Metabolic Brain Disease

, Volume 32, Issue 3, pp 827–839 | Cite as

Investigation of thymol effect on learning and memory impairment induced by intrahippocampal injection of amyloid beta peptide in high fat diet- fed rats

  • Masoumeh Asadbegi
  • Parichehreh YaghmaeiEmail author
  • Iraj Salehi
  • Alireza Komaki
  • Azadeh Ebrahim-HabibiEmail author
Original Article


Obesity and consumption of a high fat diet (HFD) are known to increase the risk of Alzheimer’s disease (AD). In the present study, we have examined the protective and therapeutic effects of thymol (main monoterpene phenol found in thyme essential oil) on a HFD-fed rat model of AD. Fourty adult male Wistar rats were randomly assigned to 5 groups:(n = 8 rats/group): group 1, control, consumed an ordinary diet, group 2 consumed a HFD for 8 weeks, then received phosphate-buffered saline (PBS) via intrahippocampal (IHP) injection, group 3 consumed HFD for 8 weeks, then received beta-amyloid (Aβ)1–42 via IHP injections to induce AD, group 4 consumed HFD for 8 weeks, then received Aβ1–42, and was treated by thymol (30 mg/kg in sunflower oil) daily for 4 weeks, and group 5 consumed HFD for 8 week, then received Aβ1–42 after what sunflower oil was administered by oral gavage daily for 4 weeks. Biochemical tests showed an impaired lipid profile and higher glucose levels upon consumption of HFD, which was ameliorated by thymol treatment. In behavioral results, spatial memory in group 3 was significantly impaired, but groups treated with thymol showed better spatial memory compared to group 3 (p ≤ 0.01). In histological results, formation of Aβ plaque in hippocampus of group 3 increased significantly compared to group 1 and group 2 (p ≤ 0.05), but group 4 showed decreased Aβ plaques compared to group 3 (p ≤ 0.01). In conclusion, thymol decreased the effects of Aβ on memory and could be considered as neuroprotective.


Alzheimer's disease Abeta High fat diet Memory Thymol 



This study has been performed in the Laboratory Complex of the Science and Research Branch of Azad University and in the Neurophysiology Research Center of Hamadan University of Medical Sciences. The project has been partly supported by grant number 9312186882 of the Hamadan University of Medical Sciences.

Compliance with ethical standards

Conflict of interests

All authors declare to have no conflict of interests.


  1. Aeschbach R, Löliger J, Scott BC, Murcia A, Butler J, Halliwell B, Aruoma OI (1994) Antioxidant actions of thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol. Food Chem Toxicol 32(1):31–36CrossRefPubMedGoogle Scholar
  2. Ahrén B, Scheurink AJ (1998) Marked hyperleptinemia after high-fat diet associated with severe glucose intolerance in mice. Eur J Endocrinol 139(4):461–467CrossRefPubMedGoogle Scholar
  3. Aman S, Moin S, Owanis M, Siddiqui MU (2013) Antioxidant activity of thymol: protective role in AAPH-induced hemolysis in diabetic erythrocytes. IJPSI 2(3):55–60Google Scholar
  4. Angelov, Ivan, Villanueva, D, Stateva, Roumiana P, Reglero, Guillermo, Ibañez, Elena & Fornari, Tiziana (2013) Extraction of Thymol from different varieties of thyme plants using green solventsGoogle Scholar
  5. Asadbegi M, Yaghmaei P, Salehi I, Ebrahim-Habibi A, Komaki A (2016) Neuroprotective effects of metformin against Aβ-mediated inhibition of long-term potentiation in rats fed a high-fat diet. Brain Res Bull 121:178–185CrossRefPubMedGoogle Scholar
  6. Azirak S, Rencuzogullari E (2008) The in vivo genotoxic effects of carvacrol and thymol in rat bone marrow cells. Environ Toxicol 23(6):728–735CrossRefPubMedGoogle Scholar
  7. Azizi Z, Ebrahimi S, Saadatfar E, Kamalinejad M, Majlessi N (2012) Cognitive-enhancing activity of thymol and carvacrol in two rat models of dementia. Behav Pharmacol 23(3):241–249CrossRefPubMedGoogle Scholar
  8. Cai Z, Yan Y, Wang Y (2013) Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder. Clin Interv Aging 8:1089–1095CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cardoso ES, Santana TA, Diniz PB, Montalvão MM, Bani CC, Thomazzi SM (2016) Thymol accelerates the recovery of the skeletal muscle of mice injured with cardiotoxin. J Pharm Pharmacol 68(3):352–360CrossRefPubMedGoogle Scholar
  10. Carroll JF, Zenebe WJ, Strange TB (2006) Cardiovascular function in a rat model of diet-induced obesity. Hypertension 48(1):65–72CrossRefPubMedGoogle Scholar
  11. Chacón MA, Barría MI, Soto C, Inestrosa NC (2004) Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits. Mol Psychiatry 9(10):953–961CrossRefPubMedGoogle Scholar
  12. De Felice FG, Vieira MN, Saraiva LM, Figueroa-Villar JD, Garcia-Abreu J, Liu R, Ferreira ST (2004) Targeting the neurotoxic species in Alzheimer's disease: inhibitors of Abeta oligomerization. FASEB J 18(12):1366–1372. doi: 10.1096/fj.04-1764com CrossRefPubMedGoogle Scholar
  13. de Melo CL, Queiroz MGR, Fonseca SGC, Bizerra AMC, Lemos TLG, Melo TS, Rao VS (2010) Oleanolic acid, a natural triterpenoid improves blood glucose tolerance in normal mice and ameliorates visceral obesity in mice fed a high-fat diet. Chem Biol Interact 185(1):59–65CrossRefPubMedGoogle Scholar
  14. El-Sayed E-SM, Mansour AM, Abdul-Hameed MS (2016) Thymol and carvacrol prevent doxorubicin-induced Cardiotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats. J Biochem Mol Toxicol 30(1):37–44CrossRefGoogle Scholar
  15. Esmaeili A, Khodadadi A (2012) Antioxidant activity of a solution of thymol in ethanol. Zahedan J Res Med Sci 14(7):14–18Google Scholar
  16. Estadella D, Oyama LM, Dâmaso AR, Ribeiro EB, Nascimento D, Oller CM (2004) Effect of palatable hyperlipidic diet on lipid metabolism of sedentary and exercised rats. Nutrition 20(2):218–224CrossRefPubMedGoogle Scholar
  17. Ghahremanitamadon, Fatemeh, Shahidi, Siamak, Zargooshnia, Somayeh, Nikkhah, Ali, Ranjbar, Akram, & Soleimani, Asl Sara. (2014). Protective effects of Borago officinalis extract on amyloid β-peptide (25–35)-induced memory impairment in male rats: a behavioral study. BioMed research international, 2014Google Scholar
  18. Ghobeh M, Ahmadian S, Meratan AA, Ebrahim-Habibi A, Ghasemi A, Shafizadeh M, Nemat-Gorgani M (2014) Interaction of Abeta (25-35) fibrillation products with mitochondria: effect of small-molecule natural products. Biopolymers 102(6):473–486. doi: 10.1002/bip.22572 CrossRefPubMedGoogle Scholar
  19. Gupta A, Bisht B, Dey CS (2011) Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology 60(6):910–920CrossRefPubMedGoogle Scholar
  20. Haque MR, Ansari SH, Najmi AK, Ahmad MA (2014) Monoterpene phenolic compound thymol prevents high fat diet induced obesity in murine model. Toxicol Mech Methods 24(2):116–123CrossRefPubMedGoogle Scholar
  21. Henderson VW (2014) Alzheimer's disease: review of hormone therapy trials and implications for treatment and prevention after menopause. J Steroid Biochem Mol Biol 142:99–106CrossRefPubMedGoogle Scholar
  22. Hernández-Zimbrón LF, Rivas-Arancibia S (2015) Oxidative stress caused by ozone exposure induces β-amyloid 1–42 overproduction and mitochondrial accumulation by activating the amyloidogenic pathway. Neuroscience 304:340–348CrossRefPubMedGoogle Scholar
  23. Jukic M, Politeo O, Maksimovic M, Milos M, Milos M (2007) In vitro acetylcholinesterase inhibitory properties of thymol, carvacrol and their derivatives thymoquinone and thymohydroquinone. Phytother Res 21(3):259–261CrossRefPubMedGoogle Scholar
  24. Karamian R, Komaki A, Salehi I, Tahmasebi L, Komaki H, Shahidi S, Sarihi A (2015) Vitamin C reverses lead-induced deficits in hippocampal synaptic plasticity in rats. Brain Res Bull 116:7–15CrossRefPubMedGoogle Scholar
  25. Karimi SA, Salehi I, Komaki A, Sarihi A, Zarei M, Shahidi S (2013) Effect of high-fat diet and antioxidants on hippocampal long-term potentiation in rats: an in vivo study. Brain Res 1539:1–6CrossRefPubMedGoogle Scholar
  26. Karimi SA, Komaki A, Salehi I, Sarihi A, Shahidi S (2015) Role of group II metabotropic glutamate receptors (mGluR2/3) blockade on long-term potentiation in the dentate gyrus region of hippocampus in rats fed with high-fat diet. Neurochem Res 40(4):811–817CrossRefPubMedGoogle Scholar
  27. Kim H, Park B-S, Lee K-G, Choi CY, Jang SS, Kim Y-H, Lee S-E (2005) Effects of naturally occurring compounds on fibril formation and oxidative stress of β-amyloid. J Agric Food Chem 53(22):8537–8541CrossRefPubMedGoogle Scholar
  28. Kim HG, Jeong HU, Park G, Kim H, Lim Y, Oh MS (2015) Mori folium and Mori Fructus mixture attenuates high-fat diet-induced cognitive deficits in mice. Evid Based Complement Alternat Med 2015:379418PubMedPubMedCentralGoogle Scholar
  29. Kim D-G, Krenz A, Toussaint LE, Maurer KJ, Robinson S-A, Yan A et al (2016) Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model. J Neuroinflammation 13(1):1CrossRefPubMedPubMedCentralGoogle Scholar
  30. Knight EM, Martins IVA, Gümüsgöz S, Allan SM, Lawrence CB (2014) High-fat diet-induced memory impairment in triple-transgenic Alzheimer's disease (3xTgAD) mice is independent of changes in amyloid and tau pathology. Neurobiol Aging 35(8):1821–1832CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kohara Y, Kuwahara R, Kawaguchi S, Jojima T, Yamashita K (2014) Perinatal exposure to genistein, a soy phytoestrogen, improves spatial learning and memory but impairs passive avoidance learning and memory in offspring. Physiol Behav 130:40–46CrossRefPubMedGoogle Scholar
  32. Komaki A, Karimi SA, Salehi I, Sarihi A, Shahidi S, Zarei M (2015) The treatment combination of vitamins E and C and astaxanthin prevents high-fat diet induced memory deficits in rats. Pharmacol Biochem Behav 131:98–103CrossRefPubMedGoogle Scholar
  33. Komatsu T, Chiba T, Yamaza H, Yamashita K, Shimada A, Hoshiyama Y, Henmi T, Ohtani H, Higami Y, de Cabo R, Ingram DK, Shimokawa I (2008) Manipulation of caloric content but not diet composition, attenuates the deficit in learning and memory of senescence-accelerated mouse strain P8. Exp Gerontol 43(4):339–346CrossRefPubMedGoogle Scholar
  34. Kulshreshtha A, Piplani P (2016) Current pharmacotherapy and putative disease-modifying therapy for Alzheimer’s disease. Neurol Sci:1–33Google Scholar
  35. Li, Hongyan, Qin, Tingting, Li, Min, Ma, Shiping (2016) Thymol improves high-fat diet-induced cognitive deficits in mice via ameliorating brain insulin resistance and upregulating NRF2/HO-1 pathway. Metabolic Brain Disease, 1–9Google Scholar
  36. Loizzo MR, Menichini F, Conforti F, Tundis R, Bonesi M, Saab AM et al (2009) Chemical analysis, antioxidant, antiinflammatory and anticholinesterase activities of Origanum Ehrenbergii Boiss and Origanum syriacum L. essential oils. Food Chem 117(1):174–180CrossRefGoogle Scholar
  37. Lotfi P, Yaghmaei P, Ebrahim-Habibi A (2015) Cymene and metformin treatment effect on biochemical parameters of male NMRI mice fed with high fat diet. J Diabetes Metab Disord 14(1):1CrossRefGoogle Scholar
  38. Marsik P, Kokoska L, Landa P, Nepovim A, Soudek P, Vanek T (2005) In vitro inhibitory effects of thymol and quinones of Nigella sativa seeds on cyclooxygenase-1-and-2-catalyzed prostaglandin E2 biosyntheses. Planta Med 71(08):739–742CrossRefPubMedGoogle Scholar
  39. Martin SAL, Jameson CH, Allan SM, Lawrence CB (2014) Maternal high-fat diet worsens memory deficits in the triple-transgenic (3xTgAD) mouse model of Alzheimer’s disease. PLoS One 9(6):e99226CrossRefPubMedPubMedCentralGoogle Scholar
  40. Mihara S, Shibamoto T (2015) The role of flavor and fragrance chemicals in TRPA1 (transient receptor potential cation channel, member A1) activity associated with allergies. Allergy, Asthma Clin Immunol 11(1):1CrossRefGoogle Scholar
  41. Miller AA, Spencer SJ (2014) Obesity and neuroinflammation: a pathway to cognitive impairment. Brain Behav Immun 42:10–21CrossRefPubMedGoogle Scholar
  42. Mogi M, Tsukuda K, Li JM, Iwanami J, Min LJ, Sakata A, Fujita T, Iwai M, Horiuchi M (2007) Inhibition of cognitive decline in mice fed a high-salt and cholesterol diet by the angiotensin receptor blocker, olmesartan. Neuropharmacology 53(8):899–905CrossRefPubMedGoogle Scholar
  43. Morris MC, Tangney CC (2014) Dietary fat composition and dementia risk. Neurobiol Aging 35:S59–S64CrossRefPubMedGoogle Scholar
  44. Öztürk M (2012) Anticholinesterase and antioxidant activities of Savoury (Satureja thymbra L.) with identified major terpenes of the essential oil. Food Chem 134(1):48–54CrossRefGoogle Scholar
  45. Park HJ, Lee MK, Park YB, Shin YC, Choi MS (2011) Beneficial effects of Undaria pinnatifida ethanol extract on diet-induced-insulin resistance in C57BL/6 J mice. Food Chem Toxicol 49(4):727–733CrossRefPubMedGoogle Scholar
  46. Pawłowska M, Kalka D (2015) Cognitive-motivational model of obesity. Motivational mechanisms and cognitive biases underlying the processing of food-related images by people with excess body weight. Psychiatr Pol 49(5):983–991CrossRefPubMedGoogle Scholar
  47. Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Burlington MA Elsevier Inc.Google Scholar
  48. Peng D, Pan X, Cui J, Ren Y, Zhang J (2013) Hyperphosphorylation of tau protein in hippocampus of central insulin-resistant rats is associated with cognitive impairment. Cell Physiol Biochem 32(5):1417–1425CrossRefPubMedGoogle Scholar
  49. Ribeiro ARS, Diniz PBF, Pinheiro MS, Albuquerque-Júnior RLC, Thomazzi SM (2016) Gastroprotective effects of thymol on acute and chronic ulcers in rats: the role of prostaglandins, ATP-sensitive K+ channels, and gastric mucus secretion. Chem Biol Interact 244:121–128CrossRefPubMedGoogle Scholar
  50. Saravanan S, Pari L (2015) Role of thymol on hyperglycemia and hyperlipidemia in high fat diet-induced type 2 diabetic C57BL/6 J mice. Eur J Pharmacol 761:279–287CrossRefPubMedGoogle Scholar
  51. Saravanan S, Pari L (2016) Protective effect of thymol on high fat diet induced diabetic nephropathy in C57BL/6 J mice. Chem Biol Interact 245:1–11CrossRefPubMedGoogle Scholar
  52. Savel J, Lafitte M, Pucheu Y, Pradeau V, Tabarin A, Couffinhal T (2012) Very low levels of HDL cholesterol and atherosclerosis, a variable relationship–a review of LCAT deficiency. Vasc Health Risk Manag 8:357–361PubMedPubMedCentralGoogle Scholar
  53. Sharifi F, Fakhrzadeh H, Varmaghani M, Arzaghi SM, Alizadeh KM, Farzadfar F, Taheri TP (2016) Prevalence of dementia and associated factors among older adults in Iran: National Elderly Health Survey (NEHS). Arch Iran Med 19(12):838–844PubMedGoogle Scholar
  54. Shea TB, Remington R (2015) Nutritional supplementation for Alzheimer's disease? Curr Opin Psychiatry 28(2):141–147PubMedGoogle Scholar
  55. Singhal AK, Naithani V, Bangar OP (2012) Medicinal plants with a potential to treat Alzheimer and associated symptoms. Int J Nutr, Pharmacol, Neurol Dis 2(2):84CrossRefGoogle Scholar
  56. Suzanne M, Wands JR (2008) Alzheimer's disease is type 3 diabetes—evidence reviewed. J Diabetes Sci Technol 2(6):1101–1111CrossRefGoogle Scholar
  57. Trombetta D, Castelli F, Sarpietro MG, Venuti V, Cristani M, Daniele C, Saija A, Mazzanti G, Bisignano G (2005) Mechanisms of antibacterial action of three monoterpenes. Antimicrob Agents Chemother 49(6):2474–2478CrossRefPubMedPubMedCentralGoogle Scholar
  58. Vargas-Robles H (2015) Rios, Amelia, Arellano-Mendoza, Monica, Escalante, Bruno a, & Schnoor, Michael (2015) antioxidative diet supplementation reverses high-fat diet-induced increases of cardiovascular risk factors in mice . doi: 10.1155/2015/467471 Oxidative medicine and cellular longevity Google Scholar
  59. Vinters HV (2015) Emerging concepts in Alzheimer's disease. Ann Rev Pathol: Mech Dis 10:291–319CrossRefGoogle Scholar
  60. Wong H, Schotz MC (2002) The lipase gene family. J Lipid Res 43(7):993–999CrossRefPubMedGoogle Scholar
  61. Yaghmaei P, Kheirbakhsh R, Dezfulian M, Haeri-Rohani A, Larijani B, Ebrahim-Habibi A (2013) Indole and trans-chalcone attenuate amyloid β plaque accumulation in male Wistar rat: in vivo effectiveness of two anti-amyloid scaffolds. Arch Ital Biol 151(3):106–113PubMedGoogle Scholar
  62. Yanishlieva NV, Marinova EM, Gordon MH, Raneva VG (1999) Antioxidant activity and mechanism of action of thymol and carvacrol in two lipid systems. Food Chem 64(1):59–66CrossRefGoogle Scholar
  63. Yilmaz M, Bukan N, Ayvaz G, Karakoç A, Törüner F, Çakir N, Arslan M (2005) The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome. Hum Reprod 20(12):3333–3340CrossRefPubMedGoogle Scholar
  64. Zargooshnia S, Shahidi S, Ghahremanitamadon F, Nikkhah A, Mehdizadeh M, Asl SS (2015) The protective effect of Borago officinalis extract on amyloid β (25–35)-induced long term potentiation disruption in the dentate gyrus of male rats. Metab Brain Dis 30(1):151–156CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
  2. 2.Neurophysiology Research CenterHamadan University of Medical SciencesHamadanIran
  3. 3.Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences InstituteTehran University of Medical SciencesTehranIran
  4. 4.Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIran

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