The Combination Neuroprotective Abilities of Resveratrol and Naringenin in Attenuation of Sleep Deprivation Complications in Rats
Abstract
Background: Sleep loss is one of the most important health problems in the world, and about 30 to 40 percent of ordinary people suffer from it. This study aimed to investigate the neuroprotective effects of the combination of resveratrol and naringenin in attenuation of sleep deprivation (SD) complications in rats. Materials and Methods: In this experimental study, 72 Wistar male rats were randomly divided into three main groups, including control, sham, and 7-days SD group. Each of its main groups consisted of three subgroups, including without drug, vehicle, and combination therapy groups (naringenin [100 mg/kg], resveratrol [100 mg/kg]). The day after the latest injection, the fear conditioning memory tests, locomotor activity test, hot plate, and forced swimming tests (FST) were carried out on all rats, and then sham and SD groups were induced 48 hours of non-REM SD (device off and on, respectively) and these behavioral tests were repeated for all rats again. Finally, the brains of all rats were removed and histopathologically examined, and stained with nissl and TUNNEL. Results: To assess fear condition memory, the rate of latency to first freezing in the visual and auditory phase increased in sham and SD rats that received vehicle or no drug (P<0.001), which indicates memory corruption. Injection of the combination of naringenin and resveratrol reduced the latency to first freezing (P<0.001), which means improved memory. In the FST test, injection of naringenin and resveratrol reduced the rate of immobility (P<0.001), which means improved depressive behavior. The naringenin and resveratrol reduced the pain perception threshold. Also, the naringenin and resveratrol reduced apoptosis compared to the control and vehicle groups (P<0.001). Conclusions: The combination of naringenin and resveratrol compared to other groups could improve memory and mood as well as reduce apoptosis, depression, and pain perception threshold. [GMJ.2021;10:e2315]References
Libman E, Fichten C, Creti L, Conrod K, Tran DL, Grad R, et al. Refreshing sleep and sleep continuity determine perceived sleep quality. Sleep Disord. 2016;2016:7170610.
https://doi.org/10.1155/2016/7170610
PMid:27413553 PMCid:PMC4927978
Nikfar B, Moazzami B, Chaichian S, Ghalichi L, Ekhlasi-Hundrieser M, Chashmyazdan M, et al. Sleep Quality and its Main Determinants Among Staff in a Persian Private Hospital. Arch Iran Med. 2018;21(11):524-9.
Eide PK, Vinje V, Pripp AH, Mardal KA, Ringstad G. Sleep deprivation impairs molecular clearance from the human brain. Brain. 2021;144(3):863-74.
https://doi.org/10.1093/brain/awaa443
PMid:33829232
Liew SC, Aung T. Sleep deprivation and its association with diseases-a review. Sleep Med. 2021;77:192-204.
https://doi.org/10.1016/j.sleep.2020.07.048
PMid:32951993
Alimohammadzadeh K, Akhlaghdoust M, Bahrainian S A, Mirzaei A. Survey on Mental Health of Iranian Medical Students: A Cross- sectional Study in Islamic Azad University, Shiraz E-Med J. 2017;18(7):e14929.
https://doi.org/10.5812/semj.14929
Cross N, Paquola C, Pomares FB, Perrault AA, Jegou A, Nguyen A, et al. Cortical gradients of functional connectivity are robust to state-dependent changes following sleep deprivation. Neuroimage. 2021;226:117547.
https://doi.org/10.1016/j.neuroimage.2020.117547
PMid:33186718
Cherubini JM, Cheng JL, Williams JS, MacDonald MJ. Sleep deprivation and endothelial function: reconciling seminal evidence with recent perspectives. Am J Physiol Heart Circ. 2021;320(1):29-35.
https://doi.org/10.1152/ajpheart.00607.2020
PMid:33064569
Chai Y, Fang Z, Yang FN, Xu S, Deng Y, Raine A, et al. Two nights of recovery sleep restores hippocampal connectivity but not episodic memory after total sleep deprivation. Sci Rep. 2020;10(1):1-1.
https://doi.org/10.1038/s41598-020-65086-x
PMid:32472075 PMCid:PMC7260173
Bishir M, Bhat A, Essa MM, Ekpo O, Ihunwo AO, Veeraraghavan VP, et al. Sleep deprivation and neurological disorders. Biomed Res Int. 2020; 2020:5764017.
https://doi.org/10.1155/2020/5764017
PMid:33381558 PMCid:PMC7755475
Vishwakarma LC, Sharma B, Singh V, Jaryal AK, Mallick HN. Acute sleep deprivation elevates brain and body temperature in rats. J Sleep Res. 2021;30(2):e13030.
https://doi.org/10.1111/jsr.13030
PMid:32297401
Joshi R, Kulkarni YA, Wairkar S. Pharmacokinetic, pharmacodynamic and formulations aspects of Naringenin: An update. Life sci. 2018;215:43-56.
https://doi.org/10.1016/j.lfs.2018.10.066
PMid:30391464
Fourny N, Lan C, Sérée E, Bernard M, Desrois M. Protective effect of resveratrol against ischemia-reperfusion injury via enhanced high energy compounds and eNOS-SIRT1 expression in type 2 diabetic female rat heart. Nutrients. 2019;11(1):105.
https://doi.org/10.3390/nu11010105
PMid:30621358 PMCid:PMC6356423
Tutunchi H, Naeini F, Ostadrahimi A, Hosseinzadeh‐Attar MJ. Naringenin, a flavanone with antiviral and anti‐inflammatory effects: A promising treatment strategy against COVID‐19. Phytother Res. 2020;34(12):3137-47.
https://doi.org/10.1002/ptr.6781
PMid:32613637 PMCid:PMC7361426
Zeng W, Jin L, Zhang F, Zhang C, Liang W. Naringenin as a potential immunomodulator in therapeutics. Pharmacol Res. 2018;135:122-6.
https://doi.org/10.1016/j.phrs.2018.08.002
PMid:30081177
Said RS, Mantawy EM, El-Demerdash E. Mechanistic perspective of protective effects of resveratrol against cisplatin-induced ovarian injury in rats: emphasis on anti-inflammatory and anti-apoptotic effects. Naunyn Schmiedebergs Arch Pharmacol. 2019;392(10):1225-38.
https://doi.org/10.1007/s00210-019-01662-x
PMid:31129703
Clementi N, Scagnolari C, D'Amore A, Palombi F, Criscuolo E, Frasca F, et al. Naringenin is a powerful inhibitor of SARS-CoV-2 infection in vitro. Pharmacol Res. 2020; 163:105255.
https://doi.org/10.1016/j.phrs.2020.105255
PMid:33096221 PMCid:PMC7574776
Meng T, Xiao D, Muhammed A, Deng J, Chen L, He J. Anti-inflammatory action and mechanisms of resveratrol. Molecules. 2021;26(1):229.
https://doi.org/10.3390/molecules26010229
PMid:33466247 PMCid:PMC7796143
Arafah A, Rehman MU, Mir TM, Wali AF, Ali R, Qamar W, et al. Multi-therapeutic potential of naringenin (4′, 5, 7-trihydroxyflavonone): experimental evidence and mechanisms. Plants (Basel). 2020;9(12):1784.
https://doi.org/10.3390/plants9121784
PMid:33339267 PMCid:PMC7766900
Chin LH, Hon CM, Chellappan DK, Chellian J, Madheswaran T, Zeeshan F, et al. Molecular mechanisms of action of naringenin in chronic airway diseases. Eur J Pharmacol. 2020;879:173139.
https://doi.org/10.1016/j.ejphar.2020.173139
PMid:32343971
Leenaars CH, Joosten RN, Zwart A, Sandberg H, Ruimschotel E, Hanegraaf MA, et al. Switch-task performance in rats is disturbed by 12 h of sleep deprivation but not by 12 h of sleep fragmentation. Sleep. 2012;35(2):211-21.
https://doi.org/10.5665/sleep.1624
PMid:22294811 PMCid:PMC3250360
Khajevand-Khazaei MR, Ziaee P, Motevalizadeh SA, Rohani M, Afshin-Majd S, Baluchnejadmojarad T, et al. Naringenin ameliorates learning and memory impairment following systemic lipopolysaccharide challenge in the rat. Eur J Pharmacol. 2018;826:114-22.
https://doi.org/10.1016/j.ejphar.2018.03.001
PMid:29518393
Singh N, Agrawal M, Doré S. Neuroprotective properties and mechanisms of resveratrol in in vitro and in vivo experimental cerebral stroke models. ACS Chem Neurosci. 2013;4(8):1151-62.
https://doi.org/10.1021/cn400094w
PMid:23758534 PMCid:PMC3750679
Raj J, Chandra M, Dogra TD, Pahuja M, Raina A. Determination of median lethal dose of combination of endosulfan and cypermethrin in wistar rat. Toxicol Int. 2013;20(1):1.
https://doi.org/10.4103/0971-6580.111531
PMid:23833430 PMCid:PMC3702116
Leenaars CH, Joosten RN, Zwart A, Sandberg H, Ruimschotel E, Hanegraaf MA, et al. Switch-task performance in rats is disturbed by 12 h of sleep deprivation but not by 12 h of sleep fragmentation. Sleep. 2012;35(2):211-21.
https://doi.org/10.5665/sleep.1624
PMid:22294811 PMCid:PMC3250360
Campbell TL, Kochli DE, McDaniel MA, Myers MK, Dunn ME, Diana VA, et al. Using Extinction-Renewal to Circumvent the Memory Strength Boundary Condition in Fear Memory Reconsolidation. Brain Sci. 2021;11(8):1023.
https://doi.org/10.3390/brainsci11081023
PMid:34439642 PMCid:PMC8393283
Moreno-Santos B, Marchi-Coelho C, Costa-Ferreira W, Crestani CC. Angiotensinergic receptors in the medial amygdaloid nucleus differently modulate behavioral responses in the elevated plus-maze and forced swimming test in rats. Behav Brain Res. 2021;397:112947.
https://doi.org/10.1016/j.bbr.2020.112947
PMid:33011187
Hazim AI, Ramanathan S, Parthasarathy S, Muzaimi M, Mansor SM. Anxiolytic-like effects of mitragynine in the open-field and elevated plus-maze tests in rats. J Physiol Sci. 2014;64(3):161-9.
https://doi.org/10.1007/s12576-014-0304-0
PMid:24464759
Bai Y, Peng W, Yang C, Zou W, Liu M, Wu H, et al. Pharmacokinetics and metabolism of naringin and active metabolite naringenin in rats, dogs, humans, and the differences between species. Front Pharmacol. 2020;11:364.
https://doi.org/10.3389/fphar.2020.00364
PMid:32292344 PMCid:PMC7118210
Radmansouri M, Ghiasvand S, Shahriari F, Aryan H, Jangholi E, Javidi MA. Hypericin Induces Apoptosis in MDA-MB-175-VII Cells in Lower Dose Compared to MDA-MB-231. Archives of Iranian Medicine. 2018;21(9):387-92.
Liaquat L, Batool Z, Sadir S, Rafiq S, Shahzad S, Perveen T, et al. Naringenin-induced enhanced antioxidant defence system meliorates cholinergic neurotransmission and consolidates memory in male rats. Life Sci. 2018;194:213-23.
https://doi.org/10.1016/j.lfs.2017.12.034
PMid:29287782
Liao D, Lv C, Cao L, Yao D, Wu Y, Long M, et al. Curcumin Attenuates Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors via Restoring Changes in Oxidative Stress and the Activation of Nrf2 Signaling Pathway in Rats. Oxid Med Cell Longev. 2020;2020:9268083.
https://doi.org/10.1155/2020/9268083
PMid:33014280 PMCid:PMC7520007
Guo Y, Gan X, Zhou H, Zhou H, Pu S, Long X, et al. Fingolimod suppressed the chronic unpredictable mild stress-induced depressive-like behaviors via affecting microglial and NLRP3 inflammasome activation. Life Sci. 2020;263:118582.
https://doi.org/10.1016/j.lfs.2020.118582
PMid:33058911
Khan H, Ullah H, Tundis R, Belwal T, Devkota H, Daglia M, et al. Dietary Flavonoids in the Management of Huntington's Disease: Mechanism and Clinical Perspective. eFood. 2020;1(1):38-52.
https://doi.org/10.2991/efood.k.200203.001
Hua FZ, Ying J, Zhang J, Wang XF, Hu YH, Liang YP, et al. Naringenin pre-treatment inhibits neuroapoptosis and ameliorates cognitive impairment in rats exposed to isoflurane anesthesia by regulating the PI3/Akt/PTEN signalling pathway and suppressing NF-kappaB-mediated inflammation. Int J Mol Med. 2016;38(4):1271-80.
https://doi.org/10.3892/ijmm.2016.2715
PMid:27572468
Ghofrani S, Joghataei MT, Mohseni S, Baluchnejadmojarad T, Bagheri M, Khamse S, et al. Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms. Eur J Pharmacol. 2015;764:195-201.
https://doi.org/10.1016/j.ejphar.2015.07.001
PMid:26148826
Tayyab M, Farheen S, M MMP, Khanam N, Mobarak Hossain M, Shahi MH. Antidepressant and Neuroprotective Effects of Naringenin via Sonic Hedgehog-GLI1 Cell Signaling Pathway in a Rat Model of Chronic Unpredictable Mild Stress. Neuromolecular Med. 2019;21(3):250-61.
https://doi.org/10.1007/s12017-019-08538-6
PMid:31037465
Rezaie M, Nasehi M, Vaseghi S, Alimohammadzadeh K, Islami Vaghar M, Mohammadi-Mahdiabadi-Hasani MH, et al. The interaction effect of sleep deprivation and cannabinoid type 1 receptor in the CA1 hippocampal region on passive avoidance memory, depressive-like behavior and locomotor activity in rats. Behav Brain Res. 2021;396:112901.
https://doi.org/10.1016/j.bbr.2020.112901
PMid:32920013
Chen L, Wang Z, Wang XM. Rapid eye-movement sleep for five days deprivation causes delayed depressive-like behavior in mice. South Med J. 2016;36(5):660-4.
Yi LT, Liu BB, Li J, Luo L, Liu Q, Geng D, et al. BDNF signaling is necessary for the antidepressant-like effect of naringenin. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 48:135-41.
https://doi.org/10.1016/j.pnpbp.2013.10.002
PMid:24121063
Arora S, Venugopalan A, Dharavath RN, Bishnoi M, Kondepudi KK, Chopra K. Naringenin Ameliorates Chronic Sleep Deprivation-Induced Pain via Sirtuin 1 Inhibition. Neurochem Res. 2021;46(5):1177-87.
https://doi.org/10.1007/s11064-021-03254-9
PMid:33599956
Javad-Moosavi BZ, Nasehi M, Vaseghi S, Jamaldini SH, Zarrindast MR. Activation and Inactivation of Nicotinic Receptnors in the Dorsal Hippocampal Region Restored Negative Effects of Total (TSD) and REM Sleep Deprivation (RSD) on Memory Acquisition, Locomotor Activity and Pain Perception. Neuroscience. 2020;433:200-11.
https://doi.org/10.1016/j.neuroscience.2020.03.006
PMid:32200080
Eydipour Z, Nasehi M, Vaseghi S, Jamaldini SH, Zarrindast MR. The role of 5-HT4 serotonin receptors in the CA1 hippocampal region on memory acquisition impairment induced by total (TSD) and REM sleep deprivation (RSD). Physiol Behav. 2020;215:112788.
https://doi.org/10.1016/j.physbeh.2019.112788
PMid:31863855
Eisenach JC, Hood DD, Curry R, Sawynok J, Yaksh TL, Li X. Intrathecal but not intravenous opioids release adenosine from the spinal cord. J Pain. 2004;5(1):64-8.
https://doi.org/10.1016/j.jpain.2003.10.001
PMid:14975380
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