Antidepressant-Like Effects of Hesperidin in Animal Model of Post-Traumatic Stress Disorder - Chinese Journal of Integrative Medicine

Objective

Post-traumatic stress disorder (PTSD) is a psychiatric disorder characterized by depression and anxiety, that arises due to an imbalance of neurotransmitters in response to excessive stress. Hesperidin (HSD) is a naturally occurring flavonoid shown to exert a variety of biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects.

Methods

This study was used the open field test (OFT) and forced swimming test (FST) to examine the effects of HSD on the depression-like response of rats after exposure to a single prolonged stress (SPS) leading to the dysregulation of the serotonergic activation system. Male rats were given HSD (20, 50, and 100 mg/kg, intraperitoneal injection, n=6–7 per group) once daily for 14 days after exposure to SPS. The influence of administration of HSD on SPS-induced behavioral responses and concentrations of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and monoamine oxidase-A (MAO-A) in the rat brain were also investigated using enzyme-linked immunoassays (ELISAs).

Results

Daily HSD administration signifificantly improved depression-like behaviors in the FST (P0.05), increased the number of lines crossed in the central zone of the OFT (P0.01), and reduced freezing behavior both in contextual and cued fear conditioning. HSD treatment also attenuated the reduction in SPS-induced 5-HT concentrations in the hippocampus and amygdala. This increase in 5-HT concentrations during HSD treatment was partially attributed to a decrease in the 5-HIAA/5-HT ratio in the hippocampus of rats with PTSD. Furthermore, HSD treatment inhibited activity of MAO-A and decreases of tryptophan hydroxylase-1 expression in the hippocampus.

Conclusion

HSD was shown to exert antidepressant effects in rats exposed to SPS, suggesting that this natural flflavonoid may be an effective medicine for PTSD.

1. Lin CC, Tung CS, Lin PH, Huang CL, Liu YP. Traumatic stress causes distinctive effects on fear circuit catecholamines and the fear extinction profile in a rodent model of posttraumatic stress disorder. Eur Neuropsychopharmacol 2016;26:1484–1495.

   Article  CAS  Google Scholar 

2. Ji LL, Tong L, Xu BK, Fu CH, Shu W, Peng JB, et al. Intrahippocampal administration of ZIP alleviates depressive and anxiety-like responses in an animal model of posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2014;54:284–288.

   Article  CAS  Google Scholar 

3. Serova LI, Laukova M, Alaluf LG, Pucillo L, Sabban EL. Intranasal neuropeptide Y reverses anxiety and depressivelike behavior impaired by single prolonged stress PTSD model. Eur Neuropsychopharmacol 2014;24:142–147.

   Article  CAS  Google Scholar 

4. Ravindran LN, Stein MB. Pharmacotherapy of post-traumatic stress disorder. Curr Top Behav Neurosci 2010;2:505–525.

   Article  Google Scholar 

5. Wu ZM, Ni GL, Shao AM, Cui R. Genistein alleviates anxiety-like behaviors in post traumatic stress disorder model through enhancing serotonergic transmission in the amygdala. Psychiatry Res 2017;255:287–291.

   Article  CAS  Google Scholar 

6. Justin Thenmozhi A, Raja TR, Janakiraman U, Manivasagam T. Neuroprotective effect of hesperidin on aluminium chloride induced Alzheimer's disease in Wistar rats. Neurochem Res 2015;40:767–776.

   Article  Google Scholar 

7. Mahmoud AM, Ashour MB, Abdel-Moneim A, Ahmed OM. Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats. J Diabetes Complications 2012;26:483–490.

   Article  Google Scholar 

8. Raza SS, Khan MM, Ahmad A, Ashafaq M, Khuwaja G, Tabassum R, et al. Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke. Brain Res 2011;1420:93–105.

   Article  CAS  Google Scholar 

9. Chang CY, Lin TY, Lu CW, Huang SK, Wang YC, Chou SS, et al. Hesperidin inhibits glutamate release and exerts neuroprotection against excitotoxicity induced by kainic acid in the hippocampus of rats. Neurotoxicology 2015;50:157–169.

   Article  CAS  Google Scholar 

10. 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;30:1415–1422.

    Article  CAS  Google Scholar 

11. Oztanir MN, Ciftci O, Cetin A, Aladag MA. Hesperidin attenuates oxidative and neuronal damage caused by global cerebral ischemia/reperfusion in a C57BL/J6 mouse model. Neurol Sci 2014;35:1393–1399.

    Article  Google Scholar 

12. Li M, Shao H, Zhang X, Qin B. Hesperidin alleviates lipopolysaccharide-Induced neuroinflammation in mice by promoting the miRNA-132 pathway. Inflammation 2016;39:1681–1689.

    Article  CAS  Google Scholar 

13. Donato F, de Gomes MG, Goes AT, Filho CB, Del Fabbro L, Antunes MS, et al. Hesperidin exerts antidepressant-like effects in acute and chronic treatments in mice: possible role of l-arginine-NO-cGMP pathway and BDNF levels. Brain Res Bull 2014;104:19–26.

    Article  CAS  Google Scholar 

14. Souza LC, de Gomes MG, Goes AT, Del Fabbro L, Filho CB, Boeira SP, et al. Evidence for the involvement of the serotonergic 5-HT(1A) receptors in the antidepressantlike effect caused by hesperidin in mice. Prog Neuropsychopharmacol Biol Psychiatry 2013;40:103–109.

    Article  CAS  Google Scholar 

15. Serova LI, Laukova M, Alaluf LG, Sabban EL. Intranasal infusion of melanocortin receptor four (MC4R) antagonist to rats ameliorates development of depression and anxiety related symptoms induced by single prolonged stress. Behav Brain Res 2013;250:139–147.

    Article  CAS  Google Scholar 

16. Lee B, Sur B, Yeom M, Shim I, Lee H, Hahm DH. L-tetrahydropalmatine ameliorates development of anxiety and depression-related symptoms induced by single prolonged stress in rats. Biomol Ther 2014;22:213–222.

    Article  CAS  Google Scholar 

17. Lee B, Shim I, Lee H, Hahm DH. Tetramethylpyrazine reverses anxiety-like behaviors in a rat model of post-traumatic stress disorder. Kor J Physiol Pharmacol 2018;22:525–538.

    Article  CAS  Google Scholar 

18. Geracioti TD, Jr. Baker DG, Kasckow JW, Strawn JR, Jeffrey MJ, Dashevsky BA, et al. Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder. Psychoneuroendocrinology 2008;33:416–424.

    Article  CAS  Google Scholar 

19. Iñiguez SD, Riggs LM, Nieto SJ, Dayrit G, Zamora NN, Shawhan KL, et al. Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice. Stress 2014;17:247–255.

    Article  Google Scholar 

20. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008;455:894–902.

    Article  CAS  Google Scholar 

21. Harrison AA, Liem YT, Markou A. Fluoxetine combined with a serotonin 1A receptor antagonist reversed reward deficits observed during nicotine and amphetamine withdrawal in rats. Neuropsychopharmacology 2001;25:55–71.

    Article  CAS  Google Scholar 

22. El Yacoubi M, Dubois M, Gabriel C, Mocaër E, Vaugeois JM. Chronic agomelatine and fluoxetine induce antidepressantlike effects in H/Rouen mice, a genetic mouse model of depression. Pharmacol Biochem Behav 2011;100:284–288.

    Article  CAS  Google Scholar 

23. Ossewaarde L, Verkes RJ, Hermans EJ, Kooijman SC, Urner M, Tendolkar I, et al. Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits. Biol Psychiatry 2011;70:568–574.

    Article  CAS  Google Scholar 

24. Geracioti TD, Jr. Baker DG, Ekhator NN, West SA, Hill KK, Bruce AB, et al. CSF norepinephrine concentrations in posttraumatic stress disorder. Am J Psychiatry 2001;158:1227–1230.

    Article  Google Scholar 

25. Miao YL, Guo WZ, Shi WZ, Fang WW, Liu Y, Liu J, et al. Midazolam ameliorates the behavior deficits of a rat posttraumatic stress disorder model through dual 18 kDa translocator protein and central benzodiazepine receptor and neurosteroidogenesis. PLoS One 2014;9:e101450.

    Article  Google Scholar 

Download references

Authors and Affiliations

1. Acupuncture and Meridian Science Research Center, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea

   Bombi Lee

2. Center for Converging Humanities, Kyung Hee University, Seoul, 02447, Republic of Korea

   Bombi Lee

3. The Graduate School of Basic Science of Medicine, College of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea

   Gwang Muk Choi

4. Department of Molecular Medicine and TIDRC, School of Medicine, Ewha Womans University, Seoul, 07985, Republic of Korea

   Bongjun Sur

Contributions

Lee B designed the experiments and drafted the manuscript. Sur B helped perform the analysis with constructive discussions and revised the manuscript. Choi GM and Sur B carried out the experiments. Lee B and Sur B contributed to the statistical analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bombi Lee.