Table 1. Bioactivity properties of hesperidin and their underlying mechanisms in animal models.
| Model | Compound and treatment protocol | Results and underlying mechanism | References |
|---|---|---|---|
| Normal status | |||
| Swiss albino mice | Hesperidin (10 mg/kg) per B.W., i.p. | Reduction in the phosphorylation state of ERK 1/2, in the cerebral cortex, cerebellum and hippocampus | [34] |
| Swiss albino mice | Hesperidin (0.1, 0.3 and 1 mg/kg, B.W.), i.p. | Decreasing the immobility time in the forced swimming test | [44] |
| Kappa-opioid, but not with the δ-opioid, μ-opioid or adenosinergic receptors mediate the antidepressant-like activity of hesperidin | |||
| Swiss albino mice | Hesperidin or hesperetin (0.1, 0.3 and 1 mg/kg, B. W.), i.p. | Significantly decreasing in nitrate/nitrite levels in the hippocampus | [45] |
| Increasing of BDNF level in the hippocampus | |||
| Inhibition of L-arginine-nitric oxide-cGMP pathway in hippocampus | |||
| Swiss albino mice | Hesperidin (0.3 mg/kg, B.W.), i.p. | Decreasing the immobility time in the tail suspension test and forced swimming time | [46] |
| Decreasing the antidepressant-like activity of hesperidin in mice with selective 5HT1A receptor antagonist | |||
| Learning and memory deficit model | |||
| Wistar rat, AlCl3-induced cognitive impairment | Hesperidin (100 mg/kg, B.W.), orally, 60 days | Prevention of cognitive deficits, biochemical anomaly and apoptosis induced by AlCl3 | [47] |
| Wistar rat, AlCl3-induced cognitive impairment | Hesperidin (100 mg/kg, B.W.), orally, 60 days | Reduction of inflammatory markers (GFAP, Iba-1, NF-κB, COX-2, IL-1β, TNF-α, iNOS) and apoptotic markers (cytosolic cytochrome c, caspase-3, -8, and -9) | [32] |
| Increasing of phospho-Akt and phospho-GSK3β | |||
| Swiss albino mice | Hesperidin (100 and 200 mg/kg, B.W.), orally, 15 days, pretreatment | Prevention of the cognitive impairment | [48] |
| STZ injection-induced cognitive impairment | Improvement of memory consolidation process as tested by Morris water maze possibly through modulation of AChE activity | ||
| Inhibition in the overexpression of inflammatory markers, including NF-κB, iNOS, COX-2, and GFAP-positive astrocytes | |||
| Sprague-Dawley rat | Hesperidin (10 or 50 mg/kg, i.p.), pretreatment | Inhibition of glutamate release | [49] |
| KA-induced neurotoxicity (Seizure model) | Protection of CA3 neurons against excitotoxicity induced by KA | ||
| Inhibition of pro-inflammatory molecules by microglia | |||
| PD model | |||
| C57BL/6 mice | Hesperidin (50 mg/kg), orally, 28 days | Improvement of memory impairment and depressive-like behavior | [12] |
| Intracerebroventricular injection of 6-OHDA–induced PD | Attenuation of reduction in glutathione peroxidase and catalase activity, total reactive antioxidant potential and the dopamine and its metabolite levels in the striatum of aged mice | ||
| Depression model | |||
| C57BL/6 mice | Hesperidin (50 mg/kg), orally, 14 days | Reverses cognitive and depressive disorder behaviorally | [15] |
| Depression induced by olfactory bulbectomy | Reduction of pro-inflammatory cytokines and AChE activity in hippocampus | ||
| Upregulation of BDNF and NGF in hippocampus | |||
| Wistar rat | Hesperidin (25, 50, and 100 mg/kg B.W.), orally, 21 days | Reversed the STZ-induced increase in immobility duration in the forced swimming test | [16] |
| Depressive-like behavior in STZ-induced diabetic rats | Attenuation of hyperglycaemia and malondialdehyde | ||
| Decreasing of IL-6 | |||
| Increasing of BDNF level | |||
| Amelioration of STZ-induced neurochemical alterations, as indicated by upregulation of monoamines (norepinephrine, dopamine, and serotonin) in the brain | |||
| NMRI mice | Ten days after mild TBIinduction, mice received oral hesperidin treatment (50 mg/kg/14 days) | Attenuation of depression-related symptoms behaviorally through sucrose preference test, forced swimming test, novelty-suppressed feeding test, and tail suspension test. | [20] |
| Depressive-like behaviors in mice with mild traumatic brain injury | Decreasing of neuro-inflammation and oxidative damage | ||
| Increasing of BDNF level in the hippocampus | |||
| Depressive-like behavior in LPS-injected mice | Hesperidin (25, 50, and 100 mg/kg) for 7 days, pretreatment | Downregulation of the serum corticosterone | [35] |
| Reduction of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) via the miRNA-132 pathway (upregulation) in the brain | |||
| Stroke model (brain ischemia-reperfusion injury) | |||
| Sprague-Dawley rat (neonatal) | Hesperidin (50 mg/kg/day), orally, 3 days after injury | Prevent an increase in intracellular reactive oxygen species and lipid peroxide levels | [50] |
| Hypoxia-ischemic brain jury | Activation of the key survival signaling kinase including Akt | ||
| Wistar rat | Hesperidin (50 mg/kg B.W.), orally, 15 days before MCAO | Reduced the neurological deficits behaviorally | [24] |
| MCAO-induced brain ischemia | Upregulation of the antioxidant enzymes | ||
| Reduced the induction of pro-inflammatory cytokines | |||
| Wistar rat | Hesperidin (50 and 100 mg/kg) orally, 7 days, pretreatment | Improved neurobehavioral alterations, oxidative defense and mitochondrial complex enzyme activities in hippocampus | [19] |
| Memory dysfunction in brain I/R injury | Inhibition of L-arginine-nitric oxide signaling pathway | ||
| Amelioration of memory dysfunction and biochemical alterations | |||
| Autoimmune CNS disease model | Hesperidin (50, 100, and 200 mg/kg), orally, daily for 25 days | Suppression of the incidence and severity of EAE. | [18] |
| C57BL/6 mice | Decrease IL-17 and IL-6 | ||
| MOG-induced EAE | Increase IL-1β and TGF-β | ||
| Increase Treg cells in spleen and lymph node | |||
| C57BL/6 mice | Hesperidin (50 mg/kg B.W.), subcutaneously for 7 days | Decrease in lipid peroxidation | [17] |
| MOG-induced EAE | Increase in elements of the antioxidant defense systems in brain tissue | ||
| Decrease in serum levels of TNF-α and IL-1β | |||
| SJL/J mice | Hesperetin (aglycone form of hesperidin, 10 mg/kg), orally, 14 or 25 days | Fail to beneficially influence the course of EAE | [43] |
| Proteolipid protein-induced | Suppress recovery from acute inflammatory damage | ||
| EAE |
B.W., body weight; i.p., intraperitoneally; ERK, extracellular signal-regulated kinases; BDNF, brain-derived neurotrophic factor; AlCl3, aluminum chloride; GFAP, glial fibrillary acidic protein; Iba-1, ionized calcium binding adaptor molecule-1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; COX, cyclooxygenase; IL, interleukin; TNF, tumor necrosis factor; iNOS, inducible nitric oxide synthase; GSK, glycogen synthase kinase; STZ, streptozotocin; AChE, acetylcholine esterase; KA, kainic acid; PD, Parkinson's disease; 6-OHDA, 6-hydroxydopamine; NGF, nerve growth factor; TBI, traumatic brain injury; LPS, lipopolysaccharide; MCAO, middle cerebral artery occlusion; I/R, ischemic/reperfusion; CNS, central nervous system; MOG, myelin oligodendrocyte glycoprotein; EAE, experimental autoimmune encephalomyelitis; TGF, transforming growth factor; Treg, regulatory T cell.