Auraptene consolidates memory, reverses scopolamine-disrupted memory in passive avoidance task, and ameliorates retention deficits in mice

Document Type : Original Article


1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran

2 Medicinal Plants Research Center, Zabol University of Medical Sciences, Zabol, Iran

3 Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran


Objective(s): Auraptene (7-geranyloxycoumarin) (AUR), from Citrus species has shown anti-inflammatory, neuroprotective, and acetylcholinesterase (AChE) and beta-secretase inhibitory effects. Scopolamine is a nonselective muscarinic receptor antagonist which causes short-term memory impairments and is used for inducing animal model of Alzheimer’s disease (AD). This research aimed to investigate the effect of AUR on scopolamine-induced avoidance memory retention deficits in step-through task in mice.
Materials and Methods: The effect of four-day pre-training injections of AUR (50, 75, and 100 mg/kg, subcutaneous (SC)) and scopolamine (1 mg/kg, IP), and their co-administration on avoidance memory retention in step-through passive avoidance task, was investigated by measuring the latency to enter to the dark chamber.
Results:Pre-training administration of AUR caused significant increase in step-through latency in comparison with control group, 48, 96, and 168 hr after training trial. The findings of this study showed that scopolamine (1 mg/kg, IP, for four consecutive days) impaired passive avoidance memory retention compared to saline-treated animals. Step-through passive avoidance task results showed that AUR markedly reversed scopolamine-induced avoidance memory retention impairments, 24 and 168 hr after training trial in step-through task.
Conclusion: Results from co-administration of AUR and scopolamine showed that AUR reversed scopolamine-induced passive avoidance memory retention impairments.


1.Gutierres JM, Carvalho FB, Schetinger MR, Agostinho P, Marisco PC, Vieira JM, et al. Neuroprotective effect of anthocyanins on acetylcholinesterase activity and attenuation of scopolamine-induced amnesia in rats. Int J Dev Neurosci 2014; 33:88-97.
2.Warburton EC, Koder T, Cho K, Massey PV, Duguid G, Barker GR, et al. Cholinergic neurotransmission is essential for perirhinal cortical plasticity and recognition memory. Neuron 2003; 38:987-996.
3.Murphy KJ, Foley AG, O'connell AW, Regan CM. Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing. Neuropsychopharmacology 2006; 31:90-100.
4.Jafari MR, Zarrindast MR, Djahanguiri B. Influence of cholinergic system modulators on morphine state-dependent memory of passive avoidance in mice. Physiol Behav 2006; 88:146-151.
5.Epifano F, Molinaro G, Genovese S, Ngomba RT, Nicoletti F, Curini M. Neuroprotective effect of prenyloxycoumarins from edible vegetables. Neurosci Lett 2008; 443:57-60.
6.Furukawa Y, Okuyama S, Amakura Y, Watanabe S, Fukata T, Nakajima M, et al. Isolation and characterization of activators of ERK/MAPK from citrus plants. Int J Mol Sci 2012; 13:1832-1845.
7.Marumoto S, Miyazawa M. beta-secretase inhibitory effects of furanocoumarins from the root of Angelica dahurica. Phytother Res 2010; 24:510-513.
8.Marumoto S, Miyazawa M. Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor. Bioorg Med Chem 2012; 20:784-788.
9.Askari M, Sahebkar A, Iranshahi M. Synthesis and purification of 7-prenyloxycoumarins and herniarin as bioactive natural coumarins. Iran J Basic Med Sci 2009; 12:63-69.
10.Okuyama S, Minami S, Shimada N, Makihata N, Nakajima M, Furukawa Y. Anti-inflammatory and neuroprotective effects of auraptene, a citrus coumarin, following cerebral global ischemia in mice. Eur J Pharmacol 2013; 699:118-123.
11.Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, et al. Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer's disease. J Pharmacol Exp Ther 2008; 326:739-744.
12.Furukawa Y, Watanabe S, Okuyama S, Nakajima M. Neurotrophic effect of citrus auraptene: neuritogenic activity in PC12 cells. Int J Mol Sci 2012; 13:5338-5347.
13.Seifhosseini S, Jahanshahi M, Moghimi A, Aazami NS. The effect of scopolamine on avoidance memory and hippocampal neurons in male wistar rats. Basic Clin Neurosci 2011; 3:9-15
14.Azami NS, Piri M, Oryan S, Jahanshahi M, Babapour V, Zarrindast MR. Involvement of dorsal hippocampal alpha-adrenergic receptors in the effect of scopolamine on memory retrieval in inhibitory avoidance task. Neurobiol Learn Mem 2010; 93:455-462.
15.Klinkenberg I, Blokland A. A comparison of scopolamine and biperiden as a rodent model for cholinergic cognitive impairment. Psychopharmaco-logy (Berl) 2011; 215:549-566.
16.Nakayama M, Uchimura K, Zhu RL, Nagayama T, Rose ME, Stetler RA, et al. Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia. Proc Natl Acad Sci USA 1998; 95:10954-10959.
17.McGeer EG, Klegeris A, McGeer PL. Inflammation, the complement system and the diseases of aging. Neurobiol Aging 2005; 26:94-97.
18.Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007; 55:453-462.
19.Loizzo MR, Tundis R, Menichini F, Menichini F. Natural products and their derivatives as cholinesterase inhibitors in the treatment of neurodegenerative disorders: an update. Curr Med Chem 2008; 15:1209-1228.
20.Miyazawa M, Tougo H, Ishihara M. Inhibition of acetylcholinesterase activity by essential oil from Citrus paradisi. Nat Prod Lett 2001; 15:205-210.
21.Karimi Gh, Iranshahi M, Hosseinalizadeh F, Riahi B, Sahebkar A. Screening of acetylcholinesterase inhibitory activity of  terpenoid and coumarin derivatives from the genus Ferula. Pharmacologyonline 2010; 1:566-574.
22.Frey U, Huang YY, Kandel ER. Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 1993; 260:1661-1664.
23.Sharifzadeh M, Tavasoli M, Naghdi N, Ghanbari A, Amini M, Roghani A. Post-training intrahippocampal infusion of nicotine prevents spatial memory retention deficits induced by the cyclo-oxygenase-2-specific inhibitor celecoxib in rats. J Neurochem 2005; 95:1078-1090.
24.Iranshahi M, Kalategi F, Rezaee R, Shahverdi AR, Ito C, Furukawa H, et al. Cancer chemopreventive activity of terpenoid coumarins from Ferula species. Planta Med 2008; 74:147-150.
25. Soltani F, Mosaffa F, Iranshahi M, Karimi G, Malekaneh M, Haghighi F,  et al. Auraptene from Ferula szowitsiana protects human peripheral lymphocytes against oxidative stress. Phythoter Res 2010; 24:85-89.
26. Nazari ZE, Iranshahi M. Biologically active sesquiterpene coumarins from Ferula species. Phytother Res 2011; 25:315-323.
27. Iranshahi M, Jabbari A, Orafaie A, Mehri R, Zeraatkar S, Ahmadi T, et al. Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors. Eur J Med Chem 2012; 57:134-142.
28. Imenshahidi M, Eghbal M, Sahebkar A, Iranshahi M. Hypotensive activity of auraptene, a monoterpene coumarin from Citrus spp. Pharm Biol 2013; 51:545-549.
29.Valiahdi SM, Iranshahi M, Sahebkar A. Cytotoxic activities of phytochemicals from Ferula species. Daru J Pharm Sci 2013; 21:39-46.
30.Razavi BM, Arasteh E, Imenshahidi M, Iranshahi M. Antihypertensive effect of auraptene, a monoterpene coumarin from the genus Citrus, upon chronic administration. Iran J Basic Med Sci 2015; 18:153-158. Medina P, Genovese S, Paillasse MR, Mazaheri M, Caze-Subra S, Bystricky K, et al. Auraptene is an inhibitor of cholesterol esterification and a modulator of estrogen receptors. Mol Pharmacol 2010; 78:827-836.