83]. High levels of xCT correlate with a high frequency of epi-seizures in GBM patients [45, 75, 80]. Glutamate, by reducing cystine uptake via xCT, decreases the production of endogenous antioxidants, exacerbating the damaging effects of reactive oxygen species [13, 21]. High levels of glutamate, affecting depolarization processes, lead to an abnormal increase in intracellular calcium and consequently exacerbate excitotoxicity [12, 21, 75].

The astrocytic enzyme GLUL is known to convert glutamate to glutamine, reducing the glutamate level in the cell, which is accompanied by a decrease in seizure activity [84]. GLUL deficiency leads to glutamate accumulation and the onset of seizures, as evidenced by lower GLUL levels in GRE patients compared to GBM patients without epilepsy [22, 85]. A GLUL expression pattern has been shown to correlate with survival rates in GBM patients [22, 85].

The increase of Cl^– ions in glioma cells and in peritumoral tissue is important in MBG-related epileptogenesis [45, 86]. Injection of GABA into peritumoral tissues after glioma removal is accompanied by a >140% increase in the expression of Na-K2Cl-cotransporter type 1 (NKCC1), which mediates the penetration of Cl^– ions into neurons [45, 86]. Increased GABA levels around glioma cells may activate excitation rather than inhibition processes with increased epileptic activity in the peritumoral zone [45, 86]. Increased Cl^– levels in glioma cells, oxidative stress, hypoxia, and acidosis contribute to tumor progression [21, 45, 72]. Given the important role of glutamate in tumor invasion and epileptogenesis in BTRE, PER, which inhibits AMPA receptors, is of particular interest [13, 47, 55]. It was shown that PER, by inhibiting the intracellular penetration of Na⁺ and K⁺ ions and preventing depolarization of neurons and glioma cells, can not only effectively control seizures in BTRE, but also suppress tumor progression [12, 13, 54]. PER also decreases glucose uptake, glutamate levels, and increases GLUL gene expression and activity [53, 67, 79].

The activation of apoptosis in malignant glioma cell lines, the ability to inhibit tumor cell migration, and the protective effect on healthy peritumoral tissues during chemoradiation are important aspects of the PER efficacy [37, 48, 69].

CONCLUSION

The experimental studies demonstrate that PER has the anti-tumor potential, does not reduce the efficacy of anti-tumor drugs and is even able to exhibit adjuvant properties in radiochemotherapy, which increases its importance in the treatment of BTRE patients [48, 67, 69].

Clinical trials, despite their small number and limited samples, indicate the potential efficacy of PER either alone or as an adjuvant AED in the treatment of BTRE patients [15, 71, 74].

Different studies have shown that the number of BTRE patients who responded to PER therapy ranged from 75% to 100%, with complete absence of seizures observed in 33.3%–94.4% and a ≥50% reduction in seizure frequency in 12.5%–57% of patients [11, 46, 72].

The efficacy of PER in BTRE patients with IDH mutations/MGMT methylation remains inconclusive based on the available clinical data. Further studies are necessary to elucidate the potential benefits of PER in this patient population [13].

Data from most clinical studies indicate good tolerability of PER in BTRE patients, and the described adverse drug reactions are mild and do not require drug withdrawal [87, 88]. In BTRE patients, PER may cause adverse drug reactions such as increased irritability or hostility; therefore, it is not used at all or used with caution in patients with serious mental conditions [87, 88]. Aggression predictors include high doses of PER (8 mg/day or higher), psychotic/depressive symptoms, and variations in glutamate levels in the amygdala, hypothalamus, and periaqueductal gray matter [64, 89]. Finally, aggression and anger, and a number of symptoms (headache, dizziness, and anxiety) may be attributed to the tumor and its progression [43, 64]. It is essential to consider the time to the symptom onset and a PER dose administered [53, 88].

AED tolerance in BTRE patients may be influenced by chemoradiation, often exacerbating/provoking adverse drug reactions to AEDs [64].

The data available to date suggest that PER is an effective and safe drug that may be used as a new adjunctive treatment for controlling epi-seizures in BTRE patients, including those with refractory BTRE, and in patients with SMART syndrome.

Considering the significance of BTRE treatment, clinical efficacy and good tolerability of PER in BTRE patients, revealed anti-tumor effect, good compatibility with temozolomide, radioprotective effect on peritumoral tissues, further controlled studies involving a larger number of patients are needed to study in depth the mechanisms of the anti-convulsant and anti-tumor efficacy of PER in the treatment of BTRE patients.

ADDITIONAL INFO

Authors’ contributions. All authors made a substantial contribution to the conception of the study, acquisition, analysis, interpretation of data for the work, drafting and revising the article, final approval of the version to be published and agree to be accountable for all aspects of the study.

Personal contribution of each author: Y. Wang, N.A. Mufazalova, L.F. Mufazalova, N.V. Ilyasova, R.R. Muradova, I.E. Kiyomov, L.Sh. Davurova, A.V. Samorodov — analysis of the obtained data, literature review, final correction; concept and design of the study, collection and processing of materials, fundraising.

Funding source. The study was carried out with the financial support of a grant from the Russian Science Foundation (project No. 23-25-00144 “Creation of a means for correcting depression in violation of cerebral circulation”, Bashkir State Medical University of the Ministry of Health of Russia, RB).

Competing interests. The authors declare that they have no competing interests.

ДОПОЛНИТЕЛЬНАЯ ИНФОРМАЦИЯ

Вклад авторов. Все авторы внесли существенный вклад в разработку концепции, проведение исследования и подготовку статьи, прочли и одобрили финальную версию перед публикацией.

Личный вклад каждого автора: Юи Ванг, Н.А. Муфазалова, Л.Ф. Муфазалова, Н.В. Ильясова, Р.Р. Мурадова, И.Э. Киёмов, Л.Ш. Давурова, А.В. Самородов — анализ полученных данных, обзор литературы, внесение окончательной правки; концепция и дизайн исследования, сбор и обработка материалов, привлечение финансирования.

Источник финансирования. Исследование выполнено при финансовой поддержке гранта Российского научного фонда (проект № 23-25-00144 «Создание средства для коррекции депрессии при нарушении мозгового кровообращения», ФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава России).

Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи.

About the authors

Yi Wang

Hangzhou Normal University

Email: makval81@rambler.ru
ORCID iD: 0000-0001-9048-0092
Scopus Author ID: 55969091300

MD, Professor

China, Hangzhou

Natalia A. Mufazalova

Bashkir State Medical University

Email: mufazalovanatalya@yandex.ru
ORCID iD: 0000-0002-0656-3459
SPIN-code: 4053-2051

Dr. Sci. (Medicine), Professor

Russian Federation, Ufa

Lyaysan F. Mufazalova

Bashkir State Medical University

Email: lya-mufazalova@yandex.ru
ORCID iD: 0000-0001-8129-9320
SPIN-code: 1542-2210

MD, Cand. Sci. (Medicine), Assistant Professor

Russian Federation, Ufa

Nailya V. Ilyasova

Bashkir State Medical University

Email: Na1lyasova@yandex.ru
ORCID iD: 0009-0008-1774-9831
SPIN-code: 4459-6602
Russian Federation, Ufa

Raila R. Muradova

Samarkand State Medical University

Email: ismagilovaln@rambler.ru
ORCID iD: 0000-0001-9202-0479
Uzbekistan, Samarkand

Ikhtiyor E. Kiyomov

Samarkand State Medical University

Email: lukmanova.gulnur@mail.ru
ORCID iD: 0009-0004-7387-7740
Uzbekistan, Samarkand

Laylo Sh. Davurova

Samarkand State Medical University

Email: anikolaev1957@rambler.ru
ORCID iD: 0009-0009-1396-1744
Uzbekistan, Samarkand

Aleksandr V. Samorodov

Bashkir State Medical University

Author for correspondence.
Email: avsamorodov@gmail.com
ORCID iD: 0000-0001-9302-499X

MD, Dr. Sci. (Medicine), Assistant Professor

Russian Federation, Ufa

References