actabiomedicaActa Biomedica ScientificaActa Biomedica Scientifica2541-94202587-9596Scientific Centre for Family Health and Human Reproduction Problems10.29413/ABS.2026-11.1.22actabiomedica-5887Research ArticleЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯEXPERIMENTAL RESEARCHESПредотвращение пол-специфичной оланзапин-индуцируемой гиперфагии и набора веса у Drosophila melanogaster посредством применения девясила высокого (Inula helenium L.)Prevention of sex-specific olanzapine-induced hyperphagia and weight gain in Drosophila melanogaster by treatment with Elecampane (Inula helenium L.)https://orcid.org/0009-0006-9300-1783ГаккоеваК. О.GakkoevaK. O.

Гаккоева Карина Олеговна - старший лаборант.

363110, РСО-А, c. Михайловское, ул. Вильямса 1

Karina O. Gakkoeva - senior assistant, Institute of Biomedical Investigations - the Affiliate of Vladikavkaz Scientific Centre of the Russian Academy of Sciences.

Williams str., 1, RNO-A, Mikhailovskoye 363110

gakkoeva2005@mail.ruhttps://orcid.org/0000-0001-6761-7011КаркусоваМ. Д.KarkusovaM. D.

Каркусова Мэги Давидовна - научный сотрудник.

363110, РСО-А, c. Михайловское, ул. Вильямса 1

Megi D. Karkusova - research assistant at the Institute of Biomedical Investigations - the Affiliate of Vladikavkaz Scientific Centre of the Russian Academy of Sciences.

Williams str., 1, RNO-A, Mikhailovskoye 363110

meghi.96@mail.ruhttps://orcid.org/0000-0002-5471-600XДзитоеваС. Г.DzitoyevaS. G.

Дзитоева Светлана Григорьевна - кандидат биологических наук, научный сотрудник.

363110, РСО-А, c. Михайловское, ул. Вильямса 1

Svetlana G. Dzitoyeva - Cand. Sc. (Biol.), senior research assistant at the Institute of Biomedical Investigations - the Affiliate of Vladikavkaz Scientific Centre of the Russian Academy of Sciences.

Williams str., 1, RNO-A, Mikhailovskoye 363110

sdzitoyeva@gmail.comИнститут биомедицинских исследований - филиал ФГБУН ФНЦ «Владикавказский научный центр Российской академии наук» (ИБМИ ВНЦ РАН)Institute of Biomedical Investigations - the Affiliate of Vladikavkaz Scientific Centre of the Russian Academy of Sciences202626032026111231237Copyright © Гаккоева К.О., Каркусова М.Д., Дзитоева С.Г., 20262026Гаккоева К.О., Каркусова М.Д., Дзитоева С.Г.Gakkoeva K.O., Karkusova M.D., Dzitoyeva S.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.actabiomedica.ru/jour/article/view/5887Обоснование

Обоснование. Несмотря на высокую клиническую эффективность атипичного антипсихотического препарата оланзапин его использование ограничено серьёзными метаболическими побочными эффектами, включающими гиперфагию, увеличение массы тела, ожирение, дислипидемию и инсулинорезистентность.

Цель

Цель. Изучить влияние экстракта Inula helenium L. на развитие метаболических нарушений, вызванных атипичным антипсихотиком оланзапином, с использованием модели Drosophila melanogaster.

Материалы и методы

Материалы и методы. Самцов и самок Drosophila melanogaster содержали на стандартной среде с добавлением оланзапина (1 мкг/мл) и/или экстракта Inula helenium L. (50 мкг/мл) в течение 7 суток. Пищевое поведение «поиск/предпочтение пищи» определяли методом поведенческого теста геотаксис. Массу тела индивидуальных особей определяли на аналитеческих весах.

Результаты

Результаты. Оланзапин вызывал выраженную гиперфагию и прибавку массы тела, особенно у самцов (увеличение массы тела на ~90 %). Добавление экстракта Inula helenium L. вместе с оланзапином полностью предотвращало индуцируемые оланзапином гиперфагию и увеличение массы тела у самцов, у самок блокирующее действие не наблюдалось. Самостоятельное введение экстракта не оказывало влияния на поведенческие и морфометрические показатели.

Заключение

Заключение. Экстракт Inula helenium L. проявляет защитные свойства против метаболических побочных эффектов оланзапина в пол-специфичной манере, что делает его перспективным кандидатом для разработки вспомогательных средств при антипсихотической терапии. Полученные результаты впервые демонстрируют на модели беспозвоночных возможность фитоэкстрактов модулировать метаболические побочные эффекты лекарственных препаратов.

Rationale

Rationale. Despite the high clinical efficacy of the atypical antipsychotic drug olanzapine, its use is limited by serious metabolic side effects, including hyperphagia, weight gain, obesity, dyslipidemia, and insulin resistance.

The aim

The aim. To study the effect of Inula helenium L. extract on the development of metabolic side effects induced by the atypical antipsychotic drug olanzapine using the Drosophila melanogaster model.

Materials and methods

Materials and methods. Male and female Drosophila melanogaster were maintained on standard medium supplemented with olanzapine (1 pg/ml) and/or Inula helenium L. extract (50 pg/ml) for 7 days. Food seeking/preference behavior was determined using the geotaxis behavioral test. The body weight of individual flies was determined using an analytical balance.

Results

Results. Olanzapine induced marked hyperphagia and weight gain, especially in males (~90 % increase in body weight). Addition of Inula helenium L. extract together with olanzapine completely prevented olanzapine-induced hyperphagia and weight gain in males; in females, the blocking effect was not observed. Administration of the extract alone had no effect on behavioral and morphometric parameters.

Conclusion

Conclusion. Inula helenium L. extract exhibits protective properties against the metabolic side effects of olanzapine in a gender-specific manner, making it a promising candidate for the development of adjuvant agents in antipsychotic therapy. The obtained results demonstrate for the first time in an invertebrate model the potential of phytoextracts to modulate the metabolic side effects of drugs.

Drosophila melanogasterоланзапинInula helenium L.девясил высокийDrosophila melanogasterolanzapineInula helenium L.elecampaneИсследование проведено в рамках финансирования гранта Российского научного фонда № 25-25-20027.ReferencesHuhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019; 394(10202): 939-951. doi: 10.1016/S0140-6736(19)31135-3Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019; 394(10202): 939-951. doi: 10.1016/S0140-6736(19)31135-3Kang D, Lu J, Liu W, Shao P, Wu R. Association between olanzapine concentration and metabolic dysfunction in drug-naive and chronic patients: similarities and differences. Schizophrenia (Heidelb). 2022; 8(1): 9. doi: 10.1038/s41537-022-00211-5Kang D, Lu J, Liu W, Shao P, Wu R. Association between olanzapine concentration and metabolic dysfunction in drug-naive and chronic patients: similarities and differences. Schizophrenia (Heidelb). 2022; 8(1): 9. doi: 10.1038/s41537-022-00211-5Li S, Zheng D, Wang W, Liu N, Li Y, Lu C, et al. Olanzapine-Induced Weight Gain and Glycolipid Metabolism Aberrations in First-Episode and Antipsychotic-Naive Schizophrenia Patients: A Longitudinal Study. Curr Neuropharmacol. 2025; 23(7): 771-779. doi: 10.2174/1570159X23666240918103730Li S, Zheng D, Wang W, Liu N, Li Y, Lu C, et al. Olanzapine-Induced Weight Gain and Glycolipid Metabolism Aberrations in First-Episode and Antipsychotic-Naive Schizophrenia Patients: A Longitudinal Study. Curr Neuropharmacol. 2025; 23(7): 771-779. doi: 10.2174/1570159X23666240918103730Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry. 2020; 7(1): 64-77. doi: 10.1016/S2215-0366(19)30416-XPillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry. 2020; 7(1): 64-77. doi: 10.1016/S2215-0366(19)30416-XHuang J, Hei GR, Yang Y, Liu CC, Xiao JM, Long YJ, Peng XJ, et al. Increased Appetite Plays a Key Role in Olanzapine-Induced Weight Gain in First-Episode Schizophrenia Patients. Front Pharmacol. 2020; 11: 739. doi: 10.3389/fphar.2020.00739Huang J, Hei GR, Yang Y, Liu CC, Xiao JM, Long YJ, Peng XJ, et al. Increased Appetite Plays a Key Role in Olan-zapine-Induced Weight Gain in First-Episode Schizophrenia Patients. Front Pharmacol. 2020; 11: 739. doi: 10.3389/fphar.2020.00739Sudar FP, Zekerallah SS, Paulzen M, Mathiak K, Gaebler AJ. Unraveling antipsychotic induced weight gain in schizophrenia - A proof-of-concept study exploring the impact of the cumulative historical occupancy of different receptors by antipsychotics. Psychiatry Res. 2025; 348: 116452. doi: 10.1016/j.psychres.2025.116452Sudar FP, Zekerallah SS, Paulzen M, Mathiak K, Gaebler AJ. Unraveling antipsychotic induced weight gain in schizophrenia - A proof-of-concept study exploring the impact of the cumulative historical occupancy of different receptors by antipsychotics. Psychiatry Res. 2025; 348: 116452. doi: 10.1016/j.psychres.2025.116452Martin WF, Correll CU, Weiden PJ, Jiang Y, Pathak S, DiPetrillo L, et al. Mitigation of Olanzapine-Induced Weight Gain with Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients with Schizophrenia. Am J Psychiatry. 2019; 176(6): 457-467. doi: 10.1176/appi.ajp.2018.18030280Martin WF, Correll CU, Weiden PJ, Jiang Y, Pathak S, DiPetrillo L, et al. Mitigation of Olanzapine-Induced Weight Gain with Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients with Schizophrenia. Am J Psychiatry. 2019; 176(6): 457-467. doi: 10.1176/appi.ajp.2018.18030280Zheng X, Wu Z, Xu J, Zhang X, Tu Y, Lei J, et al. Bioactive sesquiterpenes from Inula helenium. Bioorg Chem. 2021; 114: 105066. doi: 10.1016/j.bioorg.2021.105066Zheng X, Wu Z, Xu J, Zhang X, Tu Y, Lei J, et al. Bioactive sesquiterpenes from Inula helenium. Bioorg Chem. 2021; 114: 105066. doi: 10.1016/j.bioorg.2021.105066Jung YS, Jeong YJ, Kim JH, Jeon CH, Lee SO. Elecampane (Inula helenium) Root Extract and Its Major Sesquiterpene Lactone, Alantolactone, Inhibit Adipogenesis of 3T3-L1 Preadipocytes. Molecules. 2022; 27(15): 4765. doi: 10.3390/molecules27154765Jung YS, Jeong YJ, Kim JH, Jeon CH, Lee SO. Elecampane (Inula helenium) Root Extract and Its Major Sesquiterpene Lactone, Alantolactone, Inhibit Adipogenesis of 3T3-L1 Preadipocytes. Molecules. 2022; 27(15): 4765. doi: 10.3390/molecules27154765Jung YS, Lee HS, Cho HR, Kim KJ, Kim JH, Safe S, et al. Dual targeting of Nur77 and AMPKa by isoalantolactone inhibits adipogenesis in vitro and decreases body fat mass in vivo. Int J Obes (Lond). 2019; 43(5): 952-962. doi: 10.1038/s41366-018-0276-xJung YS, Lee HS, Cho HR, Kim KJ, Kim JH, Safe S, et al. Dual targeting of Nur77 and AMPKa by isoalantolactone inhibits adipogenesis in vitro and decreases body fat mass in vivo. Int J Obes (Lond). 2019; 43(5): 952-962. doi: 10.1038/s41366-018-0276-xTavares WR, Seca AML. Inula L. Secondary Metabolites against Oxidative Stress-Related Human Diseases. Antioxidants. 2019; 8(5): 122. doi: 10.3390/antiox8050122Tavares WR, Seca AML. Inula L. Secondary Metabolites against Oxidative Stress-Related Human Diseases. Antioxidants. 2019; 8(5): 122. doi: 10.3390/antiox8050122Rubin GM, Yandell MD, Wortman JR, Gabor Miklos GL, Nelson CR, Hariharan IK, et al. Science. 2000; 287(5461): 2204-15. doi: 10.1126/science.287.5461.2204Rubin GM, Yandell MD, Wortman JR, Gabor Miklos GL, Nelson CR, Hariharan IK, et al. Science. 2000; 287(5461): 2204-15. doi: 10.1126/science.287.5461.2204Eriksson A, Raczkowska M, Navawongse R, Choudhury D, Stewart JC, Tang YL, et al. Neuromodulatory circuit effects on Drosophila feeding behaviour and metabolism. Sci Rep. 2017; 7(1): 8839. doi: 10.1038/s41598-017-08466-0Eriksson A, Raczkowska M, Navawongse R, Choudhury D, Stewart JC, Tang YL, et al. Neuromodulatory circuit effects on Drosophila feeding behaviour and metabolism. Sci Rep. 2017; 7(1): 8839. doi: 10.1038/s41598-017-08466-0Lin S, Senapati B, Tsao CH. Neural basis of hunger-driven behaviour in Drosophila. Open Biol. 2019; 9(3): 180259. doi: 10.1098/rsob.180259Lin S, Senapati B, Tsao CH. Neural basis of hunger-driven behaviour in Drosophila. Open Biol. 2019; 9(3): 180259. doi: 10.1098/rsob.180259Erion R, King AN, Wu G, Hogenesch JB, Sehgal A. Neural clocks and Neuropeptide F/Y regulate circadian gene expression in a peripheral metabolic tissue. Elife. 2016; 5: e13552. doi: 10.7554/eLife.13552Erion R, King AN, Wu G, Hogenesch JB, Sehgal A. Neural clocks and Neuropeptide F/Y regulate circadian gene expression in a peripheral metabolic tissue. Elife. 2016; 5: e13552. doi: 10.7554/eLife.13552Beck B. Neuropeptide Y in normal eating and in genetic and dietary-induced obesity. Philos Trans R Soc Lond B Biol Sci. 2006; 361(1471): 1159-85. doi: 10.1098/rstb.2006.1855Beck B. Neuropeptide Y in normal eating and in genetic and dietary-induced obesity. Philos Trans R Soc Lond B Biol Sci. 2006; 361(1471): 1159-85. doi: 10.1098/rstb.2006.1855Chen X, Yu Y, Zheng P, Jin T, He M, Zheng M, et al. Olanzapine increases AMPK-NPY orexigenic signaling by disrupting H1R-GHSR1a interaction in the hypothalamic neurons of mice. Psychoneuroendocrinology. 2020; 114: 104594. doi: 10.1016/j.psyneuen.2020.104594Chen X, Yu Y, Zheng P, Jin T, He M, Zheng M, et al. Olanzapine increases AMPK-NPY orexigenic signaling by disrupting H1R-GHSR1a interaction in the hypothalamic neurons of mice. Psychoneuroendocrinology. 2020; 114: 104594. doi: 10.1016/j.psyneuen.2020.104594Palasz A, Bandyszewska M, Rojczyk E, Wiaderkiewicz R. Effect of extended olanzapine administration on POMC and neuropeptide Y mRNA levels in the male rat amygdala and hippocampus. Pharmacol Rep. 2016; 68(2): 292-6. doi: 10.1016/j.pharep.2015.09.012Palasz A, Bandyszewska M, Rojczyk E, Wiaderkiewicz R. Effect of extended olanzapine administration on POMC and neuropeptide Y mRNA levels in the male rat amygdala and hippocampus. Pharmacol Rep. 2016; 68(2): 292-6. doi: 10.1016/j.pharep.2015.09.012Varlamov O, Kievit P, Phu K, Reddy AP, Roberts CT Jr, Bethea CL. Preliminary Examination of Olanzapine and Diet Interactions on Metabolism in a Female Macaque. J Endocrinol Diabetes. 2014; 1(2): 9. doi: 10.15226/2374-6890/1/2/00112Varlamov O, Kievit P, Phu K, Reddy AP, Roberts CT Jr, Bethea CL. Preliminary Examination of Olanzapine and Diet Interactions on Metabolism in a Female Macaque. J Endocrinol Diabetes. 2014; 1(2): 9. doi: 10.15226/2374-6890/1/2/00112Промышленная технология лекарств. Том 2. НФАУ МТК. Харьков, 2002.Industrial technology of drugs. Vol. 2. NFAU MTK, Har'kov, 2002 (In Russ.).Gargano JW, Martin I, Bhandari P, Grotewiel MS. Rapid iterative negative geotaxis (RING): a new method for assessing age-related locomotor decline in Drosophila. Exp Gerontol. 2005; 40(5): 386-95. doi: 10.1016/j.exger.2005.02.005Gargano JW, Martin I, Bhandari P, Grotewiel MS. Rapid iterative negative geotaxis (RING): a new method for assessing age-related locomotor decline in Drosophila. Exp Gerontol. 2005; 40(5): 386-95. doi: 10.1016/j.exger.2005.02.005Madabattula ST, Strautman JC, Bysice AM, O'Sullivan JA, Androschuk A, Rosenfelt C, et al. Quantitative Analysis of Climbing Defects in a Drosophila Model of Neurodegenerative Disorders. J Vis Exp. 2015; (100): e52741. doi: 10.3791/52741Madabattula ST, Strautman JC, Bysice AM, O'Sullivan JA, Androschuk A, Rosenfelt C, et al. Quantitative Analysis of Climbing Defects in a Drosophila Model of Neurodegenerative Disorders. J Vis Exp. 2015; (100): e52741. doi: 10.3791/52741Eickelberg V, Lüersen K, Staats S, Rimbach G. Phenotyping of Drosophila Melanogaster - A Nutritional Perspective. Biomolecules. 2022; 12(2): 221. doi: 10.3390/biom12020221Eickelberg V, Lüersen K, Staats S, Rimbach G. Phenotyping of Drosophila Melanogaster - A Nutritional Perspective. Biomolecules. 2022; 12(2): 221. doi: 10.3390/biom12020221Rajan A, Perrimon N. Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell. 2012; 151(1): 123-37. doi: 10.1016/j.cell.2012.08.019. Erratum in: Cell. 2013 Feb 28; 152(5): 1197.Rajan A, Perrimon N. Drosophila cytokine un-paired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell. 2012; 151(1): 123-37. doi: 10.1016/j.cell.2012.08.019. Erratum in: Cell. 2013 Feb 28; 152(5): 1197.

The authors declare that there are no conflicts of interest present.