Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders
Abstract
:1. Introduction
2. Search Strategy
Selection Criteria
3. Environmental Stress and Cellular Stress Response
3.1. Environmental Stress
3.2. Cellular Stress Response
4. Flavonoids
5. Flavonoids and Cellular Stress Response
5.1. Role of Flavonoids in Neuroinflammation
5.2. Role of Flavonoids in Oxidative Stress
5.3. Role of Flavonoids in Proteotoxicity
5.4. Role of Flavonoids in Endoplasmic Reticulum (ER) Stress
6. Pre-Clinical/Clinical Studies of Flavonoids
7. Flavonoid Metabolism
8. Neuronal Access of Flavonoids
9. Flavonoid Extraction: A Key to Improved Flavonoid Property
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
PD | Parkinson’s disease |
HD | Huntington’s disease |
ALS | Amyotrophic lateral sclerosis |
ER | Endoplasmic reticulum |
PQC | Protein quality control |
NO | Nitric oxide |
ROS | Reactive oxygen species |
UPR | Unfolded protein response |
HSP | Heat shock protein |
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Subgroup | Chemical Structure | Plant Source | Example | Ref. |
---|---|---|---|---|
Isoflavones | Soybeans, leguminous plants, microbes, | Genistein, Daidzein, Glycerin, Formanantine | [71,72,73,74] | |
Flavones | Leaves, flowers, and fruits | Luteolin, Apigenin | [75,76] | |
Flavanones | All citrus fruits | Hesperidin, Naringenin | [77] | |
Flavonols | Onions, berries, lettuce, tomatoes, grapes, and apples | Kaempferol, Quercetin | [78] | |
Neoflavonoids | Sri Lankan endemic plant Mesuathwaitesii | Calophyllolide | [79,80] | |
Flavanols(Flavan-3-ols) | Peaches, pears, blueberries, bananas, and apples | Catechins, Epicatechins, Epigallocatechin | [81,82] | |
Anthocyanins | Bilberries, cranberries, merlot grapes, blackberries, black currants, red grapes, strawberries, blueberries, and raspberries | Cyanidin, Delphinidin, Malvidine | [83] | |
Flavones | Leaves, flowers, and fruits | Luteolin, Apigenin | [84,85] | |
Flavanones | All citrus fruits | Hesperidin, Naringenin | [77] |
Flavonoids | Cellular Stress Response | Host Model | Ref |
---|---|---|---|
Kaempferol | Inhibits the expression of GRP78 (a chaperone) and CHOP (ER stress associated pro-apoptotic transcription factor) | Human IMR32 | [146] |
Quercetin | Reduction in the expression of glucose-regulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP) | Human umbilical vein endothelial cells | [152] |
Morin | Inhibition of the expression of GRP78, Decreased ROS and apoptosis | renal proximal tubular HK-2 cells | [153] |
Methoxyflavones | Activation of the UPR pathway via activating eIF2α and Nrf2 and induces the expression of downstream genes, such as GRP78, HO-1, and CHOP, without causing ER stress | Mouse insulinoma MIN6 cells | [147] |
Agathisflavone | Increases the remyelination and alters microglial activation state. Neuroprotective effect via increase the expression of neurotrophic factors ciliary neurotrophic factor (Cntf), epidermal growth factor receptor (Egfr), and neuronal GABA b1 receptor subunit (Gabrb1) | Mice belonging to the C57BL/6 background | [154] |
Apigenin | Neuroprotection, astrocytes integrity and have an anti-neuro-inflammatory response. These responses are generated via the modulation of inflammatory cytokines mRNA expression and reduce the expression of OX42, IL-6, and gp130. Induces the expression of brain-derived neurotrophic factor (BDNF). | Wistar rats’ hemispheres brain’s Glial cells and neurons | [154] |
Hesperetin | Reduction of the expression of inflammatory Cytokines by ameliorating Toll-like receptor-4 (TLR4)-mediated ionized calcium-binding adapter molecule 1/glial fibrillary acidic protein (Iba-1/GFAP) expression. Attenuation in the LPS-induced generation of reactive oxygen species/lipid peroxidation (ROS/LPO) and improved the antioxidant protein level, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Haem-oxygenase (HO-1), in the mouse brain | C57BL/6 N mice | [155] |
Epimedium | Have anti-proteotoxic potency as it reduces the Aβ1–42- and polyQ-induced paralysis in CL4176 and AM140 | C. elegans human proteotoxic disease models (CL4176, AM140) | [144] |
Rutin | Rutin treatment reduces polyglutamine (polyQ) protein aggregation in muscle, reduced polyQ-mediated neuronal death in ASH sensory neurons, and extended lifespan. | C. elegans model of Huntington’s disease | [156] |
phenyl-γ-valerolactones (metabolites of flavan-3-ols) | (4′-OH)-PVL interferes with AβO (but not fibril) assembly and actively remodels performed AβOs into nontoxic amorphous aggregate. | Yeast strains expressing different variants of the human Aβ42 and β23 peptides | [139] |
Disease | Clinical Onsets | Behavioral Onsets | Disease Model | Flavonoids | Dose | Effect of Flavonoids Treatment on the Animal Model | Ref. |
---|---|---|---|---|---|---|---|
Alzheimer’s disease (AD) | Presence of extracellular neuritic plaques containing (Aβ) peptide and intracellular neurofibrillary tangles containing tau | AD results in a progressive loss of cognitive ability and eventually daily function activities | 5 × FAD model | 7,8-dihydroxyflavone (7,8-DHF) | IP injection (5 mg/kg) | Improved memory | [160] |
Oral administration (5 mg/kg/day) | Improvement in memory and reduction in synapse loss | [161] | |||||
2 × FAD model | Apigenin | Oral administration (40 mg/kg/day) | Improvement in learning and memory, reduction in deposition of insoluble Aβ | [162] | |||
1 × FAD model, 3 × FAD model, SAMP8 mice | Nobiletin | IP injection (10 mg/kg) | Improvement in memory and reduction in levels of both soluble and insoluble Aβ | [163] | |||
IP injections (10 and 30 mg/kg) | Improvement in memory; reduction in soluble Aβ levels | [164] | |||||
1 × FAD model | Baicalein | IP injections 10 and 50 mg/kg | Improves the memory, reduces some markers of oxidative stress | [162] | |||
(SAMP8) | Quercetin | IP injections (10 mg/kg) | Improves working memory and reduces the production of Aβ | [165] | |||
Oral administration (25 mg/kg/day) | Reduces the markers of oxidative stress, LPO and activates the ERK pathway | ||||||
Huntington’s disease (HD) | Presence of a trinucleotide repeat (CAG) that encodes an abnormally long polyglutamine tract in the huntingtin protein | Movement and psychiatric disturbances, as well as cognitive impairment | 3-NP model of HD in rats | Chrysin | Oral administration (50 mg/kg/day) | Improvement in behavior and reduction in markers of oxidative stress and cell death, and enhancement in the survival of striatal neurons | [166] |
R6/1 N-terminal transgenic mouse model | 7,8-DHF | Oral administration (5 mg/kg/day) | Delay the development of motor and cognitive deficits, prevention of the loss of striatal volume, enhances the marker of neurotrophic factor signaling, and reduction in some markers of inflammation | [167] | |||
3-NP model | Quercetin | oral administration (25 mg/kg/day) | Reduce motor deficits, improve mitochondrial function, and attenuate some markers of oxidative stress | [168] | |||
R6/1 N-terminal transgenic mouse model | Anthocyanins | 100 mg/kg/day | Delay the loss of motor function | [169] | |||
3-NP model in rats | Hesperidin | Oral administration (100 mg/kg/day) | Reduce motor deficits, as well as markers of inflammation and oxidative stress | [170] | |||
Amyotrophic Lateral Sclerosis (ALS) | Heritable gene mutations | Loss of the motor neurons that control the voluntary movement of muscles, resulting in paralysis and death | SOD1-G93A model | 7,8-DHF | IP injection (5 mg/kg) | Reduction in the age-dependent decrease in motor performance and preserving the total motor neuron count and dendritic spine density on motor neurons | [171] |
Fisetin | Oral administration (9 mg/kg) | Delay the development of motor deficits, reduction in their rate of progression, and increases lifespan | [172] | ||||
(−)-epigallocatechin gallate (EGCG) | oral administration (5.8–10 mg/kg) | Delay symptom onset and extend the lifespan | [173] |
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Devi, S.; Kumar, V.; Singh, S.K.; Dubey, A.K.; Kim, J.-J. Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders. Biomedicines 2021, 9, 99. https://doi.org/10.3390/biomedicines9020099
Devi S, Kumar V, Singh SK, Dubey AK, Kim J-J. Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders. Biomedicines. 2021; 9(2):99. https://doi.org/10.3390/biomedicines9020099
Chicago/Turabian StyleDevi, Shweta, Vijay Kumar, Sandeep Kumar Singh, Ashish Kant Dubey, and Jong-Joo Kim. 2021. "Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders" Biomedicines 9, no. 2: 99. https://doi.org/10.3390/biomedicines9020099