1,954
Views
2
CrossRef citations to date
0
Altmetric
Review Article

Hesperidin plays beneficial roles in disorders associated with the central nervous system: a review

ORCID Icon, , , &
Pages 1867-1884 | Received 13 Mar 2023, Accepted 07 Jul 2023, Published online: 20 Jul 2023

References

  • Garg, A.; Garg, S.; Zaneveld, L. J. D.; Singla, A. K. Chemistry and Pharmacology of the Citrus Bioflavonoid Hesperidin. Phytotherapy Res. 2001, 15(8), 655–669. DOI: 10.1002/ptr.1074.
  • Umeno, A.; Horie, M.; Murotomi, K.; Nakajima, Y.; Yoshida, Y. Antioxidative and Antidiabetic Effects of Natural Polyphenols and Isoflavones. Molecules. 2016, 21(6), 708. DOI: 10.3390/molecules21060708.
  • Musa, A. E.; Omyan, G.; Esmaely, F.; Shabeeb, D. Radioprotective Effect of Hesperidin: A Systematic Review. Medicina. 2019, 55(7), 370. DOI: 10.3390/medicina55070370.
  • Roohbakhsh, A.; Parhiz, H.; Soltani, F.; Rezaee, R.; Iranshahi, M. Neuropharmacological Properties and Pharmacokinetics of the Citrus Flavonoids Hesperidin and Hesperetin—A Mini-Review. Life Sci. 2014, 113(1–2), 1–6. DOI: 10.1016/j.lfs.2014.07.029.
  • Camps-Bossacoma, M.; Franch, À.; Pérez-Cano, F. J.; Castell, M. Influence of Hesperidin on the Systemic and Intestinal Rat Immune Response. Nutrients. 2017, 9(6), 580. DOI: 10.3390/nu9060580.
  • Estruel-Amades, S.; Massot-Cladera, M.; Pérez-Cano, F. J.; Franch, À.; Castell, M.; Camps-Bossacoma, M. Hesperidin Effects on Gut Microbiota and Gut-Associated Lymphoid Tissue in Healthy Rats. Nutrients. 2019, 11(2), 324. DOI: 10.3390/nu11020324.
  • Testai, L.; Calderone, V. Nutraceutical Value of Citrus Flavanones and Their Implications in Cardiovascular Disease. Nutrients. 2017, 9(5), 502. DOI: 10.3390/nu9050502.
  • Parhiz, H.; Roohbakhsh, A.; Soltani, F.; Rezaee, R.; Iranshahi, M. Antioxidant and Anti‐Inflammatory Properties of the Citrus Flavonoids Hesperidin and Hesperetin: An Updated Review of Their Molecular Mechanisms and Experimental Models. Phytotherapy Res. 2015, 29(3), 323–331. DOI: 10.1002/ptr.5256.
  • Roohbakhsh, A.; Parhiz, H.; Soltani, F.; Rezaee, R.; Iranshahi, M. Molecular Mechanisms Behind the Biological Effects of Hesperidin and Hesperetin for the Prevention of Cancer and Cardiovascular Diseases. Life Sci. 2015, 124, 64–74. DOI: 10.1016/j.lfs.2014.12.030.
  • Antunes, M. S.; Cattelan Souza, L.; Ladd, F. V. L.; Ladd, A. A. B. L.; Moreira, A. L.; Bortolotto, V. C.; Boeira, S. P.; Araújo, S. M.; Prigol, M.; Nogueira, C. W. Hesperidin Ameliorates Anxiety-Depressive-Like Behavior in 6-OHDA Model of Parkinson’s Disease by Regulating Striatal Cytokine and Neurotrophic Factors Levels and Dopaminergic Innervation Loss in the Striatum of Mice. Mol. Neurobiol. 2020, 57(7), 3027–3041. DOI: 10.1007/s12035-020-01940-3.
  • Zhu, X.; Liu, H.; Liu, Y.; Chen, Y.; Liu, Y.; Yin, X. The Antidepressant-Like Effects of Hesperidin in Streptozotocin‐Induced Diabetic Rats by Activating Nrf2/ARE/Glyoxalase 1 Pathway. Front. Pharmacol. 2020, 11, 1325. DOI: 10.3389/fphar.2020.01325.
  • Menze, E. T.; Tadros, M. G.; Abdel-Tawab, A. M.; Khalifa, A. E. Potential Neuroprotective Effects of Hesperidin on 3-Nitropropionic Acid-Induced Neurotoxicity in Rats. Neurotoxicology. 2012, 33(5), 1265–1275. DOI: 10.1016/j.neuro.2012.07.007.
  • Lee, D.; Kim, N.; Jeon, S. H.; Gee, M. S.; Ju, Y. J.; Jung, M. J.; Lee, J. K.; Lee, Y.; Lee, S.; Lee, J. K. Hesperidin Improves Memory Function by Enhancing Neurogenesis in a Mouse Model of Alzheimer’s Disease. Nutrients. 2022, 14(15), 3125. DOI: 10.3390/nu14153125.
  • Haghmorad, D.; Mahmoudi, M. B.; Salehipour, Z.; Jalayer, Z.; Kokhaei, M.; Rastin, P.; Mahmoudi, M.; Mahmoudi, M. Hesperidin Ameliorates Immunological Outcome and Reduces Neuroinflammation in the Mouse Model of Multiple Sclerosis. J. Neuroimmunol. 2017, 302, 23–33. DOI: 10.1016/j.jneuroim.2016.11.009.
  • Yu, S.; Liu, M.; Hu, K. Natural Products: Potential Therapeutic Agents in Multiple Sclerosis. Int. Immunopharmacol. 2019, 67, 87–97. DOI: 10.1016/j.intimp.2018.11.036.
  • Balsak, S.; Deveci, E. Effects of Hesperidin on the Changes Made in the Retinal Damage Induced by Traumatic Head Injury. Anal. Quant. Cytopathol. Histopathol. 2021, 43(5), 337–344.
  • Cirmi, S.; Ferlazzo, N.; Lombardo, G. E.; Ventura-Spagnolo, E.; Gangemi, S.; Calapai, G.; Navarra, M. Neurodegenerative Diseases: Might Citrus Flavonoids Play a Protective Role? Molecules. 2016, 21(10), 1312. DOI: 10.3390/molecules21101312.
  • Hajialyani, M.; Hosein Farzaei, M.; Echeverría, J.; Nabavi, S. M.; Uriarte, E.; Sobarzo-Sánchez, E. Hesperidin as a Neuroprotective Agent: A Review of Animal and Clinical Evidence. Molecules. 2019, 24(3), 648. DOI: 10.3390/molecules24030648.
  • Hwang, S. L.; Shih, P. H.; Yen, G. C. Neuroprotective Effects of Citrus Flavonoids. J. Agric. Food Chem. 2012, 60(4), 877–885. DOI: 10.1021/jf204452y.
  • Khan, A.; Ikram, M.; Hahm, J. R.; Kim, M. O. Antioxidant and Anti-Inflammatory Effects of Citrus Flavonoid Hesperetin: Special Focus on Neurological Disorders. Antioxidants. 2020, 9(7), 609. DOI: 10.3390/antiox9070609.
  • Nectoux, A. M.; Abe, C.; Huang, S. W.; Ohno, N.; Tabata, J.; Miyata, Y.; Tanaka, K.; Tanaka, T.; Yamamura, H.; Matsui, T. Absorption and Metabolic Behavior of Hesperidin (Rutinosylated Hesperetin) After Single Oral Administration to Sprague-Dawley Rats. J. Agric. Food Chem. 2019, 67(35), 9812–9819. DOI: 10.1021/acs.jafc.9b03594.
  • Raza, S. S.; Khan, M. M.; Ahmad, A.; Ashafaq, M.; Khuwaja, G.; Tabassum, R.; Javed, H.; Siddiqui, M. S.; Safhi, M. M.; Islam, F. Hesperidin Ameliorates Functional and Histological Outcome and Reduces Neuroinflammation in Experimental Stroke. Brain Res. 2011, 1420, 93–105. DOI: 10.1016/j.brainres.2011.08.047.
  • Said, U. Z.; Saada, H. N.; Abd-Alla, M. S.; Elsayed, M. E.; Amin, A. M. Hesperidin Attenuates Brain Biochemical Changes of Irradiated Rats. Int. J. Radiat. Biol. 2012, 88(8), 613–618. DOI: 10.3109/09553002.2012.694008.
  • Evans, J. A.; Mendonca, P.; Soliman, K. F. Neuroprotective Effects and Therapeutic Potential of the Citrus Flavonoid Hesperetin in Neurodegenerative Diseases. Nutrients. 2022, 14(11), 2228. DOI: 10.3390/nu14112228.
  • Hong, Y.; An, Z. Hesperidin Attenuates Learning and Memory Deficits in APP/PS1 Mice Through Activation of Akt/Nrf2 Signaling and Inhibition of RAGE/NF-Κb Signaling. Arch. Pharm. Res. 2018, 41(6), 655–663. DOI: 10.1007/s12272-015-0662-z.
  • Li, C.; Schluesener, H. Health-Promoting Effects of the Citrus Flavanone Hesperidin. Crit. Rev. Food Sci. Nutr. 2017, 57(3), 613–631.
  • Nishino, S.; Fujiki, Y.; Sato, T.; Kato, Y.; Shirai, R.; Oizumi, H.; Yamauchi, J.; Ohbuchi, K.; Miyamoto, Y.; Mizoguchi, K. Hesperetin, a Citrus Flavonoid, Ameliorates Inflammatory Cytokine-Mediated Inhibition of Oligodendroglial Cell Morphological Differentiation. Neurol. Int. 2022, 14(2), 471–487. DOI: 10.3390/neurolint14020039.
  • Chen, B.; Lu, Y.; Chen, Y.; Cheng, J. The Role of Nrf2 in Oxidative Stress-Induced Endothelial Injuries. J. Endocrinol. 2015, 225(3), R83–99. DOI: 10.1530/JOE-14-0662.
  • Zhu, C.; Dong, Y.; Liu, H.; Ren, H.; Cui, Z. Hesperetin Protects Against H2O2-Triggered Oxidative Damage via Upregulation of the Keap1-Nrf2/HO-1 Signal Pathway in ARPE-19 Cells. Biomed. Pharmacother. 2017, 88, 124–133. DOI: 10.1016/j.biopha.2016.11.089.
  • Li, X.; Xie, X.; Zhang, L.; Meng, Y.; Li, N.; Wang, M.; Li, P.; Liu, Z.; Di, T.; Zhang, L. Hesperidin Inhibits Keratinocyte Proliferation and Imiquimod-Induced Psoriasis-Like Dermatitis via the IRS-1/ERK1/2 Pathway. Life Sci. 2019, 219, 311–321. DOI: 10.1016/j.lfs.2019.01.019.
  • Muhammad, T.; Ali, T.; Ikram, M.; Khan, A.; Alam, S. I.; Kim, M. O. Melatonin Rescue Oxidative Stress-Mediated Neuroinflammation/Neurodegeneration and Memory Impairment in Scopolamine-Induced Amnesia Mice Model. J. Neuroimmune Pharmacol. 2019, 14(2), 278–294. DOI: 10.1007/s11481-018-9824-3.
  • Welbat, J. U.; Naewla, S.; Pannangrong, W.; Sirichoat, A.; Aranarochana, A.; Wigmore, P. Neuroprotective Effects of Hesperidin Against Methotrexate-Induced Changes in Neurogenesis and Oxidative Stress in the Adult Rat. Biochem. Pharmacol. 2020, 178, 114083. DOI: 10.1016/j.bcp.2020.114083.
  • Elshazly, S. M.; Abd El Motteleb, D. M.; Ibrahim, I. A. H. Hesperidin Protects Against Stress Induced Gastric Ulcer Through Regulation of Peroxisome Proliferator Activator Receptor Gamma in Diabetic Rats. Chem.-Biol. Interact. 2018, 291, 153–161. DOI: 10.1016/j.cbi.2018.06.027.
  • Agrawal, Y. O.; Sharma, P. K.; Shrivastava, B.; Ojha, S.; Upadhya, H. M.; Arya, D. S.; Goyal, S. N.; Das, A. Hesperidin Produces Cardioprotective Activity via PPAR-γ Pathway in Ischemic Heart Disease Model in Diabetic Rats. PLoS. One. 2014, 9(11), e111212. DOI: 10.1371/journal.pone.0111212.
  • Mahmoud, A. M. Hesperidin Protects Against Cyclophosphamide-Induced Hepatotoxicity by Upregulation of PPARγ and Abrogation of Oxidative Stress and Inflammation. Can. J. Physiol. Pharmacol. 2014, 92(9), 717–724. DOI: 10.1139/cjpp-2014-0204.
  • Kosari-Nasab, M.; Shokouhi, G.; Ghorbanihaghjo, A.; Abbasi, M. M.; Salari, A. A. Hesperidin Attenuates Depression-Related Symptoms in Mice with Mild Traumatic Brain Injury. Life Sci. 2018, 213, 198–205. DOI: 10.1016/j.lfs.2018.10.040.
  • Sato, K.; Sato, T.; Ohno-Oishi, M.; Ozawa, M.; Maekawa, S.; Shiga, Y.; Nakazawa, T.; Yasuda, M.; Himori, N.; Omodaka, K. CHOP Deletion and Anti-Neuroinflammation Treatment with Hesperidin Synergistically Attenuate NMDA Retinal Injury in Mice. Exp. Eye Res. 2021, 213, 108826. DOI: 10.1016/j.exer.2021.108826.
  • Aja, P. M.; Izekwe, F. I.; Famurewa, A. C.; Ekpono, E. U.; Nwite, F. E.; Igwenyi, I. O.; Ale, B. A. Hesperidin Protects Against Cadmium-Induced Pancreatitis by Modulating Insulin Secretion, Redox Imbalance and Inos/NF/NF-ĸb Signaling in Rats. Life Sci. 2020, 259, 118268.
  • Maekawa, S.; Sato, K.; Fujita, K.; Daigaku, R.; Tawarayama, H.; Murayama, N.; Nakazawa, T.; Yabana, T.; Shiga, Y.; Omodaka, K. The Neuroprotective Effect of Hesperidin in NMDA-Induced Retinal Injury Acts by Suppressing Oxidative Stress and Excessive Calpain Activation. Sci. Rep. 2017, 7(1), 6885. DOI: 10.1038/s41598-017-06969-4.
  • Martínez, M. C.; Fernandez, S. P.; Loscalzo, L. M.; Wasowski, C.; Paladini, A. C.; Marder, M.; Viola, H. Hesperidin, a Flavonoid Glycoside with Sedative Effect, Decreases Brain pErk1/2 Levels in Mice. Pharmacol. Biochem. Behav. 2009, 92(2), 291–296.
  • Kwon, J. Y.; Jung, U. J.; Kim, D. W.; Kim, S.; Moon, G. J.; Hong, J.; Jeon, M.-T., Shin, M., Chang, J. H., Kim, S. R. Beneficial Effects of Hesperetin in a Mouse Model of Temporal Lobe Epilepsy. J. Med. Food. 2018, 21(12), 1306–1309. DOI: 10.1089/jmf.2018.4183.
  • Sun, Z.; Li, X.; Yang, L.; Dong, X.; Han, Y.; Li, Y.; Li, W. SOCE-Mediated NFAT1–NOX2–NLRP1 Inflammasome Involves in Lipopolysaccharide-Induced Neuronal Damage and Aβ Generation. Mol. Neurobiol. 2022, 59(5), 3183–3205. DOI: 10.1007/s12035-021-02717-y.
  • Badshah, H.; Ikram, M.; Ali, W.; Ahmad, S.; Hahm, J. R.; Kim, M. O. Caffeine May Abrogate LPS-Induced Oxidative Stress and Neuroinflammation by Regulating Nrf2/TLR4 in Adult Mouse Brains. Biomolecules. 2019, 9(11), 719. DOI: 10.3390/biom9110719.
  • Bloem, B. R.; Okun, M. S.; Klein, C. Parkinson’s Disease. Lancet. 2021, 397(10291), 2284–2303. DOI: 10.1016/S0140-6736(21)00218-X.
  • Brusadin, A. Parkinson’s Disease and Anesthesia. Nurs. Stud. Class Projects. 2021, 474.
  • Kwok, J. Y.; Kwan, J. C.; Auyeung, M.; Mok, V. C.; Lau, C. K.; Choi, K. C.; Chan, H. Y. Effects of Mindfulness Yoga Vs Stretching and Resistance Training Exercises on Anxiety and Depression for People with Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2019, 76(7), 755–763. DOI: 10.1001/jamaneurol.2019.0534.
  • Kesh, S.; Kannan, R. R.; Sivaji, K.; Balakrishnan, A. Hesperidin Downregulates Kinases Lrrk2 and gsk3β in a 6-OHDA Induced Parkinson’s Disease Model. Neurosci. Lett. 2021, 740, 135426. DOI: 10.1016/j.neulet.2020.135426.
  • Poetini, M. R.; Araujo, S. M.; de Paula, M. T.; Bortolotto, V. C.; Meichtry, L. B.; de Almeida, F. P.; Prigol, M. Hesperidin Attenuates Iron-Induced Oxidative Damage and Dopamine Depletion in Drosophila Melanogaster Model of Parkinson’s Disease. Chem.-Biol. Interact. 2018, 279, 177–186. DOI: 10.1016/j.cbi.2017.11.018.
  • Khan, A.; Ikram, M.; Muhammad, T.; Park, J.; Kim, M. O. Caffeine Modulates Cadmium-Induced Oxidative Stress, Neuroinflammation, and Cognitive Impairments by Regulating Nrf-2/HO-1 in vivo and in vitro. J. Clin. Med. 2019, 8(5), 680. DOI: 10.3390/jcm8050680.
  • Bernhoft, R. A. Cadmium Toxicity and Treatment. Sci. World J. 2013, 2013, 1–7. DOI: 10.1155/2013/394652.
  • Khan, M. H. A.; Parvez, S. Hesperidin Ameliorates Heavy Metal Induced Toxicity Mediated by Oxidative Stress in Brain of Wistar Rats. J. Trace Elem. Med. Biol. 2015, 31, 53–60. DOI: 10.1016/j.jtemb.2015.03.002.
  • Mandolesi, G.; Grasselli, G.; Musumeci, G.; Centonze, D. Cognitive Deficits in Experimental Autoimmune Encephalomyelitis: Neuroinflammation and Synaptic Degeneration. Neurol. Sci. 2010, 31(Suppl 2), 255–259. DOI: 10.1007/s10072-010-0369-3.
  • Planche, V.; Panatier, A.; Hiba, B.; Ducourneau, E. G.; Raffard, G.; Dubourdieu, N.; Tourdias, T.; Lesté-Lasserre, T.; Brochet, B.; Dousset, V. Selective Dentate Gyrus Disruption Causes Memory Impairment at the Early Stage of Experimental Multiple Sclerosis. Brain Behav. Immun. 2017, 60, 240–254. DOI: 10.1016/j.bbi.2016.11.010.
  • Kurkowska-Jastrzębska, I.; Świątkiewicz, M.; Zaremba, M.; Cudna, A.; Piechal, A.; Pyrzanowska, J.; Widy-Tyszkiewicz, E.; Członkowska, A. Neurodegeneration and Inflammation in Hippocampus in Experimental Autoimmune Encephalomyelitis Induced in Rats by One–Time Administration of Encephalitogenic T Cells. Neuroscience. 2013, 248, 690–698. DOI: 10.1016/j.neuroscience.2013.06.025.
  • Ziehn, M. O.; Avedisian, A. A.; Tiwari-Woodruff, S.; Voskuhl, R. R. Hippocampal CA1 Atrophy and Synaptic Loss During Experimental Autoimmune Encephalomyelitis, EAE. Lab. Invest. 2010, 90(5), 774–786. DOI: 10.1038/labinvest.2010.6.
  • Jovanova-Nesic, K.; Shoenfeld, Y.; Herbert Spector, N. Aluminum Excytotoxicity and NeuroAutotoimmunity: The Role of the Brain Expression of CD32+ (FcγRIIa), ICAM-1+ and CD3ع in Aging. CAS. 2012, 5(3), 209–217. DOI: 10.2174/1874609811205030007.
  • Justin Thenmozhi, A.; William Raja, T. R.; Manivasagam, T.; Janakiraman, U.; Essa, M. M. Hesperidin Ameliorates Cognitive Dysfunction, Oxidative Stress and Apoptosis Against Aluminium Chloride Induced Rat Model of Alzheimer’s Disease. Nutr. Neurosci. 2017, 20(6), 360–368. DOI: 10.1080/1028415X.2016.1144846.
  • Justin-Thenmozhi, A.; Dhivya Bharathi, M.; Kiruthika, R.; Manivasagam, T.; Borah, A.; Essa, M. M. Attenuation of Aluminum Chloride-Induced Neuroinflammation and Caspase Activation Through the AKT/GSK-3β Pathway by Hesperidin in Wistar Rats. Neurotox. Res. 2018, 34(3), 463–476. DOI: 10.1007/s12640-018-9904-4.
  • Donato, F.; de Gomes, M. G.; Goes, A. T. R.; Borges Filho, C.; Del Fabbro, L.; Antunes, M. S.; Jesse, C. R.; Boeira, S. P.; Jesse, C. R. 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. DOI: 10.1016/j.brainresbull.2014.03.004.
  • Chang, C. Y.; Lin, T. Y.; Lu, C. W.; Huang, S. K.; Wang, Y. C.; Chou, S. S. P.; Wang, S. J. Hesperidin Inhibits Glutamate Release and Exerts Neuroprotection Against Excitotoxicity Induced by Kainic Acid in the Hippocampus of Rats. Neurotoxicology. 2015, 50, 157–169. DOI: 10.1016/j.neuro.2015.08.014.
  • Javed, H.; Vaibhav, K.; Ahmed, M. E.; Khan, A.; Tabassum, R.; Islam, F.; Safhi, M. M.; Islam, F. Effect of Hesperidin on Neurobehavioral, Neuroinflammation, Oxidative Stress and Lipid Alteration in Intracerebroventricular Streptozotocin Induced Cognitive Impairment in Mice. J. Neurol. Sci. 2015, 348(1–2), 51–59. DOI: 10.1016/j.jns.2014.10.044.
  • Nones, J.; E Spohr, T. C. L. D. S.; Gomes, F. C. A. Hesperidin, a Flavone Glycoside, as Mediator of Neuronal Survival. Neurochem. Res. 2011, 36(10), 1776–1784. DOI: 10.1007/s11064-011-0493-3.
  • Gaur, V.; Kumar, A. Hesperidin Pre-Treatment Attenuates NO-Mediated Cerebral Ischemic Reperfusion Injury and Memory Dysfunction. Pharmacol Rep. 2010, 62(4), 635–648. DOI: 10.1016/S1734-1140(10)70321-2.
  • Antunes, M. S.; Goes, A. T.; Boeira, S. P.; Prigol, M.; Jesse, C. R. Protective Effect of Hesperidin in a Model of Parkinson’s Disease Induced by 6-Hydroxydopamine in Aged Mice. Nutrition. 2014, 30(11–12), 1415–1422. DOI: 10.1016/j.nut.2014.03.024.
  • Verbeek, R.; van Tol, E. A.; van Noort, J. M. Oral Flavonoids Delay Recovery from Experimental Autoimmune Encephalomyelitis in SJL Mice. Biochem. Pharmacol. 2005, 70(2), 220–228. DOI: 10.1016/j.bcp.2005.04.041.
  • El-Marasy, S. A.; Abdallah, H. M.; El-Shenawy, S. M.; El-Khatib, A. S.; El-Shabrawy, O. A.; Kenawy, S. A. Anti-Depressant Effect of Hesperidin in Diabetic Rats. Can. J. Physiol. Pharmacol. 2014, 92(11), 945–952. DOI: 10.1139/cjpp-2014-0281.
  • Rong, Z.; Pan, R.; Xu, Y.; Zhang, C.; Cao, Y.; Liu, D. Hesperidin Pretreatment Protects Hypoxia–Ischemic Brain Injury in Neonatal Rat. Neuroscience. 2013, 255, 292–299. DOI: 10.1016/j.neuroscience.2013.09.030.
  • Carlos Filho, B.; Del Fabbro, L.; de Gomes, M. G.; Goes, A. T.; Souza, L. C.; Boeira, S. P.; Jesse, C. R. Kappa-Opioid Receptors Mediate the Antidepressant-Like Activity of Hesperidin in the Mouse Forced Swimming Test. Eur. J. Pharmacol. 2013, 698(1–3), 286–291. DOI: 10.1016/j.ejphar.2012.11.003.
  • Lee, B.; Choi, G. M.; Sur, B. Antidepressant-Like Effects of Hesperidin in Animal Model of Post-Traumatic Stress Disorder. Chin. J. Integr. Med. 2021, 27(1), 39–46. DOI: 10.1007/s11655-020-2724-4.
  • Kim, J.; Wie, M. B.; Ahn, M.; Tanaka, A.; Matsuda, H.; Shin, T. Benefits of Hesperidin in Central Nervous System Disorders: A Review. Anat. Cell Biol. 2019, 52(4), 369–377. DOI: 10.5115/acb.19.119.
  • Zhu, X.; Zhang, Y. M.; Zhang, M. Y.; Chen, Y. J.; Liu, Y. W. Hesperetin Ameliorates Diabetes-Associated Anxiety and Depression-Like Behaviors in Rats via Activating Nrf2/ARE Pathway. Metab. Brain Dis. 2021, 36(7), 1969–1983. DOI: 10.1007/s11011-021-00785-6.
  • Fu, H.; Liu, L.; Tong, Y.; Li, Y.; Zhang, X.; Gao, X.; Wang, H.; Zhao, J.; Xiao, D.; Wen, K. The Antidepressant Effects of Hesperidin on Chronic Unpredictable Mild Stress-Induced Mice. Eur. J. Pharmacol. 2019, 853, 236–246. DOI: 10.1016/j.ejphar.2019.03.035.
  • Kwatra, M.; Ahmed, S.; Gawali, B.; Panda, S. R.; Naidu, V. G. M. Hesperidin Alleviates Chronic Restraint Stress and Lipopolysaccharide-Induced Hippocampus and Frontal Cortex Damage in Mice: Role of TLR4/NF-κB, p38 MAPK/JNK, Nrf2/ARE Signaling. Neurochem. Int. 2020, 140, 104835. DOI: 10.1016/j.neuint.2020.104835.
  • Xie, L.; Gu, Z.; Liu, H.; Jia, B.; Wang, Y.; Cao, M.; Song, R.; Zhang, Z.; Bian, Y. The Anti-Depressive Effects of Hesperidin and the Relative Mechanisms Based on the NLRP3 Inflammatory Signaling Pathway. Front. Pharmacol. 2020, 11, 1251. DOI: 10.3389/fphar.2020.01251.
  • Nadar, J. S.; Kale, P. P.; Kadu, P. K.; Prabhavalkar, K.; Dhangar, R. Potentiation of Antidepressant Effects of Agomelatine and Bupropion by Hesperidin in Mice. Neurol. Res. Int. 2018, 2018, 1–7. DOI: 10.1155/2018/9828639.
  • Zhu, X.; Liu, H.; Deng, Z.; Yan, C.; Liu, Y.; Yin, X. Hesperidin Exerts Anxiolytic-Like Effects in Rats with Streptozotocin-Induced Diabetes via PKA/CREB Signaling. Curr. Mol. Pharmacol. 2023, 16(1), 91–100. DOI: 10.2174/1573413718666220314140848.
  • Hajizadeh Moghaddam, A.; Ahmadnia, H.; Jelodar, S. K.; Ranjbar, M. Hesperetin Nanoparticles Attenuate Anxiogenic-Like Behavior and Cerebral Oxidative Stress Through the Upregulation of Antioxidant Enzyme Expression in Experimental Dementia of Alzheimer’s Type. Neurol. Res. 2020, 42(6), 477–486. DOI: 10.1080/01616412.2020.1747716.
  • Matias, I.; Diniz, L. P.; Buosi, A.; Neves, G.; Stipursky, J.; Gomes, F. C. A. Flavonoid Hesperidin Induces Synapse Formation and Improves Memory Performance Through the Astrocytic TGF-β1. Front. Aging Neurosci. 2017, 9, 184. DOI: 10.3389/fnagi.2017.00184.
  • Luo, Y.; Fan, H.; Tan, X.; Li, Z. Hesperetin Rescues Emotional Memory and Synaptic Plasticity Deficit in Aged Rats. Behav. Neurosci. 2021, 135(6), 721. DOI: 10.1037/bne0000475.
  • Makvandi, A. A.; Khalili, M.; Roghani, M.; Moghaddam, S. A. Hesperetin Ameliorates Electroconvulsive Therapy-Induced Memory Impairment Through Regulation of Hippocampal BDNF and Oxidative Stress in a Rat Model of Depression. J. Chem. Neuroanat. 2021, 117, 102001. DOI: 10.1016/j.jchemneu.2021.102001.
  • Kumar, A.; Lalitha, S.; Mishra, J. Hesperidin Potentiates the Neuroprotective Effects of Diazepam and Gabapentin Against Pentylenetetrazole-Induced Convulsions in Mice: Possible Behavioral, Biochemical and Mitochondrial Alterations. Indian J. Pharmacol. 2014, 46(3), 309. DOI: 10.4103/0253-7613.132180.
  • Sharma, P.; Kumari, S.; Sharma, J.; Purohit, R.; Singh, D. Hesperidin Interacts with CREB-BDNF Signaling Pathway to Suppress Pentylenetetrazole-Induced Convulsions in Zebrafish. Front. Pharmacol. 2021, 11, 607797. DOI: 10.3389/fphar.2020.607797.
  • Lassmann, H. Multiple Sclerosis Pathology. Cold Spring Harb. Perspect. Med. 2018, 8(3), a028936. DOI: 10.1101/cshperspect.a028936.
  • Baradaran, S.; Moghaddam, A. H.; Ghasemi-Kasman, M. Hesperetin Reduces Myelin Damage and Ameliorates Glial Activation in Lysolecithin-Induced Focal Demyelination Model of Rat Optic Chiasm. Life Sci. 2018, 207, 471–479. DOI: 10.1016/j.lfs.2018.07.001.
  • Baradaran, S.; Ghasemi-Kasman, M.; Moghaddam, A. H. Nano-Hesperetin Enhances the Functional Recovery and Endogenous Remyelination of the Optic Pathway in Focal Demyelination Model. Brain Res. Bull. 2020, 164, 392–399. DOI: 10.1016/j.brainresbull.2020.09.006.
  • Schwartz, M.; Deczkowska, A. Neurological Disease as a Failure of Brain–Immune Crosstalk: The Multiple Faces of Neuroinflammation. Trends Immunol. 2016, 37(10), 668–679. DOI: 10.1016/j.it.2016.08.001.
  • Shin, T.; Kojima, T.; Tanuma, N.; Ishihara, Y.; Matsumoto, Y. The Subarachnoid Space as a Site for Precursor T Cell Proliferation and Effector T Cell Selection in Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 1995, 56(2), 171–178. DOI: 10.1016/0165-5728(94)00144-D.
  • Shin, T.; Ahn, M.; Matsumoto, Y. Mechanism of Experimental Autoimmune Encephalomyelitis in Lewis Rats: Recent Insights from Macrophages. Anat. Cell Biol. 2012, 45(3), 141–148. DOI: 10.5115/acb.2012.45.3.141.
  • Ginwala, R.; McTish, E.; Raman, C.; Singh, N.; Nagarkatti, M.; Nagarkatti, P.; Sagar, D., Jain, P., Khan, Z. K. Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions. J. Neuroimmune Pharmacol. 2016, 11(1), 36–47. DOI: 10.1007/s11481-015-9617-x.
  • Ciftci, O.; Ozcan, C.; Kamisli, O.; Cetin, A.; Basak, N.; Aytac, B. Hesperidin, a Citrus Flavonoid, Has the Ameliorative Effects Against Experimental Autoimmune Encephalomyelitis (EAE) in a C57BL/J6 Mouse Model. Neurochem. Res. 2015, 40(6), 1111–1120. DOI: 10.1007/s11064-015-1571-8.
  • van der Veen, R. C. Nitric Oxide and T Helper Cell Immunity. Int. Immunopharmacol. 2001, 1(8), 1491–1500. DOI: 10.1016/S1567-5769(01)00093-5.
  • Nath, N.; Morinaga, O.; Singh, I. S-Nitrosoglutathione a Physiologic Nitric Oxide Carrier Attenuates Experimental Autoimmune Encephalomyelitis. J. Neuroimmune Pharmacol. 2010, 5(2), 240–251. DOI: 10.1007/s11481-009-9187-x.
  • Willenborg, D. O.; Staykova, M.; Fordham, S.; O’Brien, N.; Linares, D. The Contribution of Nitric Oxide and Interferon Gamma to the Regulation of the Neuro-Inflammation in Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2007, 191(1–2), 16–25. DOI: 10.1016/j.jneuroim.2007.09.007.
  • Zhang, J.; Jiang, H.; Wu, F.; Chi, X.; Pang, Y.; Jin, H.; Zhang, S.; Zhang, S. Neuroprotective Effects of Hesperetin in Regulating Microglia Polarization After Ischemic Stroke by Inhibiting TLR4/NF-Κb Pathway. J. Healthc. Eng. 2021, 2021, 1–10. DOI: 10.1155/2021/9938874.
  • Wu, M. Y.; Yiang, G. T.; Liao, W. T.; Tsai, A. P. Y.; Cheng, Y. L.; Cheng, P. W.; Li, C. J.; Li, C.-J. Current Mechanistic Concepts in Ischemia and Reperfusion Injury. Cell. Physiol. Biochem. 2018, 46(4), 1650–1667. DOI: 10.1159/000489241.
  • Kalogeris, T.; Baines, C. P.; Krenz, M.; Korthuis, R. J. Cell Biology of Ischemia/Reperfusion Injury. Int. Rev. Cell Mol. Biol. 2012, 298, 229–317.
  • Devyatov, A. A.; Fedorova, T. N.; Berezhnoy, D. S.; Stvolinskii, S. L.; Tutelyan, V. A. Mechanisms of Neuroprotective Action of Hesperetin and Carnosine in Focal Ischemia of the Brain in Rats. Bull. Exp. Biol. Med. 2020, 169, 242–245.
  • Song, H.; Ding, Z.; Chen, J.; Chen, T.; Wang, T.; Huang, J. The AMPK-SIRT1-FoxO1-NF-Κb Signaling Pathway Participates in Hesperetin-Mediated Neuroprotective Effects Against Traumatic Brain Injury via the NLRP3 Inflammasome. Immunopharmacol. Immunotoxicol. 2022, 44(6), 970–983. DOI: 10.1080/08923973.2022.2096464.
  • Miles, E. A.; Calder, P. C. Effects of Citrus Fruit Juices and Their Bioactive Components on Inflammation and Immunity: A Narrative Review. Front. Immunol. 2021, 12, 712608. DOI: 10.3389/fimmu.2021.712608.
  • Ikram, M.; Muhammad, T.; Rehman, S. U.; Khan, A.; Jo, M. G.; Ali, T.; Kim, M. O. Hesperetin Confers Neuroprotection by Regulating Nrf2/tlr4/nf-Κb Signaling in an Aβ Mouse Model. Mol. Neurobiol. 2019, 56(9), 6293–6309. DOI: 10.1007/s12035-019-1512-7.
  • Rotimi, S. O.; Bankole, G. E.; Adelani, I. B.; Rotimi, O. A. Hesperidin Prevents Lipopolysaccharide-Induced Endotoxicity in Rats. Immunopharmacol. Immunotoxicol. 2016, 38(5), 364–371. DOI: 10.1080/08923973.2016.1214142.
  • Li, M.; Shao, H.; Zhang, X.; Qin, B. Hesperidin Alleviates Lipopolysaccharide-Induced Neuroinflammation in Mice by Promoting the MiRNA-132 Pathway. Inflammation. 2016, 39(5), 1681–1689. DOI: 10.1007/s10753-016-0402-7.
  • Youdim, K. A.; Dobbie, M. S.; Kuhnle, G.; Proteggente, A. R.; Abbott, N. J.; Rice‐Evans, C. Interaction Between Flavonoids and the Blood–Brain Barrier: In vitro Studies. J. Neurochem. 2003, 85(1), 180–192. DOI: 10.1046/j.1471-4159.2003.01652.x.
  • Li, C.; Zug, C.; Qu, H.; Schluesener, H.; Zhang, Z. Hesperidin Ameliorates Behavioral Impairments and Neuropathology of Transgenic APP/PS1 Mice. Behav. Brain Res. 2015, 281, 32–42. DOI: 10.1016/j.bbr.2014.12.012.
  • Noshy, P. A.; Azouz, R. A. Neuroprotective Effect of Hesperidin Against Emamectin Benzoate-Induced Neurobehavioral Toxicity in Rats. Neurotoxicol. Teratol. 2021, 86, 106981. DOI: 10.1016/j.ntt.2021.106981.