Pistachio Extract Improves Neurocognitive Behaviors in Ovariectomized Mice

Document Type: Original paper


1 Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.

2 Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.

3 Research Center for Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran.

4 Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.


Background and objectives: Menopause is associated with depression as well as emotional and memory disorders. Based on the anti-inflammatory and antioxidant effects of pistachio, its effect on depression, cognitive function, anxiety and physical power in ovariectomized mice was investigated. Methods: In the current study, fifty female mice were used. They were aliquoted into five groups: control, ovariectomy (OVX), ovariectomy + DMSO, ovariectomy +10 mg/kg pistachioextract and Ovariectomy +100 mg/kg pistachio extract. In order to prepare the required extract, pistachio nuts were powdered (100 g) and macerated in 1 L of ethanol (80%) for 72 h. Pistachio extract was used orally once a day in ovariectomized mice for sixty days. Anxiety, depression, working memory and physical power were evaluated by the Elevated plus-maze (EPM) test, Forced swimming test (FST), Y maze and swimming exhaustion test, respectively. Results: The results showed that extract of pistachio (more potentially at the dose of 100 mg/kg) decreased anxiety-like behaviors and depression; besides, increase in working memory and physical power was observed in the ovariectomized mice. Conclusion: The findings of the current investigation suggest that pistachio extract could be used as a potential strategy for the attenuation of ovariectomy-related manifestation


[1] Allahtavakoli M, Honari N, Pourabolli I, Kazemi Arababadi M, Ghafarian H, Roohbakhsh A, Esmaeili Nadimi A, Shamsizadeh A. Vitex Agnus Castus extract improves learning and memory and increases the transcription of estrogen receptor alpha in hippocampus of ovariectomized rats. Basic Clin Neurosci. 2015; 6(3): 185-192.

[2] Genazzani AR, Pluchino N, Luisi S, Luisi M. Estrogen, cognition and female ageing. Hum Reprod Update. 2007; 13(2): 175-187.

[3] Walker AK, Kavelaars A, Heijnen CJ, Dantzer R. Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev. 2014; 66(1): 80-101.

[4] Toufexis DJ, Myers KM, Davis M. The effect of gonadal hormones and gender on anxiety and emotional learning. Horm Behav. 2006; 50(4): 539-549.

[5] Delrobaei F, Fatemi I, Shamsizadeh A, Allahtavakoli M. Ascorbic acid attenuates cognitive impairment and brain oxidative stress in ovariectomized mice. Pharmacol Rep. 2019; 71(1): 133-138.

[6] Pompili A, Arnone B, Gasbarri A. Estrogens and memory in physiological and neuropathological conditions. Psychoneuroendocrinology. 2012; 37(9): 1379-1396.

[7] Messier V, Rabasa-Lhoret R, Barbat-Artigas S, Elisha B, Karelis AD, Aubertin-Leheudre M. Menopause and sarcopenia: a potential role for sex hormones. Maturitas. 2011; 68(4): 331-336.

[8] Warren SG, Juraska JM. Spatial and nonspatial learning across the rat estrous cycle. Behav Neurosci. 1997; 111(2): 259-266.

[9] Kritzer MF, Brewer A, Montalmant F, Davenport M, Robinson JK. Effects of gonadectomy on performance in operant tasks measuring prefrontal cortical function in adult male rats. Horm Behav. 2007; 51(2): 183-194.

[10] Pompili A, Tomaz C, Arnone B, Tavares MC, Gasbarri A. Working and reference memory across the estrous cycle of rat: a long-term study in gonadally intact females. Behav Brain Res. 2010; 213(1): 10-18.

[11] Ortiz-Perez A, Espinosa-Raya J, Picazo O. An enriched environment and 17-beta estradiol produce similar pro-cognitive effects on ovariectomized rats. Cogn Process. 2016; 17(1): 15-25.

[12] Luine V, Frankfurt M. Interactions between estradiol, BDNF and dendritic spines in promoting memory. Neuroscience. 2013; 239: 34-45.

[13] Sribnick EA, Del Re AM, Ray SK, Woodward JJ, Banik NL. Estrogen attenuates glutamate-induced cell death by inhibiting Ca2+ influx through L-type voltage-gated Ca2+ channels. Brain Res. 2009; 1276: 159-170.

[14] Craig MC, Murphy DG. Alzheimer's disease in women. Best Pract Res Clin Obstet Gynaecol. 2009; 23(1): 53-61.

[15] Osterlund MK, Hurd YL. Estrogen receptors in the human forebrain and the relation to neuropsychiatric disorders. Prog Neurobiol. 2001; 64(3): 251-267.

[16] Amin Z, Canli T, Epperson CN. Effect of estrogen-serotonin interactions on mood and cognition. Behav Cogn Neurosci Rev. 2005; 4(1): 43-58.

[17] Warren MP. A comparative review of the risks and benefits of hormone replacement therapy regimens. Am J Obstet Gynecol. 2004; 190(4): 1141-1167.

[18] Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst. 1998; 90(11): 814-823.

[19] Tsokou A, Georgopoulou K, Melliou E, Magiatis P, Tsitsa E. Composition and enantiomeric analysis of the essential oil of the fruits and the leaves of Pistacia vera from Greece. Molecules. 2007; 12(6): 1233-1239.

[20] Fatehi F, Fatemi I, Shamsizadeh A, Hakimizadeh E, Bazmandegan G, Khajehasani F, Rahmani M. The effect of hydroalcoholic extract of Pistacia vera on pentylenetetrazole-induced kindling in rat. Res J Pharmacogn. 2017; 4(4): 45-51.

[21] Tokusoglu O, Unal MK, Yemis F. Determination of the phytoalexin resveratrol (3,5,4'-trihydroxystilbene) in peanuts and pistachios by high-performance liquid chromatographic diode array (HPLC-DAD) and gas chromatography-mass spectrometry (GC-MS). J Agric Food Chem. 2005; 53(12): 5003-5009.

[22] Rajaei A, Barzegar M, Mobarez AM, Sahari MA, Esfahani ZH. Antioxidant, anti-microbial and antimutagenicity activities of pistachio (Pistachia vera) green hull extract. Food Chem Toxicol. 2010; 48(1): 107-112.

[23] Magiatis P, Melliou E, Skaltsounis AL, Chinou IB, Mitaku S. Chemical composition and antimicrobial activity of the essential oils of Pistacia lentiscus var. chia. Planta Med. 1999; 65(8): 749-752.

[24] Bomboi G, Pinna W, Sau F. Total blood lipids and lipoproteins in sheep fed Pistacia lentiscus drupe. Boll Soc Ital Biol Sper. 1988; 64(1): 93-99.

[25] Iranmanesh F, Mousaei Amin A, Shamsizadeh A, Fatemi I, Malaki Rad A, Rahnama A. Effects of Pistacia vera hydro-alcoholic extract on carbon tetrachloride-induced hepatotoxicity in male rats. Iran J Pharm Ther. 2016; 14(2): 35-39.

[26] Barreca D, Lagana G, Leuzzi U, Smeriglio A, Trombetta D, Bellocco E. Evaluation of the nutraceutical, antioxidant and cytoprotective properties of ripe pistachio (Pistacia vera L., variety Bronte) hulls. Food Chem. 2016; 196: 493-502.

[27] Ehsani V, Amirteimoury M, Taghipour Z, Shamsizadeh A, Bazmandegan G, Rahnama A, Khajehasani F, Fatemi I. Protective effect of hydroalcoholic extract of Pistacia vera against gentamicin-induced nephrotoxicity in rats. Ren Fail. 2017; 39(1): 519-525.

[28] Goldman JM, Murr AS, Cooper RL. The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies. Birth Defects Res B Dev Reprod Toxicol. 2007; 80(2): 84-97.

[29] Iwamoto Y, Morinobu S, Takahashi T, Yamawaki S. Single prolonged stress increases contextual freezing and the expression of glycine transporter 1 and vesicle-associated membrane protein 2 mRNA in the hippocampus of rats. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31(3): 642-651.

[30] Hakimizadeh E, Oryan S, Hajizadeh Moghaddam A, Shamsizadeh A, Roohbakhsh A. Endocannabinoid system and TRPV1 receptors in the dorsal hippocampus of the rats modulate anxiety-like behaviors. Iran J Basic Med Sci. 2012; 15(3): 795-802.

[31] Pellow S, Chopin P, File SE, Briley M. Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985; 14(3): 149-167.

[32] Cryan JF, Mombereau C. In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiatry. 2004; 9(4): 326-357.

[33] Duman CH, Schlesinger L, Kodama M, Russell DS, Duman RS. A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol Psychiatry. 2007; 61(5): 661-670.

[34] du Jardin KG, Jensen JB, Sanchez C, Pehrson AL. Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism. Eur Neuropsychopharmacol. 2014; 24(1): 160-171.

[35] Wolf A, Bauer B, Abner EL, Ashkenazy-Frolinger T, Hartz AM. A comprehensive behavioral test battery to assess learning and memory in 129S6/Tg2576 mice. PLoS One. 2016; Article ID 0147733.

[36] Hughes RN. The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev. 2004; 28(5): 497-505.

[37] Zamanian M, Hajizadeh MR, Esmaeili Nadimi A, Shamsizadeh A, Allahtavakoli M. Antifatigue effects of troxerutin on exercise endurance capacity, oxidative stress and matrix metalloproteinase-9 levels in trained male rats. Fundam Clin Pharmacol. 2017; 31(4): 447-455.

[38] Kopciuch D, Paczkowska A, Zaprutko T, Michalak M, Nowakowska E. Conventional or natural pharmacotherapy and the prevalence of anxiety and depression during menopause. Altern Ther Health Med. 2017; 23(2): 12-19.

[39] Picazo O, Estrada-Camarena E, Hernandez-Aragon A. Influence of the post-ovariectomy time frame on the experimental anxiety and the behavioural actions of some anxiolytic agents. Eur J Pharmacol. 2006; 530(1-2): 88-94.

[40] Pilsakova L, Riecansky I, Jagla F. The physiological actions of isoflavone phytoestrogens. Physiol Res. 2010; 59(5): 651-664.

[41] Rostampour M, Hadipour E, Oryan S, Soltani B, Saadat F. Anxiolytic-like effect of hydroalcoholic extract of ripe pistachio hulls in adult female Wistar rats and its possible mechanisms. Res Pharm Sci. 2016; 11(6): 454-460.

[42] Tavakkoli-Kakhki M, Eslami S, Motavasselian M. Nutrient-rich versus nutrient-poor foods for depressed patients based on Iranian Traditional Medicine resources. Avicenna J Phytomed. 2015; 5(4): 298-308.

[43] Gasbarri A, Pompili A, d'Onofrio A, Cifariello A, Tavares MC, Tomaz C. Working memory for emotional facial expressions: role of the estrogen in young women. Psychoneuroendocrinology. 2008; 33(7): 964-972.

[44] Dong Y, Jiang A, Yang H, Chen H, Wang Y. Phytoestrogen alpha-zearalanol improves memory impairment and hippocampal neurogenesis in ovariectomized mice. Sci World J. 2014; Article ID 862019.

[45] Fatemi I, Heydari S, Kaeidi A, Shamsizadeh A, Hakimizadeh E, Khaluoi A, Allahtavakoli M. Metformin ameliorates the age‐related changes of d‐galactose administration in ovariectomized mice. Fundam Clin Pharmacol. 2018; 32(4): 392-399.

[46] Fatemi I, Delrobaee F, Bahmani M, Shamsizadeh A, Allahtavakoli M. The effect of the anti-diabetic drug metformin on behavioral manifestations associated with ovariectomy in mice. Neurosci Lett. 2019; 690: 95-98.

[47] Bozorgi M, Memariani Z, Mobli M, Salehi Surmaghi MH, Shams-Ardekani MR, Rahimi R. Five Pistacia species (P. vera, P. atlantica, P. terebinthus, P. khinjuk, and P. lentiscus): a review of their traditional uses, phytochemistry, and pharmacology. Sci World. 2013; Article ID 219815.

[48] MacRae HS, Mefferd KM. Dietary antioxidant supplementation combined with quercetin improves cycling time trial performance. Int J Sport Nutr Exerc Metab. 2006; 16(4): 405-419.

[49] Schwarz NA, Blahnik ZJ, Prahadeeswaran S, McKinley-Barnard SK, Holden SL, Waldhelm A. (-)-Epicatechin Supplementation inhibits aerobic adaptations to cycling exercise in humans. Front Nutr. 2018; 5: 132-136.

[50] Zamanian M, Hajizadeh M, Shamsizadeh A, Moemenzadeh M, Amirteimouri M, Elshiekh M, Allahtavakoli M. Effects of naringin on physical fatigue and serum MMP-9 concentration in female rats. Pharm Biol. 2017; 55(1): 423-427.