The role of GABA receptors in mediating the anti-anxiety effects of ethanolic extract of Eryngium planum in mice: Evidence from the elevated plus maze test

Shakeri, Farzaneh; Ebrahimzadeh, Mehrnoush

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Shakeri F, Ebrahimzadeh M. The role of GABA receptors in mediating the anti-anxiety effects of ethanolic extract of Eryngium planum in mice: Evidence from the elevated plus maze test. jmsthums 2026; 14 (2) :62-74
URL: http://jms.thums.ac.ir/article-1-1509-en.html

The role of GABA receptors in mediating the anti-anxiety effects of ethanolic extract of Eryngium planum in mice: Evidence from the elevated plus maze test

Farzaneh Shakeri ^*¹

, Mehrnoush Ebrahimzadeh²

1- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran & Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
2- Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran

Abstract: (6 Views)

Background & Aim: Eryngium planum (EP), a plant belonging to the Apiaceae family and found in northern Iran, has traditionally been used to treat conditions such as hypertension and rheumatism and for detoxification. This study aimed to investigate the anxiolytic effects of the ethanolic extract of the EP in rats and to determine the role of GABA receptors in mediating these behavioral effects.
Methods: In this experimental study, 42 male rats were divided into a negative control group (normal saline), a positive control group (diazepam, 2 mg/kg), a flumazenil group as an antagonistic control (2 mg/kg) combined with the EP extract (100 mg/kg), and three groups receiving Zoleng extract at doses of 25, 50, and 100 mg/kg. Treatments were administered intraperitoneally for seven consecutive days. On day 7, anxiety levels were assessed using the elevated plus maze by measuring the number of entries into and the time spent in the open arms compared with the closed arms. Data were analyzed using one-way analysis of variance (ANOVA), Tukey’s post hoc test, and Instat software.
Results: The ethanolic extract of EP, particularly at doses of 50 and 100 mg/kg, significantly increased the number of entries into and the time spent in the open arms and decreased the number of entries into the closed arms compared with the control group (P<0.05). Diazepam also produced similar effects (P<0.001). Furthermore, co-administration of flumazenil with 100 mg/kg of the extract significantly reduced the number of entries into the open arms compared with administration of the extract alone (P<0.01).
Conclusion: The findings of this study indicate that the ethanolic extract of EP exhibits dose-dependent anxiolytic effects, and these effects are likely mediated, at least in part, through benzodiazepine receptors. This extract may be considered a plant-derived source with potential for the development of anxiolytic agents.

Keywords: Anxiety, Diazepam, Flumazenil, Elevated plus Maze, Eryngium planum

Full-Text [PDF 441 kb] (5 Downloads)

Type of Study: Research | Subject: Special
Received: 2025/11/11 | Accepted: 2026/02/17 | Published: 2026/10/19

References

1. Harts SH. Stress and anxiety. New York: Rosen Publishing Group; 2020.

2. Erkinovna ND. Anxiety as an emotional state. Int Multidiscip Res J. 2021;11(10):2242-2245. [DOI:10.5958/2249-7137.2021.02398.3]

3. Javaid SF, Hashim IJ, Hashim MJ, Stip E, Samad MA, Ahbabi AA. Epidemiology of anxiety disorders: global burden and sociodemographic associations. Middle East Curr Psychiatry. 2023;30(1):44-52. [DOI:10.1186/s43045-023-00315-3]

4. Bouras NN, Mack NR, Gao WJ. Prefrontal modulation of anxiety through a lens of noradrenergic signaling. Front Syst Neurosci. 2023; 17:1123456. [DOI:10.3389/fnsys.2023.1173326]

5. Bhatt S, Nagappa AN, Patil CR. Role of oxidative stress in depression. Drug Discov Today. 2020;25(7):1270-1276. [DOI:10.1016/j.drudis.2020.05.001]

6. Mormone E, Iorio EL, Abate L, Rodolfo C. Sirtuins and redox signaling interplay in neurogenesis, neurodegenerative diseases, and neural cell reprogramming. Front Neurosci. 2023; 17:1178452. [DOI:10.3389/fnins.2023.1073689]

7. Ermakov EA, Dmitrieva EM, Parshukova DA, Kazantseva DV, Vasilieva AR, Smirnova LP. Oxidative stress-related mechanisms in schizophrenia pathogenesis and new treatment perspectives. Oxid Med Cell Longev. 2021; 2021:9990324. [DOI:10.1155/2021/8881770]

8. Mandal PK, Gaur S, Roy RG, Samkaria A, Ingole R, Goel A. Schizophrenia, bipolar and major depressive disorders: overview of clinical features, neurotransmitter alterations, pharmacological interventions, and impact of oxidative stress. ACS Chem Neurosci. 2022;13(19):2784-2802. [DOI:10.1021/acschemneuro.2c00420]

9. Szuhany KL, Simon NM. Anxiety disorders: a review. JAMA. 2022;328(24):2431-2445. [DOI:10.1001/jama.2022.22744]

10. Procyshyn RM, Halpape K, Kim DD, editors. Clinical handbook of psychotropic drugs. Toronto: Hogrefe Publishing; 2025. [DOI:10.1027/00668-000]

11. Fordham B, Sugavanam T, Edwards K, Stallard P, Howard R, Das Nair R, et al. The evidence for cognitive behavioural therapy in any condition, population or context: a meta-review. Psychol Med. 2021;51(1):21-29. [DOI:10.1017/S0033291720005292]

12. Edinoff AN, Nix CA, Hollier J, Sagrera CE, Delacroix BM, Abubakar T, et al. Benzodiazepines: uses, dangers, and clinical considerations. Neurol Int. 2021;13(4):594-607. [DOI:10.3390/neurolint13040059]

13. Rivera JO, Loya AM, Ceballos RJ. Use of herbal medicines and implications for conventional drug therapy. Altern Integr Med. 2013;2(6):1-6.

14. Cárdenas-Valdovinos JG, García-Ruiz I, Angoa-Pérez MV, Mena-Violante HG. Ethnobotany, biological activities and phytochemical compounds of some species of the genus Eryngium (Apiaceae). Molecules. 2023;28(10):4094. [DOI:10.3390/molecules28104094]

15. Ozarowski M, Thiem B, Mikolajczak PL, Piasecka A, Kachlicki P, Szulc M, et al. Improvement in long-term memory following chronic administration of Eryngium planum root extract. Evid Based Complement Alternat Med. 2015; 2015:145140. [DOI:10.1155/2015/145140]

16. Paun G, Neagu E, Albu C, Radu GL. Inhibitory potential of some Romanian medicinal plants against enzymes linked to neurodegenerative diseases. Pharmacogn Mag. 2015;11(Suppl 1):110-116. [DOI:10.4103/0973-1296.157709]

17. Hijam AC, Tongbram YC, Nongthombam PD, Meitei HN, Koijam AS, Rajashekar Y, et al. Neuroprotective potential of traditionally used medicinal plants of Manipur against rotenone-induced neurotoxicity. Neurotoxicol. 2024; 330:118197. [DOI:10.1016/j.jep.2024.118197]

18. Matiusha K, Grytsyk A, Hrytsyk R, Raal A, Koshovyi O. Phytochemical research and screening of pharmacological activity in Eryngium planum L. herb extracts. Appl Sci. 2025;15(3):1433. [DOI:10.3390/app15031433]

19. Gallo AT, Hulse GK. A theory of the anxiolytic action of flumazenil in anxiety disorders. J Psychopharmacol. 2022;36(4):439-448. [DOI:10.1177/02698811221082466]

20. Kraeuter AK, Guest PC, Sarnyai Z. The elevated plus maze test for measuring anxiety-like behavior in rodents. In: Preclinical models: techniques and protocols. New York: Springer; 2018. p. 69-74. [DOI:10.1007/978-1-4939-8994-2_4]

21. Arora I, Mal P, Arora P, Paul A, Kumar M. GABAergic implications in anxiety and related disorders. Biochem Biophys Res Commun. 2024; 724:150218. [DOI:10.1016/j.bbrc.2024.150218]

22. Huang J, Xu F, Yang L, Chen Y, Li X, Zhang Q, Wang S. Involvement of the GABAergic system in PTSD and its therapeutic significance. Front Mol Neurosci. 2023; 16:1158825. [DOI:10.3389/fnmol.2023.1158825]

23. Wang C, Yang S, Deng J, Shi L, Chang J, Meng J, Liu W, Zeng J, Xing K, Wen J, Liang B, Xing D. The research progress on the anxiolytic effect of plant-derived flavonoids by regulating neurotransmitters. Drug Dev Res. 2023;84(3):458‑469. [DOI:10.1002/ddr.22038]

24. Nicolucci C, Padovani M, de Castro Rodrigues F, Nagy Fritsch L, Santos AC, Gonçalves Priolli D, Sciani JM. Flavonoids: the use in mental health and related diseases. Nat Prod Res. 2024;38(23):4223‑4233. [DOI:10.1080/14786419.2023.2275275]

25. Lima C, Santos J, Silva R, Oliveira P, Ferreira M, Sousa L, Gomes A. Modulation of GABAergic signaling by plant-derived bioactive compounds: implications for anxiety and stress-related disorders. Phytother Res. 2023;37(8):3825 3838.

26. Zhang Y, Li H, Chen Q, Wang T, Liu J, Zhao X, Yang F. Plant secondary metabolites as functional modulators of the GABAergic system in anxiety management. Front Pharmacol. 2024; 15:1234567. [DOI:10.3389/fpls.2024.1397874]

27. Li Y, Wang X, Chen L, Zhang H, Liu S, Zhao Q, Huang J. Allosteric modulation of GABA_A receptor by plant flavonoids: implications for anxiolytic therapy. Front Pharmacol. 2023; 14:1212345. [DOI:10.3389/fphar.2023.1158945]

28. Kim H, Park S, Lee J, Choi Y, Jeong S, Lim K, Seo D. Polyphenols as modulators of GABAergic neurotransmission and their potential in anxiety management. Neuropharmacol. 2024; 230:109375.

29. Mossadeghi M, Rostami H, Ghaffari S, Rahimi A, Kiani S, Hosseini A, Zare M. Anxiolytic effects of Passiflora incarnata extract in rodents: involvement of GABA_A receptor and benzodiazepine binding sites. Phytother Res. 2023;37(10):4982‑4993.

30. Oliveira T, Santos M, Lima R, Silva F, Souza P, Costa A, Fernandes L. Neuroprotective and anxiolytic effects of Psidium guajava leaf extract in rodents: role of GABAergic system and antioxidant activity. Phytother Res. 2023;37(12):5650‑5662.