Anxiolytic-like effects of orientin in mice: behavioral and neurochemical investigations

Year 2025, Volume: 50 Issue: 3, 796 - 805, 30.09.2025

Tuğçe Selcen Arslan , Hazal Eken , Feyza Alyu Altınok , Nurcan Bektaş Türkmen , Rana Arslan

https://doi.org/10.17826/cumj.1679733

Abstract

Purpose: Orientin, a water-soluble flavonoid C-glycoside found in various medicinal plants, exhibits diverse pharmacological properties. This study aimed to evaluate its anxiolytic-like effects in mice and to explore the potential roles of adrenergic, serotonergic, and GABAergic neurotransmitter systems in mediating these effects.
Materials and Methods: Orientin was administered intraperitoneally to mice at 20, 40, or 80 mg/kg. Anxiolytic-like effects were assessed using the light–dark box, elevated plus maze, hole-board, and open-field tests. For mechanism studies, separate groups received α₂-adrenergic antagonist yohimbine (5 mg/kg), 5-HT1A antagonist WAY-100635 (1 mg/kg), or GABAA antagonist flumazenil (3 mg/kg) prior to 20 mg/kg orientin.
Results: Orientin at 20 mg/kg elicited significant anxiolytic-like effects in the hole-board, light–dark box, and open-field tests. The 40 mg/kg dose produced a significant effect only in the hole-board test, whereas the 80 mg/kg dose failed to elicit significant changes in any behavioral paradigm. The pronounced efficacy observed at 20 mg/kg suggests a bell-shaped dose–response profile. Pretreatment with α₂-adrenergic, 5-HT1A serotonergic, or GABAA receptor antagonists partially or completely attenuated the effects of orientin, with the degree of reversal varying among the behavioral assays.
Conclusion: The present findings provide compelling evidence that orientin exerts anxiolytic-like effects, potentially mediated via α₂-adrenergic, 5-HT1A serotonergic, and GABAA receptor pathways.

Keywords

Anxiolytic Effects , Flumazenil , Orientin , WAY-100635 , Yohimbine

Ethical Statement

The experiments were conducted with approval from the Anadolu University Local Ethics Committee (Decision no: 2017-13).

Project Number

AUBAP-1610S655.

Orientinin fare modellerinde anksiyolitik benzeri etkileri: davranışsal ve nörokimyasal incelemeler

Abstract

Amaç: Orientin, çeşitli tıbbi bitkilerde bulunan suda çözünebilen bir flavonoid C-glikozididir ve geniş bir farmakolojik aktivite yelpazesine sahiptir. Bu çalışma, orientinin anksiyolitik benzeri etkilerini değerlendirmeyi ve bu etkilerde adrenerjik, serotonerjik ve GABAerjik sistemlerin potansiyel rolünü araştırmayı amaçladı.
Gereç ve Yöntem: Orientin, farelere intraperitoneal olarak 20, 40 veya 80 mg/kg dozlarında uygulandı. Anksiyolitik benzeri etkiler, aydınlık-karanlık kutu, yükseltilmiş artı labirent, delikli tahta ve open-field testleri ile değerlendirildi. Mekanizma çalışmalarında, ayrı gruplara 20 mg/kg orientin uygulanmadan önce α₂-adrenerjik antagonist yohimbine (5 mg/kg), 5-HT1A antagonist WAY-100635 (1 mg/kg) veya GABAA antagonist flumazenil (3 mg/kg) verildi.
Bulgular: 20 mg/kg orientin, delikli tahta, aydınlık-karanlık kutu ve açık alan testleri testlerinde anlamlı anksiyolitik benzeri etkiler göstermiştir. 40 mg/kg doz, yalnızca delikli tahta testinde anlamlı bir etki üretirken, 80 mg/kg doz hiçbir davranışsal parametrede anlamlı değişiklik oluşturamamıştır. 20 mg/kg’de gözlenen belirgin etki, çan şeklinde bir doz-cevap profilini işaret etmektedir. α₂-adrenerjik, 5-HT1A serotonerjik veya GABAA reseptör antagonistleri ile ön tedavi, orientinin etkilerini kısmen veya tamamen azaltmış, geri dönüşün derecesi davranış testleri arasında değişiklik göstermiştir.
Sonuç: Orientin, büyük ölçüde α₂-adrenerjik, 5-HT1A serotonerjik ve GABAA reseptör yolları aracılığıyla anksiyolitik benzeri etkiler göstermektedir.

Keywords

Anksiyolitik etkiler , Flumazenil , Orientin , WAY-100635 , Yohimbin

Project Number

AUBAP-1610S655.

References

• Bandelow S, Michaelis S. Epidemiology of anxiety disorders in the 21st century. Dialogues Clin Neurosci. 2015;17:327-35.
• Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602.
• Merikangas KR, Low NC. Genetic epidemiology of anxiety disorders. Handb Exp Pharmacol. 2005;169:163-79.
• Dhawan K, Kumar S, Sharma A. Comparative anxiolytic activity profile of various preparations of Passiflora incarnata linneaus: a comment on medicinal plants' standardization. J Altern Complement Med. 2002;8:283-91.
• Bandelow B, Michaelis S, Wedekind D. Treatment of anxiety disorder. Dialogues Clin Neurosci. 2017;19:93-107.
• Miroddi M, Calapai G, Navarra M, Minciullo PL, Gangemi S. Passiflora incarnata L.: ethnopharmacology, clinical application, safety and evaluation of clinical trials. J Ethnopharmacol. 2013;150:791-804.
• Deng J, Zhou Y, Bai M, Li H, Li L. Anxiolytic and sedative activities of Passiflora edulis f. flavicarpa. J Ethnopharmacol. 2010;128:148-53.
• Lam KY, Ling AP, Koh RY, Wong YP, Say YH. A review on medicinal properties of orientin. Adv Pharm Sci. 2016;2016:4104595.
• Ku SK, Kwak S, Bae JS. Orientin inhibits high glucose-induced vascular inflammation in vitro and in vivo. Inflammation. 2014;37:2164-73.
• Liu Y, Lan N, Ren J, Wu Y, Wang ST, Huang XF et al. Orientin improves depression-like behavior and BDNF in chronic stressed mice. Mol Nutr Food Res. 2015;59:1130-42.
• Bektas N, Arslan R, Alyu F. The anxiolytic effect of perampanel and possible mechanisms mediating its anxiolytic effect in mice. Life Sci. 2020;261:118359.
• Haj-Mirzaian A, Amiri S, Kordjazy N, Rahimi-Balaei M, Haj-Mirzaian H, Marzban A et al. Blockade of NMDA receptors reverses the depressant, but not anxiogenic effect of adolescence social isolation in mice. Eur J Pharmacol. 2015;750:160-6.
• Chen J, Lin D, Zhang C, Li G, Zhang N, Ruan L et al. Antidepressant-like effects of ferulic acid: involvement of serotonergic and norepinergic systems. Metab Brain Dis. 2015;30:129-36.
• Marazioti A, Spyraki C, Thermos K. GABA antagonists reverse the somatostatin dependent attenuation of rat locomotor activity. Neuropeptides. 2009;43:207-12.
• Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc. 2007;2:322-8.
• Vieira MP, Silva OB, Souza GF, Cavalcante GT, Souza FM, Gitaí DL et al. First evaluation of the anxiolytic-like effects of a bromazepam palladium complex in mice. J Inorg Biochem. 2022;237:112012.
• Es-Safi I, Mechchate H, Amaghnouje A, Elbouzidi A, Bouhrim M, Bencheikh N et al. Assessment of antidepressant-like, anxiolytic effects and impact on memory of Pimpinella anisum L. total extract on Swiss albino mice. Plants. 2021;10:1573.
• Tucker LB, McCabe JT. Measuring anxiety-like behaviors in rodent models of traumatic brain injury. Front Behav Neurosci. 2021;15:682935.
• Pentkowski NS, Rogge-Obando KK, Donaldson TN, Bouquin SJ, Clark BJ. Anxiety and Alzheimer’s disease: behavioral analysis and neural basis in rodent models of Alzheimer’s-related neuropathology. Neurosci Biobehav Rev. 2021;127:647-58.
• Eken H, Turkmen NB, Senel B, Arslan R. Examination of the effects of vitexin and vitexin-loaded solid lipid nanoparticles on neuropathic pain and possible mechanisms of action. Neuropharmacology. 2024;253:109961.
• Terao T, Ishii N, Hirakawa H, Aoshima E. Is the bell-shaped dose-response curve of the selective serotonin reuptake inhibitor due to 5-HT1A auto-receptors? Med Hypotheses. 2020;140:109681.
• Yu HS, Lee SY, Jang CG. Involvement of 5-HT1A and GABA(A) receptors in the anxiolytic-like effects of Cinnamomum cassia in mice. Pharmacol Biochem Behav. 2007;87:164-70.
• La-Vu M, Tobias BC, Schuette PJ, Adhikari A. To approach or avoid: an introductory overview of the study of anxiety using rodent assays. Front Behav Neurosci. 2020;14:145.
• Berumen LC, Rodriguez A, Miledi R, Garcia-Alcocer G. Serotonin receptors in hippocampus. Sci World J. 2012;2012:823493.
• Yamada R, Wada A, Stickley A, Newman‐Tancredi A, Sumiyoshi T. Augmentation therapy with serotonin 5‐HT1A receptor partial agonists on cognitive function in depressive disorders: a systematic review of randomized controlled studies. Neuropsychopharmacol Rep. 2025;45:e70023.
• Renda B, Leri F. The anxiogenic drug yohimbine is a reinforcer in male and female rats. Neuropsychopharmacol. 2024;50:432-43.
• Shiozaki K, Kawabe M, Karasuyama K, Kurachi T, Hayashi A, Ataka K et al. Neuropeptide Y deficiency induces anxiety-like behaviours in zebrafish (Danio rerio). Sci Rep. 2020;10:5913.
• Reyes AAA, Chandler DJ. Convergence of pro-stress and pro-inflammatory signaling in the central noradrenergic system: implications for mood and anxiety disorders. Neuroglia. 2023;4:87-101.
• Hogg S. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav. 1996;54:21-30.
• Dawson GR, Tricklebank MD. Use of the elevated plus maze in the search for novel anxiolytic agents. Trends Pharmacol Sci. 1995;16:33-6.