Ali Gomar, Abdolkarim Hosseini, Naser Mirazi

Department of Biology, Faculty of Basic science, Bu-Ali Sina University, Hamedan, Iran.

Memory enhancement by administration of ginger (Zingiber officinale) extract on morphine-induced memory impairment in male rats

Ali Gomar, Abdolkarim Hosseini*, Naser Mirazi

Department of Biology, Faculty of Basic science, Bu-Ali Sina University, Hamedan, Iran.

To study the chronic treatment with hydroethanolic extract of ginger (50, 100 and 200 mg/kg, p.o) would effect on the passive avoidance learning (PAL) and memory in rat. Methods: The rats were divided into eight groups. On the training trial, the mice received an electric shock when the animals were entered into the dark compartment. Twenty-four hours later, 30 min after treatment, the STL (step-through latency) and TDC (total time in dark compartments) was recorded and defined as the retention trial. Results: The time latency in morphine-treated group was lower than control (P＜0.001). Treatment of the animals by 100 and 200 mg/kg of ginger extract before the training trial increased the time latency at 24 hours after the training trial (P＜0.01 andP＜0.001). Administration of both 100 and 200 mg/kg doses of the extract in morphine received animal groups before retention trials also increased the time latency than the morphine-treated group groups (P＜0.001). Conclusion: The results revealed that the ginger extract attenuated morphineinduced memory impairment.

ARTICLE INFO

Article history:

Received 26 June 2014

Received in revised form 15 July 2014

Accepted 25 August 2014

Available online 20 September 2014

Memory

Learning

Zingiber officinale

Ginger

Morphine

Rat

1. Introduction

Zingiber officinale(Z. officinale) Roscoe (Zingiberaceae), commonly known as ‘Ginger’, is one of the frequently used spices in the world. Ginger has been cultivated for thousands of years and used safely in cooking, and medicinally in folk and home remedies. It is used extensively in traditional medicine to treat cold, fever, headache, nausea and digestive problems; and is also used in Western herbal medical practices for the treatment of arthritis, rheumatic disorders and muscular discomfort[1]. It has been reported that ginger or its extracts possess some pharmacological activities including antiemesis[2], analgesic effect[3], anti-tumor[4], anti-oxidant[5], antiinflammatory effect[6,7]and a neuroprotective effect[8,9].

The oleoresin (i.e.,oily resin) from the rhizomes (i.e.,roots) of Ginger contains many bioactive components, such as 6-gingerol, which is the primary pungent ingredient that is believed to exert a variety of remarkable pharmacological and physiological activities. Ginger has been used for thousands of years for the treatment of numerous ailments, such as colds, arthritis, migraines, and hypertension[10]. It is used in traditional Asian medicine for the treatment of stomach aches[11], nausea, diarrhea, and joint and muscle pain[12].

Antioxidants in ginger include gingerols, shogaols and some phenolic ketone derivatives. The anti-inflammatory and anti-oxidant properties in ginger help relieve various inflammatory disorders like gout, osteoarthritis, and rheumatoid arthritis. It provides substantial relief in pain caused by inflammation and help decrease swelling and morning stiffness[13]. Another study suggests that Ginger can reduce cell death and restore motor function in a rat spinal cord injury[14].

Learning and memory in laboratory animals are known to be affected by opioids and their antagonists[15]. For example, pretraining administration of morphine impairs memory retrieval in passive avoidance tests which will be restored by pretest administration of the same dose ofmorphine[16]. Hippocampus is one of the areas involved in learning and memory in which both opioid peptides and opioid receptors are expressed[17]. Endogenous opioid peptides consider important neuromodulators in the brain, which are rich in the hippocampus and cerebral cortex[18]. Using different animal models, it was shown that repeated administering morphine can impair memory and learning processes[17, 19, 20].

With regard to the possible effects of ginger on learning and memory and its interactions with opioid system, the aim of the present study was to evaluate the effect of hydroethanolic extract ofZ. officinaleon morphineinduced memory impairment in mice using the passive avoidance test.

2. Material and methods

2.1. Plant material

The fresh rhizomes ofZ. officinale(herbarium code no. 1483) was purchased from the Institute of Medicinal Plants Tehran, Iran. The plant material was dried with room temperature (25℃), shade dried and powdered.

2.2. Preparation of Plant Extracts

Approximately 500 g of the dried powder fromZ. officinalewere extracted with 5 L of 80% aqueous ethanol using the percolation method at room temperature. The extracts were filtered through filter paper and evaporated to dryness under reduced pressure at a maximum of 40℃using a rotary evaporator. The hydroethanolic extract of ginger was stored in small samples at -20℃until use. The extract was dissolved in saline and was then applied.

2.3. Drugs

The drugs used in the present study was morphine sulfate (darou pakhsh, Tehran, Iran). Morphine dissolved in physiologic saline solution.

2.4. Animals

Sixty-four locally produced male Wistar rats (250-280 g) from the Iranian Razi Institute, were used in the present experiments. All animals were maintained at a constant temperature (22±2)℃and on a 12 h light/dark cycle. They had free access to laboratory chow and tap water. Each Experimental group consisted of eight animals that were chosen randomly from different cages. Each rat was used only once.

2.5. Experimental design

The animals were divided into eight equal groups (n=8);

(1): Normal control group received normal saline via oral gavage, (2): control group received morphine sulfate at dose 5 mg/kg via i.p injection 30 min before training, (3-5): groups receivedZ. officinaleextract at doses 50, 100 and 200 mg/kg via oral gavage 30 min before training, (6-8): groups received morphine at dose 5 mg/kg andZ. officinaleextract at doses 50, 100 and 200 mg/kg via oral gavage 30 min before training. Thirty minutes after the treatment, learning and memory were evaluated. The operator was unaware of the specific treatment groups to which an animal belonged. Animals were handled in accordance with the criteria outlined in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health (NIH) publication 86-23; revised 1985). All the protocols were also approved by the institutional ethics committee of Bu-Ali Sina University.

2.6. Passive avoidance task

The apparatus used for evaluation of the passive avoidance task was two-way shuttle box (Borj Sanaat Co. Iran), which consisted of two adjacent Plexiglas compartments of identical dimensions (27 cm×14.5 cm×14 cm). For the experimental procedure, on the first day (adaptation day) each rat was allowed a 3 min adaptation period and free access to either the light or dark compartment of the box to avoidance training and after being placed in a shuttle box. Following this adaptation period, on the second day (training phase), rats were placed in the illuminated compartment and 30 s later the sliding door was raised. Upon entering the dark compartment, the door was closed and a 1.5 mA constant-current shock was applied for 3 s. After 20 s, the rat was removed from the dark compartment and placed into home cage. In order to test short- and long-term memories, 24 h after receiving foot shock, the rats were placed in illuminated chamber and 30 s later the sliding door was raised and the latency of entering the dark compartment (step-through latency) and the time spent there during 5 min were recorded again, because the maximum time that was considered in this procedure was 300 s[21-24].

2.7. Statistical analysis

The data are expressed as mean values with their standard errors. Following a significant P-value,post hocanalysis (Tukey’s test) was performed for multiple comparison. Statistical analysis was performed using SPSS (version 21; SPSS Inc., Chicago, IL, USA). A level forP＜0.05 was considered to be significant.

3. Result

The retention test which was conducted 24 h after training. It revealed a significant difference in the STL among the groups (Figure 1). There was a significant difference in STLbetween saline treated control groups and Ginger treated groups at dose 100 and 200 mg/kg (P＜0.01andP＜0.001, respectively). But there was no significant difference in STL between extract treated group at dose 50 mg/kg and control group. Specifically, the STL of morphine treated group at dose 5 mg/kg were significantly lower than the saline control group. Administration of ginger at doses 100 and 200 mg/ kg to animals that received morphine (5 mg/kg) resulted in longer STL compared to morphine treated animals (P＜0.001). There was a significant difference in STL between extract treated at dose 200 mg/kg that received morphine and saline treated control groups (P＜0.01).

Figure 1. Effect of ginger on the step-through latency in the acquisition trial (STL) of passive avoidance learning (PAL) task in the rats. Columns represent mean ± SEM. **P＜0.01, ***P＜0.001 as compared with its related Control group. ###P＜0.001, as compared with its related Morphine received group.

Figure 2. Effect of ginger on the time spent in the dark compartment in the retention trial (TDC) which was carried out 24 h after acquisition of passive avoidance learning (PAL) task in the control and diabetic groups. Columns represent mean ± SEM. **P＜0.01, ***P＜0.001 as compared with control group. ###P＜0.001 as compared with morphine treated group.

Also there was a statistically significant difference in TDC among the experimental groups (Figure 2). Consistent with a cognitive impairment, TDC of the Morphine treated rats was greater than the saline treated control group (P＜0.01). Time spent in the dark compartment in the group that treated extract at doses 100 and 200 mg/kg was significantly less than the respective saline treated control group (P＜0.001). Also it was a significant difference in TDC between Ginger extract treated at doses 100 and 200 mg/kg that received Morphine and Morphine treated groups (P＜0.001). There was a statistically significant difference in TDC between extract treated at dose 50 mg/kg that received Morphine than the Morphine treated group (P＜0.01).

4. Discussion

It has long been known that learning and memory are affected by opioids. According to present results, which are in agreement with previous reports, pretraining administration of morphine impaired memory acquisition[25,26]that is partially restored by pretest administration of the same opioid[27, 28]. Some studies have demonstrated that opioid agonists such as morphine and endorphin, possessing higher affinity for μ-opioid receptors, inhibit cholinergic activity in the hippocampus[29]. Moreover, it has been reported that mu and delta opioid receptors located on the cholinergic terminals are normally under tonic inhibition by the opiate system[30]. It has been demonstrated that morphine, at a dose that impairs memory, decreases hippocampal acetylcholine output. Moreover, learning and memory impairment caused by acute administration of morphine is suggested, at least in part, to be related to a decrease in hippocampal acetylcholine release[31]. By using in vivo microdialysis, it has been demonstrated that acute morphine administration significantly decreased the release of acetylcholine in some brain regions[32-34].

It has been shown that the degree of memory impairment is related to the degree of cholinergic loss in early Alzheimer’s disease[35]. Computational models linking AChrelated behaviors to the cellular effects of ACh provide additional evidence of the role of ACh in learning and memory[36]. Cholinergic neurotransmission is a central process underlying memory and cognitive function. Cholinergic basal forebrain neurons in the nucleus basalis magnocellularis innervate the cerebral cortex, amygdaloid complex and hippocampus, and are essential for learning and memory formation[37,38]. Hippocampus and cortex are innervated by cholinergic projections. Abnormalities in cholinergic functions lead to impaired processing of the hippocampal region[39].

Ginger (Z. officinaleRoscoe, Zingiberacae) has been traditionally used for a wide range and unrelated ailments that include fever and infectious diseases, stomachaches, abdominal spasm, nausea and vomiting, motion sickness, arthritis, rheumatism, ulcerative colitis, gingivitis,hypertension, and diabetes[1,40]. The bioactive components ofZ. officinalewere characterized by spectroscopic analysis as zingerone, gingerdione, dehydrozingerones which exhibited potent antioxidant, shogaols, gingerols and volatile oil[41]. Sesquiterpene lactones (SLs) are natural products responsible for the anti-inflammatory activity[42].

High antioxidant activity of ginger and its compounds has been demonstrated in numerous reports[43,44]. Furthermore, Lee and colleagues showed that 6-Gingerol, a bioactive component of Ginger, efficiently suppresses β-amyloidinduced intracellular accumulation of reactive oxygen and nitrogen species and restores endogenous antioxidant glutathione levels and up-regulates the expression of antioxidant enzymes[45]. 6-shogaol is one of the most bioactive components of Ginger rhizome which has been shown to decrease inducible nitric oxide syntheses (iNOS) levels in LPS-treated astrocytes[46]and macrophages[47]. Recent accumulating lines of evidence show that antioxidants could also improve cognitive performance in healthy elderly subjects[48,49]. According to the cognitive enhancing effects of substances possessing antioxidant activity, the concentration of gingerol and shogaol of the extract, and the antioxidant activity ofZ. officinale, we suggest that the cognitive enhancing effect of this plant extract on working memory observed in this study might be partly related to its antioxidant effect. However, the precise underlying mechanism and possible active ingredient responsible for the cognitive enhancing effect ofZ. officinalestill require further investigation.

Recent findings also suggest an important role of the hippocampus in spatial working memory[50]. In addition, it was found that dopamine, and norepinephrine play a key role in numeric working memory including word and picture recognition (organized by the lateral PFC), while acetylcholine and serotonin in the hippocampus simultaneously were activated during spatial working memory tasks[51]. Various investigators have previously demonstrated that extract of Ginger and its fractions have anti-5HT3-receptor effects[52-54]. 5-HT3-receptor stimulation contributes to fast excitatory synaptic transmission in the central nervous system[55, 56]and also modulates the release of several neurotransmitters including Acetylcholine, Cholecystokinin (CCK), Dopamine, Glutamate, Norepinephrine and Particularly γ-Aminobutyric Acid (GABA), the exocytosis of which is enhanced by direct Ca2+ influx through the ionophore of presynaptic 5-HT3-receptors[57, 58]. Zingerone and other derivatives from Ginger inhibits the release of most neurotransmitter especially serotonin[59, 60]. 5-HT3-receptor antagonists have multiple pharmacological actions[61]. It has been shown that 5-HT3-receptor antagonists also possess improve cognitive and memory[62]. Moreover, this plant extract and its active component, 6-Gingerol, also inhibited the cholinesterase activity which in turn increased acetylcholine (ACh), a neurotransmitter that plays an important role in learning and memory[63]. Therefore, taking all data together, we suggest that the cognitive enhancing effects ofZ. officinalemight be partly associated with the modulation effect of this plant extract on the alteration of both the monoamine system and the cholinergic system in various brain areas, including the prefrontal cortex and hippocampus.

It is well known thatZ. officinaleand its components have potent anti-inflammatory effects in different animal models of inflammation[3]. Recently, Liet al. (2011) demonstrated that the anti-inflammatory effect of Ginger occurs through the inhibition of TNFα and IL-1β gene expression[64]. Cyclooxygenase-2 (COX-2), the inducible isoform of COX, is rapidly up-regulated in damaged tissue, for example in the central nervous system (CNS) damage. COX-2 induction in CNS overall contributes to inflammation and injury mainly by producing prostanoids. Prostaglandin E2 (PGE2), a dominant enzymatic product of COX-2 in the brain[65]. Researchers have hypothesized that the anti-inflammatory effects of Ginger might be related to its ability to inhibit prostaglandin and leukotriene biosynthesis[66]. Some others have showed that Gingerols actively inhibit arachidonate 5-lipoxygenase, an enzyme of leukotriene biosynthesis. 8-Gingerol, was shown to inhibit COX-2 expression, which is induced during inflammation to increase formation of prostaglandins[67]. Therefore, it seems that antiinflammatory and anti-phospholipase properties of ginger are also the other possible mechanisms for our result in this study. However, those possible issues need to be clarified by further investigation.

Conflict of interest statement

The authors declare that they have no competing interests.

[1] Rasmussen, P. Ginger-Zingiber officinale Roscoe, Zingiberaceae. J Primary Health Care 2011; 3: 235-236.

[2] Sharma SS, Gupta YK. Effect of ginger (Zingiber officinale) against cisplatin induced delay in gastric emptying in rats. J Ethnopharmacol 1998; 62: 49-55.

[3] Young HY, Luo YL, Cheng HY, Hsieh WC, Liao JC, Peng WH. Analgesic and anti-inflammatory activities of [6]-Gingerol. J Ethnopharmacol 2005; 96(1-2): 207-210.

[4] Katiyar SK, Agarwal R, Mukhtar H. Inhibition of tumor promotion in SENCAR mouse skin by ethanol extract of Zingiber officinale rhizome. Cancer Res 1996; 56: 1023-1030.

[5] Shanmugam KR, Ramakrishna CH, Mallikarjuna K, Sathyavelu Reddy K. Protective effect of ginger in alcohol-induced renal damage and antioxidant enzymes in male albino rats. Ind J Exp Biol 2010; 4: 143-149.

[6] Chang CP, Chang JY, Wang FY, Chang JG. The effect of Chinese medicinal herb Zingiberis rhizome extract on cytokinesecretion by human peripheral blood mononuclear cells. J Ethnopharmacol 1995; 48: 13-19.

[7] Lantz RC, Chen GJ, Sarihan M, So′lyom AM, Jolad SD, Timmermann BN. The effect of extracts from ginger rhizome on inflammatory mediator production. Phytomedicine 2007; 14: 123-128.

[8] Waggas AM. Neuroprotective evaluation of extract of ginger (Zingiber officinale) root in monosodium glutamateinduced toxicity in different brain areas male albino rats. Pak J Biol Sci 2009; 12(3): 201-212.

[9] Kondeti Ramudu Shanmugam, Korivi Mallikarjuna, Nishanth Kesireddy, Kesireddy Sathyavelu Reddy. Neuroprotective effect of ginger on anti-oxidant enzymes in streptozotocininduced diabetic rats. Food Chem Toxicol 2011: 49; 893-897.

[10] Iris FF Benzie, Sissi Wachtel-Galor. Herbal medicine biomolecular clinical aspects, Second Edition. United Kingdom: Taylor and Francis Group; 2011.

[11] Mascolo N, Jain R, Jain SC, Capasso F. Ethnopharmacologic investigation of ginger (Zingiber officinale). J Ethnopharmacol 1989; 27(1-2): 129-140.

[12] Ojewole JA. Analgesic, antiinflammatory and hypoglycaemic effects of ethanol extract of Zingiber officinale (Roscoe) rhizomes (Zingiberaceae) in mice and rats. Phytother Res 2006; 20(9): 764-772.

[13] Habib SH, Makpol S, Abdul Hamid NA, Das S, Ngah WZ, Yusof YA. Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-induced hepatoma rats. Clinics 2008; 63(6): 807-813.

[14] Kyung KS, Gon JH, Geun KY, Sup JJ, Suk WJ, Ho KJ. 6-Shogaol, a natural product, reduces cell death and restores motor function in rat spinal cord injury. Eur J Neurosci 2006; 24(4): 1042-1052.

[15] I Izquierdo, MAMR De Almeida, VR Emiliano. Unlikeβendorphin, dynorphin1-13 does not cause retrograde amnesia for shuttle avoidance or inhibitory avoidance learning in rats. Psychopharmacology 1985; 87(2): 216-218.

[16] S Khavandgar, H Homayoun, MR Zarrindast. The effect of L-NAME and L-arginine on impairment of memory formation and state-dependent learning induced by morphine in mice. Psychopharmacology 2003; 167(3): 291-296.

[17] F Motamedi, M Ghasemi, F Davoodi, N Naghdi. Comparison of learning and memory in morphine dependent rats using different behavioral models. Iranian J Pharma Res 2003: 2(4): 225-230.

[18] AL Vaccarino, GA Olson, RD Olson, AJ Kastin. Endogenous opiates: 1998. Peptides 1999: 20(12):1527-1574.,

[19] K Saadipour, A Sarkaki, H Alaei, M Badavi, F Rahim. Forced exercise improves passive avoidance memory in morphineexposed rats. Pakistan J Biol Sci 2009: 12(17): 1206-1211.

[20] H Alaei, L Borjeian, M Azizi, S Orian, A Pourshanazari, O Hanninen. Treadmill running reverses retention deficit induced by morphine. Eur J Pharmacol 2006: 536(1-2): 138-141.

[21] Moazedi AA, Ehsani Vostacolaee S, Chinipardaz R. Effect of oral aluminum chloride administration during lactation on short and long-term memory of their offspring. Biol Sci 2008; 4: 676 -722.

[22] Moazedi AA, khombi shooshtari M, Parham GA. Dose dependent effects of iron supplementation on short-term and long-term memory in adult male wistar rats. J Biol Sci 2010; 10: 648-652.

[23] Criswell HE, Breese GR. Similar effects of ethanol and flumazenil on acquisition of a shuttle-box avoidance response during withdrawal from chronic ethanol treatment. Br J Pharmacol 1993; 110: 753-760.

[24] Takeda A, T amanoH, Tochigi M. Zinc homeostasis in the hypocampus of zinc-dependent young adult rats. Neurochem Int 2005; 46: 221-225.

[25] Izquierdo I. Effect of β-endorphin and naloxone on acquisition, memory, and retrieval shuttle avoidance and habituation learning in rats. Psychopharmacology 1980; 69: 111-115.

[26] Homayoun H, Khavandgar S, Zarrindast MR. Morphine statedependent learning: interactions with alpha2-adrenoceptors and acute stress. Behav Pharmacol 2003; 14: 41-48.

[27] Bruins Slot LA, Colpaert FC. Opiate state of memory: receptor mechanisms. J Neurosci 1999; 19: 10520-10529.

[28] Bruins Slot LA, Colpaert FC. Recall rendered dependent on an opiate state. Behav Neurosci 1999; 113: 337-344.

[29] Decker MW, McGaugh JL. The role of interactions between the cholinergic system and other neuromodulatory systems in learning and memory. Synapse 1991; 7: 151-168.

[30] Heijna MH, Padt M, Hogenboom F, Portoghese PS, Mulder AH, Schoffelmeer AN. Opioid receptor-mediated inhibition of dopamine and acetylcholine release from slices of rat nucleus accumbens, olfactory tubercle and frontal cortex. Eur J Pharmacol 1990; 181: 267-278.

[31] Ragozzino ME, Gold PE. Glucose injections into the medial septum reverse the effects of intraseptal morphine infusions on hippocampal acetylcholine output and memory. Neuroscience 1995; 68: 981-988.

[32] Arenas E, Alberch J, Sanchez Arroyos R, Marsal J. Effect of opioids on acetylcholine release evoked by K+ or glutamic acid from rat neostriatal slices. Brain Res 1990; 523: 51-6.

[33] Lapchak PA, Araujo DM, Collier B. Regulation of endogenous acetylcholine release from mammalian brain slices by opiate receptors: hippocampus, striatum and cerebral cortex of guinea-pig and rat. Neuroscience 1989; 31: 313-25.

[34] Rada P, Mark GP, Pothos E, Hoebel BG. Systemic morphine simultaneously decreases extracellular acetylcholine and increases dopamine in the nucleus accumbens of freely moving rats. Neuropharmacology 1991; 30: 1133-1136.

[35] Bierer LM, Haroutunian V, Gabriel S. Neurochemical correlates of dementia severity in Alzheimer’s disease: relative importance of the cholinergic deficits. J Neurochem 1995; 64: 749-760.

[36] Newman EL, Gupta K, Climer JR, Monaghan CK, Hasselmo ME. Cholinergic modulation of cognitive processing: insights drawn from computational models. Front Behav Neurosci 2012; 6: 24.

[37] Aigner TG. Pharmacology of memory: cholinergic-glutamatergic interactions. Curr Opin Neurobiol 1995; 5: 155-160.

[38] Gallagher M, Colombo PJ. Ageing: the cholinergic hypothesis of cognitive decline. Curr Opin Neurobiol 1995; 5: 161-168.

[39] Mesulam MM, Hersh LB, Mash DC, Geula C. Differential cholinergic innervation within functional subdivisions of the human cerebral cortex: a choline acetyltransferase study. J Comp Neurol 1992; 318: 316-328.

[40] Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol 2008; 46: 409-420.

[41] Riazur Rehman, M Akram, Naveed Akhtar, Qaiser Jabeen, Tariq Saeed, SM Ali Shah, et al. Zingiber officinale Roscoe (pharmacological activity). J Med Plants Res 2011; 5(3): 344-348.

[42] Ernst E, Pittler MH. Efficacy of Ginger for nausea and vomiting: a systematic review of randomized clinical trials. Br J Anesth 2000; 84: 367-371.

[43] Ghasemzadeh A, Jaafar HZ, Rahmat A. Antioxidant activities, total phenolics and flavonoids content in two varieties of Malaysia young Ginger (Zingiber officinale Roscoe). Molecules 2010; 15: 4324-4333.

[44] Rehman R, Akram M, Akhtar N, Jabeen Q, Saeed T, Ali Shah SM, et al. Zingiber officinale Roscoe (pharmacological activity). J Med Plants Res 2011; 5: 344-348.

[45] Lee C, Park GH, Kim CY, Jang JH. [6]-Gingerol attenuates β-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system. Food and Chem Toxicol 2011; 49: 1261-1269.

[46] Shim S, Kim S, Choi DS, Kwon YB, Kwon J. Anti-inflammatory effects of [6]-shogaol: potential roles of HDAC inhibition and HSP70 induction. Food Chem Toxicol 2011; 49: 2734-2740.

[47] Levy AS, Simon OR. Six-shogaol inhibits production of tumor necrosis factor alpha, interleukin-1 beta and nitric oxide from lipopolysaccharide stimulated RAW 264.7 macrophages. West Indian Med J 2009; 58: 295-300.

[48] WJ Perrig, P Perrig, HB Stahelin. The relation between antioxidants and memory performance in the old and very old. J Am Geriatrics Soc 1997; 45(6): 718-724.

[49] SC Monteiro, C Matt′ e, CS Bavaresco, CA Netto, ATS Wyse. Vitamins E and C pretreatment prevents ovariectomy-induced memory deficits in water maze. Neurobiol Learning Memory 2005; 84(3): 192-199.

[50] MB Moser, EI Moser. Distributed encoding and retrieval of spatial memory in the hippocampus. J Neurosci 1998; 18(18): 7535-7542.

[51] R Stancampiano, S Cocco, C Cugusi, L Sarais, F Fadda. Serotonin and acetylcholine release response in the rat hippocampus during a spatial memory task. Neuroscience 1999; 89(4): 1135-1143.

[52] Huang Q, H Matsuda, K Sakai, J Yamahara, Y Tamai. The effect of Ginger on serotonin induced hypothermia and diarrhea. Yakugaku Zasshi 1990; 110: 936-942.

[53] Abdel-Aziz H, T Windeck, M Ploch, EJ Verspohl. Mode of action og Gingerols and shogaols on 5-HT3 receptors: Binding studies, cation uptake by the receptors channel and contraction of isolated guinea-pig ileum. Eur J Phannacol 2006; 530: 136-143.

[54] Riyazi A, A Hemel, K Bauer, N Geissler, S Schaaf, EJ Verspohl. The effect of the volatile oil from Ginger rhizomes (Zingiber officinale), its fractions and isolated compounds on the 5-HT3 receptor complex and the serotoninergic system of the rat ileum. Planta Med 2007; 73: 355-362.

[55] Sugita S, KZ Shen, RA North. 5- hydroxytryptamine is a fast excitatory transmitter at 5-HT3 receptors in rat amygdale. Neuron 1992; 8: 199-203.

[56] Ferezou I, B Cauli, EL Hill, J Rossier, E Hamel, B Lambolez. 5-HT3 receptors medate serotonergic fast synaptic excitation of neocortical vasoactive intestinal peptide cholecystokinin intemeurom. J Neurosci 2002; 22: 7389-7397.

[57] Chameau P, JA Van-Hooft. Serotonin 5-HT (3) receptors in the central nervous system. Cell Tissue Res 2006; 326: 573-581.

[58] Fink KB, M Gothert. 5-HT receptor regulation of neurotrammitter release. Phacol Rev 2007; 59: 360-417.

[59] Marles RJ. J Kaminski, JT Amason, L Pazos-Sanou, S Heptimtall. A bioassay for inhibition of serotonin release from bovine platelets. J Nat Prod 1992; 55: 1044-1056.

[60] Hasenohrl RU, CH Nichau, CH Frisch, MA De-Souza-Silva. Anxiolytic-like effect of combined extracts of Zingiber officinale and Ginkgo biloba in the elevated plus-maze. Phacol Biochem Behav 1996; 53: 271-275.

[61] SL Vishwakarma, SC Pal, Veena S Kasture, SB Kasture. Anxiolytic and Antiemetic Activity of Zingiber officinale. Phytother Res 2002; 16: 621-626.

[62] Arnsten AF, Lin CH, Van Dyck CH, Stanhope KJ. The effects of 5-HT3 receptor antagonists on cognitive performance in aged monkeys. Neurobiol Aging 1997; 18(1): 21-28.

[63] MN Ghayur, AH Gilani, T Ahmed. Muscarinic, Ca(++) antagonist and specific butyrylcholinesterase inhibitory activity of dried Ginger extract might explain its use in dementia. J Pharm Pharmacol 2008; 60(10): 1375-1383.

[64] Li XH, McGrath KC, Nammi S, Heather AK, Roufogalis BD. Attenuation of liver pro-inflammatory responses by Zingiber officinale via inhibition of NF-kappa B activation in high-fat diet-fed rats. Basic Clin Pharmacol Toxicol 2011; doi:10.1111/ j.1742-7843.

[65] Jianxiong Jiang, Thota Ganesh, Yuhong Du, Yi Quan, Geidy Serrano, Min Qui, et al. Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2. Proc Natl Acad Sci U S A 2012; 109(8): 3149-3154.

[66] Srivastava KC, T Mustafa. Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. Med Hypotheses 1992; 39(4): 342-348.

[67] Kiuchi F, S Iwakami, M Shibuya, F Hanaoka, U Sankawa. Inhibition of prostaglandin and leukotriene biosynthesis by Gingerols and diarylheptanoids. Chem Pharm Bull (Tokyo) 1992; 40(2): 387-391.

ment heading

10.1016/S2221-6189(14)60047-0

*Corresponding author: Abdolkarim Hosseini, Department of Biology, Faculty of Basic science, Bu-Ali Sina University, Hamedan, Iran.

Tel: +989112783301

Fax: +988118381058

E-mail: khosseini32@alumni.ut.ac.ir