Journal of Natural Medicines

, Volume 72, Issue 1, pp 44–56 | Cite as

Effect of oleuropein on cognitive deficits and changes in hippocampal brain-derived neurotrophic factor and cytokine expression in a rat model of post-traumatic stress disorder

  • Bombi LeeEmail author
  • Insop Shim
  • Hyejung Lee
  • Dae-Hyun Hahm
Original Paper


Post-traumatic stress disorder (PTSD) is a condition that develops after an individual has experienced a major trauma. This psychopathological response to traumatic stressors induces learning and memory deficits in rats. Oleuropein (OLE), a major compound in olive leaves, has been reported to possess several pharmacological properties, including anti-cancer, anti-diabetic, anti-atherosclerotic and neuroprotective activities. However, the cognitive effects of OLE and its mechanism of action have remained unclear in PTSD. In this study, we examined whether OLE improved spatial cognitive impairment induced in rats following single prolonged stress (SPS), an animal model of PTSD. Male rats were treated intraperitoneally (i.p.) with vehicle or various doses of OLE for 14 consecutive days after the SPS procedure. The SPS procedure resulted in cognitive impairment in the object recognition task and the Morris water maze test, which was reversed by OLE (100 mg/kg, i.p). Additionally, as assessed by immunohistochemistry and reverse transcription-polymerase chain reaction analysis, the administration of OLE significantly alleviated memory-associated decreases in the levels of brain-derived neurotrophic factor and cAMP response element-binding protein and mRNA in the hippocampus. Together, these findings suggest that OLE attenuated SPS-induced cognitive impairment significantly by inhibiting the expression of pro-inflammatory mediators in the rat brain. Thus, OLE reversed several behavioral impairments triggered by the traumatic stress of SPS and might be a potential useful therapeutic intervention for PTSD.


Oleuropein Memory Post-traumatic stress disorder Brain-derived neurotrophic factor cAMP response element-binding protein Pro-inflammatory cytokines 



This research was supported by a Grant from the National Research Foundation of Korea funded by the Korean government (2016R1D1A1A09917012).


  1. 1.
    Shafia S, Vafaei AA, Samaei SA, Bandegi AR, Rafiei A, Valadan R, Hosseini-Khah Z, Mohammadkhani R, Rashidy-Pour A (2017) Effects of moderate treadmill exercise and fluoxetine on behavioural and cognitive deficits, hypothalamic-pituitary-adrenal axis dysfunction and alternations in hippocampal BDNF and mRNA expression of apoptosis-related proteins in a rat model of post-traumatic stress disorder. Neurobiol Learn Mem 139:165–178CrossRefGoogle Scholar
  2. 2.
    Brunello N, Davidson JR, Deahl M, Kessler RC, Mendlewicz J, Racagni G, Shalev AY, Zohar J (2001) Posttraumatic stress disorder: diagnosis and epidemiology, comorbidity and social consequences, biology and treatment. Neuropsychobiology 43:150–162CrossRefGoogle Scholar
  3. 3.
    Nemeroff CB, Bremner JD, Foa EB, Mayberg HS, North CS, Stein MB (2006) Posttraumatic stress disorder: a state-of-the-science review. J Psychiatr Res 40:1–21CrossRefGoogle Scholar
  4. 4.
    Lee B, Sur B, Yeom M, Shim I, Lee H, Hahm DH (2014) L-tetrahydropalmatine ameliorates development of anxiety and depression-related symptoms induced by single prolonged stress in rats. Biomol Ther 22:213–222CrossRefGoogle Scholar
  5. 5.
    Andero R, Ressler KJ (2012) Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes Brain Behav 11:503–512CrossRefGoogle Scholar
  6. 6.
    Karpova NN, Pickenhagen A, Lindholm J, Tiraboschi E, Kulesskaya N, Agústsdóttir A, Antila H, Popova D, Akamine Y, Bahi A, Sullivan R, Hen R, Drew LJ, Castrén E (2011) Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science 334:1731–1734CrossRefGoogle Scholar
  7. 7.
    Emad S, Qadeer S, Sadaf S, Batool Z, Haider S, Perveen T (2017) Attenuation of stress induced memory deficits by nonsteroidal anti-inflammatory drugs (NSAIDs) in rats: role of antioxidant enzymes. Pharmacol Rep 69:300–305CrossRefGoogle Scholar
  8. 8.
    Lee B, Sur B, Yeom M, Shim I, Lee H, Hahm DH (2016) Effects of systemic administration of ibuprofen on stress response in a rat model of post-traumatic stress disorder. Korean J Physiol Pharmacol 20:357–366CrossRefGoogle Scholar
  9. 9.
    Garabadu D, Ahmad A, Krishnamurthy S (2015) Risperidone attenuates modified stress-re-stress paradigm-induced mitochondrial dysfunction and apoptosis in rats exhibiting post-traumatic stress disorder-like symptoms. J Mol Neurosci 56:299–312CrossRefGoogle Scholar
  10. 10.
    Liberzon I, López JF, Flagel SB, Vázquez DM, Young EA (1999) Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J Neuroendocrinol 11:11–17CrossRefGoogle Scholar
  11. 11.
    Nie H, Peng Z, Lao N, Wang H, Chen Y, Fang Z, Hou W, Gao F, Li X, Xiong L, Tan Q (2014) Rosmarinic acid ameliorates PTSD-like symptoms in a rat model and promotes cell proliferation in the hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 51:16–22CrossRefGoogle Scholar
  12. 12.
    Serova LI, Laukova M, Alaluf LG, Pucillo L, Sabban EL (2014) Intranasal neuropeptide Y reverses anxiety and depressive-like behavior impaired by single prolonged stress PTSD model. Eur Neuropsychopharmacol 24:142–147CrossRefGoogle Scholar
  13. 13.
    Yamamoto S, Morinobu S, Takei S, Fuchikami M, Matsuki A, Yamawaki S, Liberzon I (2009) Single prolonged stress: toward an animal model of posttraumatic stress disorder. Depress Anxiety 26:1110–1117CrossRefGoogle Scholar
  14. 14.
    Serova LI, Laukova M, Alaluf LG, Sabban EL (2013) 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 250:139–147CrossRefGoogle Scholar
  15. 15.
    Lin CC, Tung CS, Lin PH, Huang CL, Liu YP (2016) Traumatic stress causes distinctive effects on fear circuit catecholamines and the fear extinction profile in a rodent model of posttraumatic stress disorder. Eur Neuropsychopharmacol 26:1484–1495CrossRefGoogle Scholar
  16. 16.
    Li XM, Han F, Liu DJ, Shi YX (2010) Single-prolonged stress induced mitochondrial-dependent apoptosis in hippocampus in the rat model of post-traumatic stress disorder. J Chem Neuroanat 40:248–255CrossRefGoogle Scholar
  17. 17.
    Li X, Han F, Liu D, Shi Y (2010) Changes of Bax, Bcl-2 and apoptosis in hippocampus in the rat model of post-traumatic stress disorder. Neurol Res 32:579–586CrossRefGoogle Scholar
  18. 18.
    Takei S, Morinobu S, Yamamoto S, Fuchikami M, Matsumoto T, Yamawaki S (2011) Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder. J Psychiatr Res 45:460–468CrossRefGoogle Scholar
  19. 19.
    Hadrich F, Mahmoudi A, Bouallagui Z, Feki I, Isoda H, Feve B, Sayadi S (2016) Evaluation of hypocholesterolemic effect of oleuropein in cholesterol-fed rats. Chem Biol Interact 252:54–60CrossRefGoogle Scholar
  20. 20.
    Dufourny L, Leroy D, Warembourg M (2000) Differential effects of colchicine on the induction of nitric oxide synthase in neurons containing progesterone receptors of the guinea pig hypothalamus. Brain Res Bull 52:435–443CrossRefGoogle Scholar
  21. 21.
    Kaeidi A, Esmaeili-Mahani S, Sheibanib V, Abbasnejad M, Rasoulian B, Hajializadeh Z, Afrazi S (2011) Olive (Olea europaea L.) leaf extract attenuates early diabetic neuropathic pain through prevention of high glucose-induced apoptosis: in vitro and in vivo studies. J Ethnopharmacol 136:188–196CrossRefGoogle Scholar
  22. 22.
    Khalatbary AR, Ahmadvand H (2012) Neuroprotective effect of oleuropein following spinal cord injury in rats. Neurol Res 34:44–51CrossRefGoogle Scholar
  23. 23.
    Del JR (2003) Enhancement of phenolic compounds in olive plants (Olea europaea L.) and their influence on resistance against Phytophthora s.p. Food Chem 83:75–78CrossRefGoogle Scholar
  24. 24.
    Dekanski D, Selaković V, Piperski V, Radulović Z, Korenić A, Radenović L (2011) Protective effect of olive leaf extract on hippocampal injury induced by transient global cerebral ischemia and reperfusion in Mongolian gerbils. Phytomedicine 18:1137–1143CrossRefGoogle Scholar
  25. 25.
    Luccarini I, Ed Dami T, Grossi C, Rigacci S, Stefani M, Casamenti F (2014) Oleuropein aglycone counteracts Aβ42 toxicity in the rat brain. Neurosci Lett 558:67–72CrossRefGoogle Scholar
  26. 26.
    Pourkhodadad S, Alirezaei M, Moghaddasi M, Ahmadvand H, Karami M, Delfan B, Khanipour Z (2016) Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats. J Physiol Sci 66:397–405CrossRefGoogle Scholar
  27. 27.
    van der Stelt EF, Hoek-van den Hil HJM, Swarts JJM, Vervoort L, Hoving L, Skaltsounis (2015) Nutraceutical oleuropein supplementation prevents high fat diet-induced adiposity in mice. J Funct Foods 14:702–715CrossRefGoogle Scholar
  28. 28.
    Alirezaei M, Rezaei M, Hajighahramani S, Sookhtehzari A, Kiani K (2017) Oleuropein attenuates cognitive dysfunction and oxidative stress induced by some anesthetic drugs in the hippocampal area of rats. J Physiol Sci 67:131–139CrossRefGoogle Scholar
  29. 29.
    Serova LI, Tillinger A, Alaluf LG, Laukova M, Keegan K, Sabban EL (2013) Single intranasal neuropeptide Y infusion attenuates development of PTSD-like symptoms to traumatic stress in rats. Neuroscience 236:298–312CrossRefGoogle Scholar
  30. 30.
    Boultadakis A, Georgiadou G, Pitsikas N (2010) Effects of the nitric oxide synthase inhibitor L-NAME on different memory components as assessed in the object recognition task in the rat. Behav Brain Res 207:208–214CrossRefGoogle Scholar
  31. 31.
    Okuda S, Roozendaal B, McGaugh JL (2004) Glucocorticoid effects on object recognition memory require training-associated emotional arousal. Proc Natl Acad Sci USA 101(3):853–858CrossRefGoogle Scholar
  32. 32.
    Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, Rakic P, Davtyan H, Agadjanyan MG, Kepe V, Barrio JR, Bannykh S, Szekely CA, Pechnick RN, Town T (2013) A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci 33:6245–6256CrossRefGoogle Scholar
  33. 33.
    Haider S, Sadir S, Naqvi F, Batool Z, Tabassum S, Khaliq S, Anis L, Sajid I, Haleem DJ (2016) Magnesium treatment palliates noise-induced behavioral deficits by normalizing DAergic and 5-HTergic metabolism in adult male rats. Metab Brain Dis 31:815–825CrossRefGoogle Scholar
  34. 34.
    Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, vol 3. Academic Press, New York, pp 54–85Google Scholar
  35. 35.
    Singh I, Mok M, Christensen AM, Turner AH, Hawley JA (2008) The effects of polyphenols in olive leaves on platelet function. Nutr Metab Cardiovasc Dis 18:127–132CrossRefGoogle Scholar
  36. 36.
    El SN, Karakaya S (2009) Olive tree (Olea europaea) leaves: potential beneficial effects on human health. Nutr Rev 67:632–638CrossRefGoogle Scholar
  37. 37.
    Baharvand B, Esmailidehaj M, Alihosaini J, Bajoovand S, Esmailidehaj S, Hafizie Z (2016) Prophylactic and therapeutic effects of oleuropein on reperfusion-induced arrhythmia in anesthetized rat. Iran Biomed J 20:41–48PubMedPubMedCentralGoogle Scholar
  38. 38.
    Patki G, Li L, Allam F, Solanki N, Dao AT, Alkadhi K, Salim S (2014) Moderate treadmill exercise rescues anxiety and depression-like behavior as well as memory impairment in a rat model of posttraumatic stress disorder. Physiol Behav 130:47–53CrossRefGoogle Scholar
  39. 39.
    Kim BK, Seo JH (2013) Treadmill exercise alleviates post-traumatic stress disorder-induced impairment of spatial learning memory in rats. J Exerc Rehabil 9:413–419CrossRefGoogle Scholar
  40. 40.
    Janasson Z (2005) Meta-analysis of sex differences in rodent models of learning and memory: a review of behavioral and biological data. Neurosci Biobehav Rev 28:811–825CrossRefGoogle Scholar
  41. 41.
    Solanki N, Alkadhi I, Atrooz F, Patki G, Salim S (2015) Grape powder prevents cognitive, behavioral, and biochemical impairments in a rat model of posttraumatic stress disorder. Nutr Res 35:65–75CrossRefGoogle Scholar
  42. 42.
    Peng Z, Wang H, Zhang R, Chen Y, Xue F, Nie H, Chen Y, Wu D, Wang Y, Wang H, Tan Q (2013) Gastrodin ameliorates anxiety-like behaviors and inhibits IL-1beta level and p38 MAPK phosphorylation of hippocampus in the rat model of posttraumatic stress disorder. Physiol Res 62:537–545PubMedPubMedCentralGoogle Scholar
  43. 43.
    Mohagheghi F, Bigdeli MR, Rasoulian B, Hashemi P, Pour MR (2011) The neuroprotective effect of olive leaf extract is related to improved blood-brain barrier permeability and brain edema in rat with experimental focal cerebral ischemia. Phytomedicine 18:170–175CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan KK 2017

Authors and Affiliations

  • Bombi Lee
    • 1
    Email author
  • Insop Shim
    • 1
    • 2
  • Hyejung Lee
    • 1
    • 2
  • Dae-Hyun Hahm
    • 1
    • 2
  1. 1.Acupuncture and Meridian Science Research Center, College of Korean MedicineKyung Hee UniversitySeoulRepublic of Korea
  2. 2.The Graduate School of Basic Science of Korean Medicine, College of Korean MedicineKyung Hee UniversitySeoulRepublic of Korea

Personalised recommendations