Neuroprotective Potential of Chrysin: Mechanistic Insights and Therapeutic Potential for Neurological Disorders
Abstract
:1. Introduction
2. Chemistry and Pharmacokinetics of Chrysin
3. Potential Neuroprotective Mechanisms of Chrysin
3.1. Chrysin as an Anti-Oxidant Agent
3.2. Chrysin as an Anti-Inflammatory Agent
3.3. Chrysin as an Anti-Apoptotic Agent
3.4. Chrysin as a MAO Inhibitor
3.5. Neuroprotective Role of Chrysin via a GABA Mimetic Action
4. Role of Chrysin in Different Neurological Disorders
4.1. Chrysin in AD
4.2. Chrysin in PD
4.3. Chrysin in Epilepsy
4.4. Chrysin in MS
4.5. Chrysin in Traumatic and Ischemic Brain Injury
4.6. Chrysin in Gliomas
4.7. Possible Limitations of Chrysin and Strategies to Mitigate
4.8. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
6-OHDA | 6-hydroxydopamine |
AD | Alzheimer’s diseases |
ARE | Antioxidant response element |
BBB | Blood–brain barrier |
DA | Dopaminergic |
DAMPs | Damage-associated molecular patterns |
EAE | Experimental autoimmune encephalomyelitis |
GPx: | Glutathione peroxidase |
LPS | lipopolysaccharide |
MPTP | 1-methyl-4-phenyl-1: 2, 3, 6-tetrahydropyridine; |
MS | Multiple sclerosis |
NF-κB | Nuclear factor kappa light chain-enhancer of activated B cells |
Nrf2 | Nuclear factor erythroid |
PAMPs | Pathogen-associated molecular patterns |
PD | Parkinson’s disease |
PRRs | Pattern recognition receptors |
PTZ | Pentylenetetrazol |
ROS | Reactive oxygen species |
SOD | Superoxide dismutase |
TBI | Traumatic brain injury |
TH | Tyrosine hydroxylase |
TLR | Toll-like receptors |
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# | Dose and Route | Experimental Model | Animal/Cell Lines | Outcome | Ref. |
---|---|---|---|---|---|
In Parkinson’s Disease | |||||
1. | Chrysin (100 µM) | 2,4-dinitrophenol-induced mitophagy | Caenorhabditis elegans (Bristol N2 wild-type, ucp-4 deletion mutant, pdr-1, and zdIs5) | Chrysin served as mitochondrial uncoupler and mitigated neurodegeneration possibly via PINK1/Parkin mitophagy | [75] |
2. | Chrysin (50, 100, and 200 mg/kg, p.o.) for 5 days | MPTP-induced rodent model of PD | Male C57BL/6 J mice (18–22 g) | Improvement in motor dysfunction and dopaminergic neuroprotection in nigro-striatal region, possibly by mitigating oxidative stress and neuroinflammation | [68] |
3. | Chrysin (10 mg/kg, i.g.) for 28 days | 6-OHDA-induced rodent model of PD | Female C57B/6 J mice (30–40 g, 20 months) | Improvement in motor and cognitive functions along with reduction in oxidative stress, neuroinflammation | [65] |
4. | Chrysin (50 mg/Kg, i.p.) for 4 weeks | Rotenone-induced rodent model of PD | Sprague–Dawley rats | Improvement in motor impairments and attenuation of nigrostriatal dopaminergic neurodegeneration | [76] |
5. | Chrysin (10 mg/kg, p.o.) for 28 days | 6-OHDA-induced rodent model of PD | Male C57B/6 J mice (20–30g, 90 days) | Improvement in motor functions and restoration of dopaminergic neurons, inflammatory cytokines, and neurotrophic factors levels | [77] |
6 | Chrysin (50 mM) | MPP+-induced neurotoxicity | Primary Cerebellar Granule Neuron Culture | Neuroprotection via inhibition of apoptosis by activating MEF2D via AKT-GSK3β signaling | [61] |
7 | Chrysin (10, 100 mg/kg, p.o.) | MPTP-induced rodent model of PD | Male C57BL/6 mice (28 ± 2 g, 8–9 weeks) | Restoration of dopaminergic neuronal loss via anti-apoptotic, activation of the AKT-GSK3β/MEF2D pathway, and inhibition of MAO-B activity | [61] |
8 | Chrysin (25 µM) | 6-OHDA-induced neurotoxicity | Rat pheochromocytoma (PC12) cells | Neuroprotection by attenuating oxidative stress (NRF-2/HO-1 pathway), neuroinflammation (NF-κB/iNOS pathway) | [78] |
9 | Chrysin (3, 6, and 12 µM) | 6-OHDA-induced dopaminergic neurotoxicity | Zebrafish larvae (AB strain) | Protection of dopaminergic neurons | [78] |
10 | Chrysin (40 µM) | MPP+-induced neurotoxicity | Primary mesencephalic neurons | Neuroprotection of mesencephalic dopaminergic neurons via attenuation of oxidative stress and apoptosis | [79] |
In Alzheimer’s Disease | |||||
1 | Chrysin (50 µM) | Amylin-induced amylin amyloidosis | C6 Rat Glioma Cell lines | Reduction in amylin amyloidosis | [80] |
2 | Chrysin (10 mg/kg, p.o.) for 3 months | Zinc-induced cognitive impairment and amyloidosis | Male Swiss mice | Improvement in cognitive functions and neuroprotection of hippocampal neurons | [81] |
3 | Chrysin loaded lipid-core nano capsules (1 and 5 mg/kg., p.o.) for 14 days | Aβ1–42-induced animal model of AD | Female Swiss mice (30–35 g, 18–22 months) | Improvement in learning and memory impairment via attenuation of oxidative stress and neuroinflammation | [82] |
4 | Chrysin loaded magnetic PEGylated silica nanospheres (30 µM) | Aβ-induced amyloidosis in hippocampal culture model | Sprague–Dawley rat (neonates) | Improved antioxidant profile and protection against Aβ-induced oxidative stress | [83] |
5 | Chrysin (50 mg/kg) for 21 days | Acrylamide or gamma-irradiation induced neurotoxicity | Male Wister rats (120–150 g) | Neuroprotective effect via attenuation of oxidative stress, amyloidosis, and apoptosis | [84] |
6 | Chrysin loaded sloid lipid nanoparticles (5, 10, 50, 100 mg/kg, p.o.) for 21 days | Aβ25–35-induced rodent model of AD | Male Sprague–Dawley rats (250–300 g) | Improved memory impairment and amelioration of hippocampal neuronal loss possibly via mitigation of neuronal loss | [22] |
In Epilepsy | |||||
1 | Chrysin-loaded PLGA nanoparticle (5 and 10 µg/mL) | PTZ-induced kindling | Wistar rats | Anticonvulsant effect through mitigating oxidative stress via the NRF2/HO-1 pathway | [15] |
2 | Chrysin (2.5, 5, and 10 mg/kg; p.o.) | PTZ-induced convulsions | Male Charles Foster rats (180–220 g) | Anticonvulsant effect possibly via alleviation of oxidative stress in hippocampus and cortex | [85] |
3 | Hydroethanolic extract of Passiflora incarnata (150, 300, and 600 mg/kg, i.p.) for 11 days | PTZ-induced kindling | Male Swiss mice (20–30 g) | Presence of chrysin in the extract and anticonvulsant, antidepressant effects | [86] |
4 | Extract of Passiflora incarnata (150, 300, and 600 mg/kg; i.p.) | PTZ-induced convulsions | Male Swiss mice (25–35 g) | Presence of chrysin in the extracts and anticonvulsant effect of the extracts | [87] |
5 | Chrysin (40 µg, i.c.v.) | PTZ-induced convulsions | Swiss mice (22–28 g) | Anticonvulsant effect via activation of benzodiazepine receptors | [88] |
Chrysin in Traumatic Brain Injury | |||||
1 | Chrysin (25, 50 and 100 mg/kg, p.o.) | Closed head weight-drop-induced rodent model TBI | Male Wistar rats (250–300 g) | Improved neurobehavioral impairments possibly via modulation of inflammation and apoptosis | [89] |
2 | Chrysin (25, 50 and 100 mg/kg, p.o.) | Closed head weight-drop-induced rodent model TBI | Adult male Wistar rats (250–300 g) | Improved motor coordination and memory impairment possibly via anti-oxidant and anti-apoptotic effects | [62] |
Chrysin in Ischemic Brain Injury | |||||
1 | Chrysin (10, and 20 mg/kg) for 7 days | Middle cerebral artery occlusion-induced cerebral ischemia/reperfusion injury model | Male Sprague-Dawley rats (250–280 g) | Reduction in ischemia/reperfusion injury in brain, possibly via alleviation of proinflammatory cytokine release and improvement of antioxidant defense by activating the PI3K/Akt/mTOR pathway | [45] |
2 | Chrysin (10, 30, and 100 mg/kg, p.o.) for 21 days | Bilateral common carotid arteries occlusion model of cerebral ischemia reperfusion injury | Male Wistar rats (250–300 g, 6 month) | Improvement in cognitive impairment and restoration of hippocampal neurons possibly by reducing oxidative stress and PGE2 levels | [90] |
3 | Chrysin (10, 30, and 100 mg/kg, p.o.) for 21 days | Bilateral common carotid arteries occlusion model of cerebral ischemia reperfusion injury | Male Wistar rats (250–300 g) | Improvement in cognitive impairment possibly by alleviating neuroinflammation | [91] |
4 | Chrysin (30 mg/kg, p.o.) for 14 days | Bilateral common carotid arteries occlusion model of cerebral ischemia reperfusion injury | Male Wistar rats (200–250 g) | Neuroprotection against ischemia reperfusion injury possibly by attenuating oxidative stress | [92] |
5 | Chrysin (50 mg/kg, p.o.) for 10 days | Bilateral common carotid arteries occlusion model of cerebral ischemia reperfusion injury | Male C57BL/6 J mice (18–22 g) | Reduction in degenerative changes in neurons possibly by mitigating oxidative stress | [93] |
6 | Chrysin (75 mg/kg, p.o.) for 7 days | Middle cerebral artery occlusion-induced ischemia reperfusion injury | Male C57/BL6 mice (10–12 weeks) | Reduction in neurological deficit scores and infarct volumes, possibly via inhibition of neuroinflammation (by suppression of NF-κB, COX-2, and iNOS expression) | [94] |
7 | Chrysin (30, and 100 mg/kg; i.g.) for 26 days | Bilateral common carotid arteries occlusion model of cerebral ischemia reperfusion injury | Male Wistar rats, (330–350 g) | Improvement in dementia and neurodegeneration possibly via attenuation of oxidative stress and neuroinflammation | [95] |
Chrysin in gliomas | |||||
1 | Chrysin (5, 30, 60, 120, and 240 µM) | Human glioblastoma cell lines | T98, U251, U87 cells | Anticancer activity in glioblastoma cell lines possibly via the ERK/Nrf2 signaling pathway | [96] |
2 | Chrysin (10, 20, 40, 80 and 120 µM) and Cisplatin (0.5, 1.0 and 2.0 µM) combination | Human glioma cell lines | U87 cells | Potentiation of antiproliferative effect of Cisplatin | [97] |
3 | Chrysin (50 µM) | Human glioblastoma cell lines | GL-15 and U251 cells | Damaged mitochondria, and rough endoplasmic reticulum, apoptosis, and reduction in MMP-2 expression | [98] |
4 | Chrysin (100 µM) | Human glioblastoma cell lines | GBM8901 glioblastoma cells | Induction of apoptosis and suppression of migration and invasion. Inhibition of temozolomide-induced autophagy and O6-methylguanine-DNA | [99] |
5 | Chrysin (10, 30, and 50 µM) | Rat glioma cell line | C6 glioma cells | Induction of G1 phase cell cycle arrest through induction of p21Waf1/Cip1 and inhibition of proteasome activity | [100] |
Chrysin in MS | |||||
1 | Chrysin (20 mg/kg, i.g.) for 25 days | Myelin oligodendrocyte glycoprotein-induced EAE | Male C57BL/6 mice (20–25 g) | Reduction in HDAC activity, GSK-3β and proinflammatory cytokine release | [101] |
2 | Chrysin (100 mg/kg, i.g.) for 3 days | Myelin oligodendrocyte glycoprotein-induced EAE | Female C57BL/6 mice (6–8 weeks) | Amelioration of EAE and anti-inflammatory and immune suppressive effects via suppression of dendritic cells and Th1 cells | [102] |
Miscellaneous | |||||
1 | Chrysin (0.05 mM) | Diclofenac-induced neurotoxicity | SH-SY5Y cells | Neuroprotective effect of mitigating oxidative stress and apoptosis | [60] |
2 | Chrysin (400 µM) | Cyclophosphamide-induced neurotoxicity | SH-SY5Y cells | Neuroprotection via suppression of oxidative stress and apoptotic cell death | [59] |
3 | Chrysin (5, and 10 μM) | LPS-induced inflammation | BV2 microglia cells and Primary mouse microglia cells | Suppression of neuroinflammation by downregulating NF-κB/TRAF6 pathway and upregulating zinc figure protein A20 | [103] |
Chrysin (25 and 50 mg/kg, p.o.) for 4 days | LPS-induced neuroinflammation | Male Balb/c mice (20 ± 2 g, 8 weeks) | |||
4 | Chrysin (20 mg/kg, i.g.) for 28 days | Methimazole induced hypothyroidism and associated neurobehavioral impairments | Female C57BL/6 mice (3–4 months) | Improvement in depression-like behavior via improvement of cortical and hippocampal serotonin levels and hippocampal dopamine levels | [66] |
5 | Chrysin (60, 80, 100, 150 and 200 µg/mL) | LPS-induced neuroinflammation | RAW264.7 macrophage cells | Reduction in inflammatory response by blocking the JAK-STAT pathway mediated by ROS | [51] |
6 | Chrysin (10–100 μM) | LPS-induced in vitro study | Mouse cerebral vascular endothelial (bEnd.3) cells | Reduction in VCAM-1 expression by inhibition of NF-κB/MAPK pathway resulted in anti-inflammatory effect | [46] |
7 | Chrysin (100 mg/kg, p.o.) | Ammonium chloride-induced neuroinflammation | Male Wistar rats | Attenuation of neuroinflammation by reducing expression of pro-inflammatory markers (TNF-α, IL-1β, IL-6, NF-κB, iNOS and COX-2) in the brain | [104] |
8 | Chrysin (50 mg/kg, p.o.) for 14 days | 3-nitro propionic acid-induced neurotoxicity | Male Wistar rats (250–300 g) | Improvement in neurobehavioral impairments, mitochondrial dysfunction, oxidative stress, and apoptosis | [63] |
9 | Chrysin (10 mg/kg, p.o.) for 60 days | Age-related memory decline in mice | Male Swiss Mice (3 and 20 months) | Improvement in age-related memory decline by attenuating oxidative stress and Na+/K+ ATPase activity in prefrontal cortex and hippocampus | [26] |
10 | Chrysin (5 and 20 mg/kg, p.o.) for 28 days | Chronic unpredictable mild stress | Female C57B/6 J mice (20–25 g, 90 days) | Alleviation of depression-like symptoms possibly by upregulation of BDNF, NGF levels, antioxidant defense factor (GPx, GR, Catalase) and reduction in ROS level and Na+/K+ ATPase activity | [105] |
11 | Chrysin (30 and 100 mg/kg, i.g.) for 26 days | Weight-drop method-induced spinal cord injury model | Wistar rats (230–250 g) | Augmentation in neuronal recovery and reduction in pro-inflammatory markers and iNOS expression | [106] |
12 | Chrysin in vitro (0.5–5 µM) for 12 and 24 h | Acrylamide-induced neurotoxicity | PC12 cells | Neuroprotection | [107] |
13 | Chrysin in vivo (12.5, 25, and 50 mg/kg) | Acrylamide-induced toxicity in vivo | Male Wistar rats (230–250 g) | Reduction in gait abnormality | [107] |
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Mishra, A.; Mishra, P.S.; Bandopadhyay, R.; Khurana, N.; Angelopoulou, E.; Paudel, Y.N.; Piperi, C. Neuroprotective Potential of Chrysin: Mechanistic Insights and Therapeutic Potential for Neurological Disorders. Molecules 2021, 26, 6456. https://doi.org/10.3390/molecules26216456
Mishra A, Mishra PS, Bandopadhyay R, Khurana N, Angelopoulou E, Paudel YN, Piperi C. Neuroprotective Potential of Chrysin: Mechanistic Insights and Therapeutic Potential for Neurological Disorders. Molecules. 2021; 26(21):6456. https://doi.org/10.3390/molecules26216456
Chicago/Turabian StyleMishra, Awanish, Pragya Shakti Mishra, Ritam Bandopadhyay, Navneet Khurana, Efthalia Angelopoulou, Yam Nath Paudel, and Christina Piperi. 2021. "Neuroprotective Potential of Chrysin: Mechanistic Insights and Therapeutic Potential for Neurological Disorders" Molecules 26, no. 21: 6456. https://doi.org/10.3390/molecules26216456