Anti-depressant effect of hesperidin in ovariectomized mice: possible involvement of dopaminergic and serotoninergic systems

Document Type : Research Paper

Authors

1 Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 Department of Clinical Sciences, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran

3 Division of Physiology, Department of Basic Sciences, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran

Abstract

Objective: This study aimed to determine anti-depressant effect of hesperidin in ovariectomized mice and its possible interaction with dopaminergic and serotoninergic systems.
Materials and Methods: In experiment 1, mice were kept as control and sham groups, ovariectomized (OVX), OVX+ hesperidin (12.5 mg/kg), OVX+ hesperidin (25 mg/kg) and OVX+hesperidin (50 mg/kg). In experiment 2, mice were kept as control and sham, OVX, OVX+hesperidin (50 mg/kg), OVX+dopamine (25 mg/kg) and OVX+co-injection of hesperidin and dopamine. Experiments 3-5 were like experiment 2, except 6-OHDA (dopamine inhibitor, 100 mg/kg), fluoxetine (selective serotonin reuptake inhibitor, 5 mg/kg) and cyproheptadine (serotonergic receptor antagonist, 4 mg/kg) was injected instead of dopamine. Then, forced swimming test (FST), tail suspension test (TST) and open field test (OFT) were done. Also, serum malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and total antioxidant status (TAS) levels were determined.
Results: According to the results, OVX increased immobility time in FST and TST tests as compared to control group (P<0.05). Hesperidin (50 mg/kg) decreased immobility time as compared to OVX group (P<0.05). Co-injection of hesperidin+dopamine decreased immobility time in TST and FST and increased number of crossing in OFT (P<0.05). Co-injection of hesperidin+6-OHDA significantly decreased antidepressant activity of the hesperidin on immobility time and decreased positive effect of the hesperidin on the number of crossing (P<0.05). Co-injection of hesperidin+Fluoxetine significantly amplified antidepressant activity of the hesperidin on immobility time and number of crossing (P<0.05). Co-injection of hesperidin+cyproheptadine decreased antidepressant activity of hesperidin on immobility time (P<0.05). Hesperidin (12.5, 25 and 50 mg/kg) decreased the MDA, while increased SOD and GPx levels in OVX mice (P<0.05).
Conclusion: It is assumed that antidepressant activity of hesperidin is mediated via dopaminergic and serotoninergic receptors in OVX mice.

Keywords

References

  1.  Saravi SSS, Arefidoust A, Yaftian R, Saravi SSS, Dehpour AR. 17 alpha-ethinyl estradiol attenuates depressive-like behavior through GABA(A) receptor activation/nitrergic pathway blockade in ovariectomized mice. Psychopharmacology 2016; 233(8):1467-85. doi: 10.1007/s00213-016-4242-9.
  2. Albert KM, Newhouse PA. Estrogen, stress, and depression: cognitive and biological interactions. Annual Review of Clinical Psychology 2019; 15:399-423. doi: 10.1146/annurev-clinpsy-050718-095557
  3. Newhouse P, Albert K. Estrogen, stress, and depression: a neurocognitive model. JAMA Psychiatry 2015; 72(7):727-9. doi: 10.1001/jamapsychiatry.2015.0487.
  4. Albert K, Gau V, Taylor WD, Newhouse PA. Attention bias in older women with remitted depression is associated with enhanced amygdala activity and functional connectivity. Journal of Affective Disorders 2017; 210:49-56. doi: 10.1016/j.jad.2016.12.010.
  5. Heydarpour P, Salehi-Sadaghiani M, Javadi-Paydar M, Rahimian R, Fakhfouri G, Khosravi M, et al. Estradiol reduces depressive-like behavior through inhibiting nitric oxide/cyclic GMP pathway in ovariectomized mice. Hormones Behaviour 2013; 63(2):361-9. doi: 10.1016/j.yhbeh.2012.12.005.
  6. Amin B, Nakhsaz A, Hosseinzadeh H. Evaluation of the antidepressant-like effects of acute and sub-acute administration of crocin and crocetin in mice. Avicenna Journal of Phytomedicine 2015; 5(5): 458-468. PMID: 26468466
  7. Macqueen G, Frodl T. The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Molecular Psychiatry 2011; 16(3):252-64. doi: 10.1038/mp.2010.80.
  8. Madhavan A, Argilli E, Bonci A, Whistler JL. Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area. Journal of Neuroscience 2013; 33(30):12329-36. doi: 10.1523/JNEUROSCI.0809-13.2013.
  9. Miguelez C, Berrocoso E, Mico JA, Ugedo L. L-DOPA modifies the antidepressant-like effects of reboxetine and fluoxetine in rats. Neuropharmacology 2013; 67:349-58. doi: 10.1016/j.neuropharm.2012.11.016.
  10. Luo Z, Narayanan NS, Fisher RA. Age-dependent nigral dopaminergic neurodegeneration and a-synuclein accumulation in RGS6-deficient mice. JCI Insight; 2019; 5(13):e126769. doi: 10.1172/jci.insight.126769.
  11. Rajkumar R, Mahesh R. The auspicious role of the 5-HT3 receptor in depression: a probable neuronal target. Journal of Psychopharmacology 2010; 24(4):455-69. doi: 10.1177/0269881109348161.
  12. Blohberger J, Buck T, Berg D, Berg U, Kunz L, Mayerhofer A. L-DOPA in the human ovarian follicular fluid acts as an antioxidant factor on granulosa cells. Journal of Ovarian Research 2016; 9(1):62. doi: 10.1186/s13048-016-0269-0.
  13. Song D, Ma K, Verkhratsky A, Peng L. L-Dopa and fluoxetine upregulate astroglial 5-HT2B receptors and ameliorate depression in Parkinson’s disease mice. Neuroglia 2018; 1(6):48-62. doi:10.3390/neuroglia1010006.
  14. Adongo DW, Kukuia KKE, Mante PK, Ameyaw EO, Woode E. Antidepressant-like effect of the leaves of Pseudospondias microcarpa in mice: evidence for the involvement of the serotoninergic system, NMDA receptor complex, and nitric oxide pathway. BioMed Research International 2015:397943. doi: 10.1155/2015/397943.
  15. Li C, Schluesener H. Health-promoting effects of the citrus flavanone hesperidin. Critical Reviews in Food Science and Nutrition 2017; 57: 613-631.
  16. Iranshahi M, Rezaee R, Parhiz H, Roohbakhsh A, Soltani F. Protective effects of flavonoids against microbes and toxins: The cases of hesperidin and hesperetin. Life Science 2015; 137:125-32. doi: 10.1016/j.lfs.2015.07.014.
  17. Hajialyani M, Farzaei MH, Echeverría J, Nabavi SM, Uriarte E, Sobarzo-Sánchez E. Hesperidin as a neuroprotective agent: A review of animal and clinical evidence. Molecule 2019; 24(3):648. doi: 10.3390/molecules24030648.
  18. Khan MHA, Parvez S. Hesperidin ameliorates heavy metal induced toxicity mediated by oxidative stress in brain of Wistar rats. Journal of Trace Elements in Medicine and Biology 2015; 31:53-60. doi: 10.1016/j.jtemb.2015.03.002.
  19. Matias I, Diniz LP, Buosi A, Neves G, Stipursky J, Gomes FCA. Flavonoid hesperidin induces synapse formation and improves memory performance through the astrocytic TGF-β1. Front Aging Neuroscience 2017; 9:184. doi: 10.3389/fnagi.2017.00184. eCollection 2017.
  20. Antunes MS, Goes AT, Boeira SP, Prigol M, Jesse CR. Protective effect of hesperidin in a model of Parkinson's disease induced by 6-hydroxydopamine in aged mice. Nutrition 2014; 30(11-12):1415-22. doi: 10.1016/j.nut.2014.03.024.
  21. Souza LC, de Gomes MG, Goes AT, Del Fabbro L, Carlos Filho B, Boeira SP, et al. Evidence for the involvement of the serotonergic 5-HT 1A receptors in the antidepressant-like effect caused by hesperidin in mice. Progress in Neuro-Psychopharmacology 2013; 40:103-9. doi: 10.1016/j.pnpbp.2012.09.003.
  22. Filho CB, Souza LC, de Gomes MC, Goes ATR, Souza LC, Boeira SP, et al. Kappa-opioid receptorsmediate the antidepressant-like activity of hesperidin in the mouse forced swimming test. European Journal of Pharmacology 2013; 698(1-3):286-91. doi: 10.1016/j.ejphar.2012.11.003.
  23. Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983; 16(2):109-110. doi: 10.1016/0304-3959(83)90201-4.
  24. Donato F, de Gomes MG, Goes AT, Filho CB, Del Fabbro, Antunes M.S, et al.  Hesperidin exerts antidepressant-like effects in acute and chronic treatments in mice: possible role of l-arginine-NOcGMP pathway and BDNF levels. Brain Research Bulletin 2014; 104:19-26. doi: 10.1016/j.brainresbull.2014.03.004.
  25. Kalbasi Anaraki D, Sianati S, Sadeghi M, Ghasemi M, Paydar MJ, Ejtemaei Mehr S, et al. Modulation by female sex hormones of the cannabinoid-induced catalepsy and analgesia in ovariectomized mice. European Journal of Pharmacology 2008; 586(1-3):189-96. doi: 10.1016/j.ejphar.2008.02.055.
  26. Sadeghi M, Sianati S, Anaraki DK, Ghasemi M, Paydar MJ, Sharif B, et al. Study of morphine-induced dependence in gonadectomized male and female mice. Pharmacology Biochemistry & Behavior 2009; 91(4):604-9. doi: 10.1016/j.pbb.2008.09.015.
  27. Malekinejad H, Hamidi M, Sadrkhanloo RA, Ahmadi A. The effect of tamoxifen on the fetal and neonatal ovarian follicles development in rats. Iranian Journal of Basic Medical Sciences 2011; 14(3):240–248.
  28. Castagné V, Moser P, Roux S, Porsolt RD. Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Current Protocols in Neuroscience 2011; Chapter 8:Unit 8.10A. doi: 10.1002/0471142301.ns0810as55.
  29. Cryan JF, Mombereau C, Vassout A. The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neuroscience & Biobehavioral Reviews 2005; 29(4-5):571-625. doi: 10.1016/j.neubiorev.2005.03.009.
  30. Steru LR, Chermat B, Thierry PS. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 1985; 85(3): 367–370.
  31. Kulkarni SK, Dhir A. On the mechanism of antidepressant-like action of berberine chloride. European Journal of Pharmacology 2008; 589(1-3):163-72. doi: 10.1016/j.ejphar.2008.05.043.
  32. Soto-Otero R, M_endez-Alvarez E, Hermida-Ameijeiras A, Mu~noz- Pati~no AM, Labandeira-Garcia JL. Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson’s disease. Journal of Neurochemistry 2000; 74(4):1605-12. doi: 10.1046/j.1471-4159.2000.0741605.x.
  33. Zhao G, He F, Wu C, Li P, Li N, Deng J, et al. Betaine in Inflammation: Mechanistic Aspects and Applications. Frontiers in Immunology 2018; 9:1070. doi: 10.3389/fimmu.2018.01070.
  34. Martínez AL, González-Trujano ME, Chávez M, Pellicer F, Moreno J, López-Muñoz FJ. Hesperidin produces antinociceptive response and synergistic interaction with ketorolac in an arthritic gout-type pain in rats. Pharmacology Biochemistry & Behavior 2011; 97(4):683-9. doi: 10.1016/j.pbb.2010.11.010.
  35. Du B, Tang X, Liu F, Zhang C, Zhao G, Ren F, et al. Antidepressant-like effects of the hydroalcoholic extracts of Hemerocallis Citrina and its potential active components. BMC Complementary and Alternative Medicine 2014; 14:326. doi: 10.1186/1472-6882-14-326.
  36. Nadar JS, Kale PP, Kadu PK, Prabhavalkar K, Dhangar R. Potentiation of antidepressant effects of agomelatine and bupropion by hesperidin in mice. Neurology Research International 2018:9828639. doi: 10.1155/2018/9828639. eCollection 2018.
  37. Tominaga K, Kido T, Ochi M, Sadakane C, Mase A, Okazaki H, Yamagami H, Tanigawa T, Watanabe K, Watanabe T, Fujiwara Y. The traditional Japanesemedicine rikkunshito promotes gastric emptying via the antagonistic action of the 5-HT 3 receptor pathway in rats. Evidence-Based Complementary and Alternative Medicine 2011; https://doi.org/10.1093/ecam/nep173.
  38. Takeda H, Sadakane C, Hattori T, Katsurada T, Ohkawara T, Nagai K, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology 2008; 134(7):2004-13. doi: 10.1053/j.gastro.2008.02.078.
  39. Jin YR, Han XH, Zhang YH, Lee JJ, Y Lim, Chung JH, Yun YP. Antiplatelet activity of hesperetin, a bioflavonoid, is mainly mediated by inhibition of PLC-γ2 phosphorylation and cyclooxygenase-1 activity. Atherosclerosis 2007; 194(1):144-52. doi: 10.1016/j.atherosclerosis.2006.10.011.
  40. Mahmoudi J, Nayebi AM, Reyhani-Rad S, Samini M. Fluoxetine improves the effect of levodopa on 6-hydroxy dopamine-induced motor impairments in rats. Advanced Pharmaceutical Bulletin 2012;2(2):149-55. doi: 10.5681/apb.2012.023.
  41. Khodadadeh A, Hassanpour S, Akbari G. Exposure to Hesperidin during pregnancy exerts antidepressant-like effects postpartum in mice. Iranian Journal of Veterinary Medicine 2020; 14(3):261-272.
  42. Roohbakhsh A, Parhiz H, Soltani F, Rezaee R, Iranshahi M. Neuropharmacological properties and pharmacokinetics of the citrus flavonoids hesperidin and hesperetin - A mini-review. Life Science 2014; 113(1-2):1-6. doi: 10.1016/j.lfs.2014.07.029.
  43. Pari L, Karthikeyan A, Karthika P, Rathinam A. Protective effects of hesperidin on oxidative stress,dyslipidaemia and histological changes in iron-inducedhepatic and renal toxicity in rats. Toxicology Reports 2015; 2:46–55. doi: 10.1016/j.toxrep.2014.11.003. eCollection 2015.
  44. Visnagri A, Kandhare AD, S Chakravarty, P Ghosh, Bodhankar SL. Hesperidin, a flavanoglycone attenuates experimental diabetic neuropathy via modulation of cellular and biochemical marker to improve nerve functions. Pharmaceutical Biology 2014; 52(7): 814–28. doi: 10.3109/13880209.2013.870584.
  45. Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BW. Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology 2015; 51: 164-175. doi: 10.1016/j.psyneuen.2014.09.025.
  46. Huang S, Tsai S, Lin J, Wu C, Yen G. Cytoprotective effects of hesperetin and hesperidin against amyloid b-induced impairment of glucose transport through downregulation of neuronal autophagy. Molecular Nutrition Food Research 2012; 56(4): 601–609. https://doi.org/10.1002/mnfr.201100682.
Journal of Basic and Clinical Pathophysiology
Volume 9, Issue 1
May 2021
Pages 1-15

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