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

Figures & data

Figure 1. Sources of Hesperidin.

Figure 2. Chemical Structures of Hesperidin and Hesperetin.

Figure 3. Common examples of central nervous system diseases.

Figure 4. Mechanism of antioxidant activity of Hesperidin.

Table 1. Hesperidin’s bioactivity in animal models and the underlying mechanisms.

Models	Administration Protocol of Test Compound	Results and Mechanism of Action behind observed effects	References
Alzheimer’s disease/Dementia models
Aluminium chloride-induced cognitive dysfunction Wistar rat	Oral administration of 100 mg of Hesperidin per kg body weight for 60 days	Amelioration of cognitive impairment, biochemical oddity and cell death triggered by AlCl3	^[Citation57]
Streptozotocin-induced cognitive dysfunction Swiss albino mice	Oral administration of 100 mg and 200 mg of Hesperidin per kg body weight for 15 days	Amelioration of cognitive deterioration Morris water maze testing revealed that memory consolidation could be improved by possibly modifying AChE activity Inhibition of inflammatory markers that are overexpressed	^[Citation61]
Aluminium chloride-induced cognitive dysfunction Wistar rat	Oral administration of 100 mg of Hesperidin per kg body weight for 60 days	Decrease of apoptotic and inflammatory markers	^[Citation58]
Parkinson’s disease model
6-hydroxydopamine-induced PD C57BL/6 mice model	Oral administration of 50 mg of Hesperidin per kg body weight for 28 days	Reduction of memory loss and depressive-like traits Reduced loss in catalase and glutathione peroxidase activity, total reactive antioxidant capacity, and levels of dopamine and its metabolites in the striatum of old mice	^[Citation64]
Central Nervous System related Autoimmune disease models
Myelin oligodendrocyte glycoprotein -induced Experimental Autoimmune Encephalomyelitis C57BL/6 mice model	Daily Oral administration of 50 mg, 100 mg and 200 mg of Hesperidin per kg body weight for 25 days	Suppression of the severity of Experimental Autoimmune Encephalomyelitis. Decrease in interleukin-17 and interleukin-6 level Increase in transforming growth factor level	^[Citation14]
Proteolipid protein-induced Experimental Autoimmune Encephalomyelitis SJL/J mice model	Oral administration of 10 mg of Hesperetin per kg body weight for 14 or 25 days	Inability to positively affect the course of Experimental Autoimmune Encephalomyelitis Impede the healing of acute inflammatory injury	^[Citation65]
Depression model
Depressive-like behaviour in Streptozotocin-induced diabetic Wistar rat model	Oral administration of 25 mg, 50 mg and 100 mg of Hesperidin per kg body weight for 21 days	Reversed the forced swimming test’s increased immobility time caused by Streptozotocin Malondialdehyde and hyperglycemia are reduced Decrease in level of interleukin-6 Increase of brain-derived necrosis factor level Neurochemical changes brought on by streptozotocin are improved, as presented by increase in the expression of monoamines in the brain	^[Citation66]
Stroke Model
Memory dysfunction in brain ischemic/reperfusion injury Wistar rat model	Oral administration of 50 mg and 100 mg of Hesperidin per kg body weight for 7 days	Enhanced oxidative defense, mitochondrial complex enzyme activity, and changes in neurobehavioral patterns in the hippocampus L-arginine-nitric oxide signaling pathway inhibition Improvement of cognitive impairment and metabolic changes	^[Citation63]
Hypoxia-ischemic brain jury Sprague-Dawley rat (neonatal) model	Daily Oral administration of 50 mg of Hesperidin per kg body weight for 3 days following injury	Limit the production of lipid peroxide and intracellular ROS Activation of Akt, a crucial survival signalling enzyme	^[Citation67]

Figure 5. Illustration of the roles of hesperidin in the central nervous system.

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar