Thymoquinone recovers learning function in a rat model of Alzheimer’s disease

Document Type: Short communication


1 Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 Aerospace Research Institute, Ministry of Science Research and Technology, Tehran, Iran


Objective: Alzheimer's disease is a neurodegenerative disorder characterized by accumulation of amyloid beta in the hippocampus. In recent decades, herbal medicine has been widely used to treat many neurodegenerative disorders,as in comparison to conventional drugs, herbal remedies exert minimal side effects. Here, the effects of thymoquinone, as the main active component of Nigella sativa, on passive avoidance memory in rat model of Alzheimer’s disease, were evaluated.
Materials and Methods: Hippocampal injection of amyloid beta (Aβ) was used to induce Alzheimer’s disease in male Wistar rats, followed by intra peritoneal administrations of 5 and 10 mg/kg thymoquinone on a daily basis for 4 weeks. Animals were subjected to fear learning behavior in passive avoidance test and histopathological analysis of the hippocampus was done. Shuttle box test was used to evaluate the condition studying memory. Thioflavin-S and Hematoxylin and Eosine staining were done to confirm Aβ plaque formation and to evaluate the effect of thymoquinone on the pyramidal cells in the hippocampal CA1 region.
Results: Amyloid beta caused cognitive dysfunction reflected by increasing initial and step-through latency along with plaque formation and degeneration of pyramidal cells in the hippocampus. Thymoquinone administration ameliorated this effect by significant reductions in plaque formation in CA1 region of the hippocampus and increased latency time. It also increased the number of surviving neurons in the hippocampus.
Conclusion: It seems that thymoquinone improved learning function in a rat model of Alzheimer’s disease. Thus, thymoquinone could be possibly used as an anti-neurodegenerative agent for protecting hippocampal neurons against neurotoxic effects of Aβ in patients with Alzheimer’s disease.


Main Subjects

Akhondzadeh S, Abbasi SH. 2006. Herbal medicine in the treatment of Alzheimer’s disease.Am J Alzheimers Dis, 21: 113-118.

Alhebshi AH, Gotoh M, Suzuki I. 2013.Thymoquinone protects cultured rat primary neurons against amyloid β induced neurotoxicity. Biochem Biophys Res Commun, 433: 362–367.

Ali BHBlunden G. 2003. Pharmacological and toxicological properties of Nigella sativa. Phytother Res, 17: 299-305.

Al-Majed AA, Al-Omar FA, Nagi MN. 2006. Neuroprotective effects of thymoquinone against transient forebrain ischemia in the rat hippocampus. Eur J Pharmacol, 543: 40–47.

Azad N, Rasoolijazi H, Joghataie MT, Soleimani S. 2011. Neuroprotective effects of carnosic acid in an experimental model of Alzheimer’s disease in rats. Cell j (Yakhteh), 13: 39-44.

Baluchnejadmojarad T, Roghani M, karimi N, kamran M. 2011.Varenicline ameliorates learning and memory deficits in amyloid β (25–35) rat model of Alzheimer’s disease. Basic and clinical Neuroscience, 3: 48-57.

Belluti F, Rampa A, Gobbi S, Bisi A. 2013. Small-molecule inhibitors/modulators of amyloid-β peptide aggregation and toxicity for the treatment of Alzheimer's disease: a patent review (2010 - 2012). Expert OpinTher Pat, 23: 581-96.

Bin Sayeed MSAsaduzzaman MMorshed HHossain MMKadir MFRahman MR. 2013. The effect of Nigella sativa Linn. Seed on memory, attention and cognition in healthy human volunteers.J Ethnopharmacol. 148: 780-6.

Bin Sayeed MSShams TFahim Hossain SRahman MRMostofa AFahimKadir MMahmood SAsaduzzaman M. 2014. Nigella sativa L. seeds modulate mood, anxiety and cognition in healthy adolescent males. J Ethnopharmacol. 152:156-62.

Burits MBucar F. 2009. Antioxidant activity of Nigella sativa essential oil. Phytother Res, 14: 323-8.

Burns A, Iliffe S. 2009. Alzheimer's disease. B M J, 338: b158.

Committee for the update of the guide for the care and use of laboratory animals. 1996. Guide for the care and use of laboratory animals. Washington DC: National Academy Press, USA.

Esposito L, Raber J,Kekonius L, Yan F, Yu GQ, Bien-Ly N,Puoliväli J,Scearce-Levie K,Masliah E,Mucke L. 2006. Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice.  J Neurosci, 26: 5167-5179.

Everss E, Parra A. 1998. Inhibitory avoidance with a two-way shuttle-box. Universidad de Valencia Psicothema, 10: 387-391.

Francis PT. 2005. The interplay of neurotransmitters in Alzheimer's disease. CNS Spectr, 10: 6-9.

Houghton PJZarka Rde las Heras BHoult JR. 1995. Fixed oil of Nigella sativa and derived thymoquinone inhibit eicosanoid generation in leukocytes and membrane lipid peroxidation. Planta Med, 61: 33-36.

Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, Tanzi RE, Bush AI. 1999. The Aβ peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry, 38: 7609–7616.

Imam A, Ajao MS, Ajibola MI, Amin A, Abdulmajeed WI, Lawal AZ, Alli-Oluwafuyi A, Akinola OB, Oyewopo AO, Olajide OJ, Adana MY. 2016, Black seed oil ameliorated scopolamine-induced memory dysfunction and cortico-hippocampal neural alterations in male Wistar rats. Bulletin of Faculty of Pharmacy, Cairo University. 54: 49-57.

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: 259–261.

Kanter M. 2008a. Nigella sativa and derived thymoquinone prevents hippocampal neurodegeneration after chronic toluene exposure in rats. Neurochem Res, 33: 579–588.

Kanter M. 2008b. Protective effects of Nigella sativa on the neuronal injury in frontal cortex and brain stem after chronic toluene exposure.Neurochem Res, 33: 2241–2249.

Kanter M. 2011. Protective effects of thymoquinone on the neuronal injury in frontal cortex after chronic toluene exposure. J MolHistol, 42: 39–46.

Kanter MCoskun OKalayci MBuyukbas SCagavi F. 2006. Neuroprotective effects of Nigella sativa on experimental spinal cord injury in rats. Hum Exp Toxicol, 25: 127-33.

Kehoe PG, Miners S, Love S. 2009. Angiotensins in Alzheimer's disease - friend or foe? Trends Neurosci, 32: 619-628.

Kihara T, Shimohama S. 2004. Alzheimer's disease and acetylcholine receptors. ActaNeurobiolExp (Wars), 64: 99-105.

Lee VM, Goedert M, Trojanowski JQ. 2001. Neurodegenerative tauopathies. Annu Rev Neurosci, 24:1121–1159.

Lobo V, Patil A, Phatak A, Chandra N. 2010. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev, 4: 118–26.  

McGleenon BM,  Dynan KB,  Passmore AP. 1999. Acetylcholinesterase inhibitors in Alzheimer’s disease.Br J Clin Pharmacol, 48:  471–480.

Mount C, Downton C. 2006. Alzheimer disease: progress or profit? Nat Med, 12: 780-4.

Paxinos G, Watson C. 1986. The rat brain in stereotaxic coordinates (2nd ed.). New York: Academic Press.

Perry G,  Cash AD,  Smith MA. 2002. Alzheimer disease and oxidative stress. J Biomed Biotechnol, 2: 120–123.

Saido TC. 2013. Metabolism of amyloid β peptide and pathogenesis of Alzheimer's disease. Proc JpnAcadSer B Phys BiolScI, 89: 321-339.

Sarkaki A, Rezaiei M, Gharibnaseri MK, Rafieirad M. 2013. Improving active and passive avoidance memories deficits due to permanent cerebral ischemia by pomegranate seed extract in female rats. Malays J Med Sci, 20: 25-34.

Sberna G, Sáez-Valero J, Beyreuther K, Masters CL, Small DH. 1997. The amyloid beta-protein of Alzheimer's disease increases acetylcholinesterase expression by increasing intracellular calcium in embryonal carcinoma P19 cells. J Neurochem, 69: 1177-84.

Selvam AB. 2008. Inventory of vegetable crude drug samples housed in botanical survey of India, Howrah. Pharmacognosy Rev, 2: 61–94.

Suvarna KS,  Layton C, Bancroft JD. 2008. Bancroft's theory and practice of histological techniques (6th ed.) New York, London, San Francisco Tokyo: Churchill Livingstone.

Takata K, Kitamura Y, Yanagisawa D, Morikawa S, Morita M, Inubushi T, Tsuchiya D, Chishiro S, Saeki M, Taniguchi T, Shimohama S, Tooyama I. 2007. Microglial transplantation increases amyloid-b clearance in Alzheimer model rats. FEBS Lett, 581: 475-478.

Vinod T, Anurag K, Mahendra B, Kanwaljit C. 2009. Chronic treatment with tocotrienol, AN isoform of vitamin E, prevents intracerebroventricular streptozotocin-induced cognitive impairment and oxidative-nitrosative stress in rats. Pharm Biochem Behave, 93: 183-9. 

Wu QY, Li J, Feng ZT, Wang TH. 2007. Bone marrow stromal cells of transgenic mice can improve the cognitive ability of an Alzheimer’s disease rat model. Neurosci Lett, 417: 281-285.