Evaluation of the Neurobehavioral Properties of Naringin in Swiss Mice

Abstract

Objectives This study was carried out to investigate the neurobehavioral properties of naringin, a flavonoid compound formed from naringenin on behavioral models in mice.

Method The neurobehavioral property of naringin (2.5, 5 and 10 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced rearing, locomotor behavior using open field test; anxiolytic effect was evaluated using hole-board, light and dark box, and elevated-plus maze paradigms. The anti-depressant-like property was also assessed using forced swim test (FST), tail suspension test (TST) and social interaction test (SIT). The cognitive enhancing effect of naringin was evaluated using Y-maze test.

Results Intraperitoneal administration of naringin (2.5 and 5 mg/kg) demonstrated significant (p<0.05) increase in rearing behavior but not the spontaneous motor activity in comparison to control. In the anti-depressant test, naringin (2.5, 5 and 10 mg/kg, i.p.) significantly decreased the duration of immobility in the FST and TST, and increased the % social interaction preference in the SIT relative to controls, suggesting anti-depressant-like and increased social behaviors. Moreover, naringin also exhibited anxiolytic and memory enhancing properties in mice.

Conclusion These findings suggest that naringin possesses anti-depressant- and anxiolytic-like activities as well as memory enhancing effect in mice.

Key words

Anxiolytic - anti-depressant - social behavior - cognitive function

• References

• 1 Ghasemzadeh A, Jaafar HZ. Profiling of phenolic compounds and their antioxidant and anticancer activities in pandan (Pandanus amaryllifolius Roxb.) extracts from different locations of Malaysia. BMC Complement Altern Med 2013; 13: 341
• 2 Wong KC, Pang WY, Wang XL. et al. Drynaria fortunei-derived total flavonoid fraction and isolated compounds exert oestrogen like protective effects in bone. Bri J Nutr 2013; 110: 475-485
• 3 Yin L, Cheng W, Qin Z et al. Effects of naringin on proliferation and osteogenic differentiation of human periodontal ligament stem cells in vitro and In Vivo. Stem Cells Int article 2015; ID. 758706 2015
• 4 Benavente-Garcïa O, Castillo J. Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem 2008; 56: 6185-6205
• 5 Bors W, Heller W, Michel C. et al. Flavonoids as antioxidants: Determination of scavenging efficiencies. Methods in Enzymol 1990; 186: 343-355
• 6 Sharma AK, Bharti S, Ojha S. et al. Up-regulation of PPARgamma, heat shock protein-27 and -72 by naringin attenuates insulin resistance, beta-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes. Br J Nutr 2011; 106: 1713-1723
• 7 Kandhare AD, Raygude KS, Ghosh P. et al. Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia 2012; 83: 650-659
• 8 Luo YL, Zhang CC, Li PB. et al. 2012; Naringin attenuates enhanced cough, airway hyperresponsiveness and airway inflammation in a guinea pig model of chronic bronchitis induced by cigarette smoke. Int Immunopharmacol 2012; 13: 301-307
• 9 Li HZ, Yang B, Huang J. et al. Naringin inhibits growth potential of human triple-negative breast cancer cells by targeting b-catenin signaling pathway. Toxicol Lett 2013; 220: 219-228
• 10 Li NH, Jiang YP, Wooley PH. et al. Naringin promotes osteoblast differentiation and effectively reverses ovariectomy-associated osteoporosis. J Orthop Sci 2013; 18: 478-485
• 11 Jeon SM, Kim HK, Kim HJ. et al. Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in high-cholesterol fed rats. Transl Res 2007; 149: 15-21
• 12 Gopinath K, Sudhandiran G. Naringin modulates oxidative stress and inflammation in 3-nitropropionic acid-induced neurodegeneration through the activation of nuclear factor-erythroid 2-related factor-2 signalling pathway. Neuroscience 2012; 227: 134-143
• 13 Nie YC, Wu H, Li PB. et al. Antiinflammatory effects of naringin in chronic pulmonary neutrophilic inflammation in cigarette smoke-exposed rats. J Med Food 2012; 15: 894-900
• 14 Singh RP, Sharad S, Kapur S. Free radicals and oxidative stress in neurodegenerative diseases: Relevance of dietary antioxidants. JIACM 2014; 5: 218-225
• 15 Wood SJ, Yucel M, Pantelis C. et al. Neurobiology of schizophrenia spectrum disorders: The role of oxidative stress. Ann Acad Med Singapore 2009; 38: 396-396
• 16 Rogerio AP, Kanashiro A, Fontanari C. et al. Anti-inflammatory activity of quercetin and isoquercitrin in experimental murine allergic asthma. Inflamm Res 2007; 56: 402-408
• 17 Sreedharan V, Venkatachalam KK, Namasivayam N. Effect of morin on tissue lipid peroxidation and antioxidant status in 1, 2- dimethylhydrazine induced experimental colon carcinogenesis. Invest New Drugs 2009; 27: 21-30
• 18 Anjaneyulu M, Chopra K, Kaur I. Antidepressant activity of quercetin, a bioflavonoid, in streptozotocin-induced diabetic mice. J Med Food 2003; 6: 391-395
• 19 Donato F, de Gomes MG, Goes AT. et al Hesperidin exerts antidepressant-like effects in acute and chronic treatments in mice: Possible role of L-arginine-NO-cGMP pathway and BDNF levels. Brain Res Bull 2014; 104: 19-26
• 20 Ben-Azu B, Aderibigbe AO, Omogbiya IA. et al. Morin pretreatment attenuates schizophrenia-like behaviors in experimental animal models. Drug Res 2017; 67: 1-9 https://doi.org/10.1055/s-0043-119127
• 21 Jeong KH, Jung UJ, Kim SR. Naringin attenuates autophagic stress and neuroinflammation in kainic acid-treated hippocampus in vivo. Evid Based Complement Alternat Med article 2015; ID 354326
• 22 EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP). Scientific opinion on the safety and efficacy of naringin when used as a sensory additive for all animal species. EFSA J 2011; 9: 2416
• 23 Li P, Wang S, Guan X. et al. Acute and 13 weeks subchronic toxicological evaluation of naringin in Sprague-Dawley rats. Food Chem Toxicol 2013; 60: 1-9
• 24 Li P, Wang S, Guan X. et al. Six months chronic toxicological evaluation of naringin in Sprague-Dawley rats. Food Chem Toxicol 2014; 66: 65-75
• 25 Adeoluwa OA, Aderibigbe AO, Agu GO. et al. Neurobehavioral and analgesic properties of Ethanol bark exctract of Terminalia ivorensis A. Chev. (Combrataceae) in mice. Drug Res 2015; 65: 545-551
• 26 Ben-Azu B, Omogbiya IA, Adeoluwa OA. et al. Amelioration of chronic unpredictable mild stressinduced behavioral perturbations by noni juice in mice: Possible involvement of antioxidant system. European J Med Plants 2016; 17: 1-17
• 27 Eduviere AT, Umukoro S, Aderibigbe AO. et al. Methyl jasmonate enhances memory performance through inhibition of oxidative stress and acetylcholinesterase activity in mice. Life Sci 2015; 132: 20 -26
• 28 Akanmu MA, Adeosu SO, Ilesanmi OR. Neuropharmacological effects of oleaminde in male and female mice. Behav Brain Res 2007; 182: 88-94
• 29 Brown RE, Corey SC, Moore AK. Differences in measures of exploration and fear in MHC-congenic C578L/61 and B6-H-2 K mice. Behav Genet 1999; 26: 263-271
• 30 Ben-Azu B, Aderibigbe AO, Ajayi AM. et al. Neuroprotective effects of the ethanol stem bark extracts of Terminalia ivorensis in ketamine-induced schizophrenia-like behaviors and oxidative damage in mice. Pharm Biol 2016; 54: 2871-2879
• 31 Dorr M, Joycee D, Porsolt RD. et al. Persistence of dose-related behavior in mice. Nature 1971; 231: 121-123
• 32 Ben-Azu B, Omogbiya IA, Adeoluwa OA. et al. Amelioration of chronic unpredictable mild stressinduced behavioral perturbations by noni juice in mice: Possible involvement of antioxidant system. European J Med Plants 2016; 17: 1-17
• 33 Lister RG. The use of a plus-maze to measure Anxiety in the mouse. Psychopharmacology 1987; 111: 323-333
• 34 Nina MW, Sandra JM. Deussing, “Mouse models of depression, psychiatric disorders – Trends and Developments”. Dr. Toru Uehara, ed. 2011 ISBN: 978-953-307:45-1
• 35 Monte AS, Greicy CS, Roger SM. et al. Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: Possible involvement of antioxidant and nitrergic pathway. J Psychopharmacol 2013; 27: 1032-1043
• 36 Steru L, Chermat R, Thierry B. et al. The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology 1985; 85: 367-370
• 37 Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: A primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977; 229: 327-336
• 38 Blanchard DC, Griebel G, Blanchard RJ. Mouse defensive behaviors: Pharmacological and behavioral assays for anxiety and panic. Neurosci Biobehav Rev 2001; 25: 205-218
• 39 Aderibigbe AO, Agboola OI. Neuropharmacological property of struchium sparganophora (Linn) O. ktze in mice. Asian J Tradit Med 2011; 6: 104-111
• 40 Umukoro S, Adebesin A, Agu G. et al. Antidepressant-like activity of methyl jasmonate involves modulation of monoaminergic pathways in mice. Adv Med Sci 2017; 63: 36-42
• 41 Umukoro S, Ogboh SI, Omorogbe O. et al. Evidence for the Involvement of Monoaminergic Pathways in the Antidepressant-Like Activity of Cymbopogon citratus in Mice. Drug Res 2017; 67: 419-424
• 42 Detke MJ, Rickels M, Lucki I. Active behavior in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology 1995; 121: 66-72
• 43 Levand O, Larson HO. Some chemical constituents of Morinda citrifolia. Planta Med 1979; 36: 186-187
• 44 Yi LT, Liu BB, Li J. et al. BDNF signaling is necessary for the antidepressant-like effect of naringenin. Prog Neuropsychopharmacol Biol Psychiatry 2013; 48: 135-141
• 45 Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: Implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213: 93-118
• 46 Cryan JF, Holmes A. “The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 2005; 4: 775-790
• 47 Crawley JN, Skolnick P, Paul SM. Absence of intrinsic antag- onist actions of benzodiazepine antagonist on an exploratory model of anxiety in the mouse. Neuropharmacol 1984; 23: 531-537
• 48 Bourin M, Hascoet M. The mouse light/dark box test. Eur J Pharmacol 2003; 463: 55-65
• 49 Borsini F, Podhorna J, Marazziti D. Do animal models of anxiety predict anxiolytic-like effects of antidepressants?. Psychopharmacology 2002; 163: 121-141
• 50 Marder M, Paladini AC. GABA-A receptor ligands of flavonoid structure. Curr Top Med Chem 2002; 2: 853-867
• 51 Mangaiarkkarasi A, Viswanathan S, Ramaswamy S. et al. Anxiolytic effect of morin in mice. IJLPR 2012; 2: 52-60
• 52 Adeoluwa OA, Aderibigbe AO, Agu GO. et al. Neurobehavioral and analgesic properties of Ethanol bark exctract of Terminalia ivorensis A. Chev. (Combrataceae) in mice. Drug Res 2015; 65: 545-551
• 53 Marder M, Paladini AC. GABA-A receptor ligands of flavonoid structure. Curr Top Med Chem 2002; 2: 853-867
• 54 Lee M, Yun B, Zhang D. et al. Effect of aqueous antler extract on scopolamine induced memory impairment in mice and antioxidant activities. Food Sci Biotechnol 2010; 19: 655-661
• 55 Rothbart M. Development of spontaneous alternation in infancy. J Cognitive Neurosci 2007; 4: 351-354
• 56 Wang D, Yan J, Chen J. et al. Naringin improves neuronal insulin signaling, brain mitochondrial function, and cognitive function in High-Fat Diet-induced obese mice. Cell Mol Neurobiol 2015; 35: 1061-1071
• 57 Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361: 31-39
• 58 Wang DM, Yang YJ, Zhang L. et al. Naringin enhances CaMKII activity and improves long-term memory in a mouse model of Alzheimer's disease. Int J Mol Sci 2013; 14: 5576-5586
• 59 Maratha SR, Mahadevan N. Memory enhancing activity of naringin in unstressed and stressed mice. Possible cholinergic and nitriergic modulation. Neurochem Res 2012; 37: 2206-2212
• 60 Liu J, Yu H, Ning X. Effect of quercetin on chronic enhancement of spatial learning and memory of mice. Sci China Life Sci 2006; 49: 583-590
• 61 Remya C, Dileep KV, Tintu I. et al. Design of potent inhibitors of acetylcholinesterase using morin as the starting compound. Front Life Sci 2012; 6: 107-117
• 62 Sriraksa N, Wattanathorn J, Muchimapura S. Cognitive-Enhancing Effect of Quercetin in a Rat Model of Parkinson's Disease Induced by 6-Hydroxydopamine. Evidence-Based Complementary and Alternative Medicine. 2012; Article ID 823206 1-9