Abstract
Flavonoids are an important class of natural polyphenolic compounds reported to exert beneficial effects in cardiovascular and metabolic diseases, cancer, autoimmune and neurological disorders. Flavonoids possess potential antioxidant, anti-inflammatory, antiapoptotic and immuno-modulation properties. Intriguingly, the importance of flavonoids in different neurological disorders is gaining more attention due to the safety, better pharmacokinetic profile and blood–brain barrier penetration, cost-effectiveness and readiness for clinical uses/trials. Many in vitro and in vivo research studies have established the neuroprotective mechanism of flavonoids in the central nervous system (CNS) diseases. The present review summarizes the benefits of various classes of flavonoids (flavones, flavonols, flavanones, anthocyanidins, isoflavones, flavanols), chemical nature, classification, their occurrence and distribution, pharmacokinetics and bioavailability. The manuscript also presents available evidences relating to the role of flavonoids in regulating key signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, mitogen-activated protein kinase (MAPK) pathway, Janus kinase and signal transducer and activator of transcription proteins (JAK/STAT) pathway, Toll-like receptors (TLR) pathway, nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and cAMP response element-binding protein (CREB) pathway involved in neuroinflammation associated with major neurological disorders. Literature search was conducted using electronic databases like Google Scholar, Scopus, PubMed central, Springer search and Web of science. Chemical structures used in the present analysis were drawn using Chemdraw Professional 15.0 software. This collective information provides comprehensive knowledge on disease pathways and therapeutic benefits of flavonoids in neurological disorders, druggability and future scope for research.
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Abbreviations
- CNS:
-
Central nervous system
- NF-κB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- MAPK:
-
Mitogen-activated protein kinase
- JAK/STAT:
-
Janus kinase and signal transducer and activator of transcription proteins
- TLR:
-
Toll-like receptors
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- CREB:
-
CAMP response element-binding protein
- NI:
-
Neuroinflammation
- DC:
-
Dendritic cells
- NKT:
-
Natural killer T
- NK:
-
Natural killer
- CD4:
-
Cluster of differentiation 4
- CD8:
-
Cluster of differentiation 8
- B cells:
-
B lymphocytes
- PD:
-
Parkinson’s disease
- MS:
-
Multiple sclerosis
- AD:
-
Alzheimer’s disease
- HD:
-
Huntington’s disease
- iNOS:
-
Inducible nitric oxide synthase
- NO:
-
Nitric oxide
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- ECG:
-
Epicatechin-3-gallate
- EGC:
-
Epigallocatechin
- EC:
-
Epicatechin
- GCG:
-
Gallocatechin-3-gallate
- GC:
-
Gallocatechin
- EGCG:
-
Epigallocatechin-3-gallate
- C:
-
Catechin
- ALS:
-
Amyotrophic lateral sclerosis
- EAE:
-
Experimental autoimmune encephalomyelitis
- TNF-α:
-
Tumor necrosis factor-alpha
- TLR4:
-
Toll-like receptor 4
- mRNA:
-
Messenger RNA (ribonucleic acid)
- BDNF:
-
Brain-derived neurotrophic factor
- HO-1:
-
Heme oxygenase 1
- PGE2:
-
Prostaglandin E2
- ERK:
-
Extracellular-signal-regulated kinase
- c-JNK:
-
c-Jun N-terminal Kinase
- GCLC:
-
Glutamate-cysteine ligase catalytic subunit
- PI3K/AKT:
-
Phosphatidylinositol 3-kinase/protein kinase B
- TYK2:
-
Tyrosine kinase 2
- Th1:
-
T helper type 1
- Th17:
-
T helper type 17
- IL-17:
-
Interleukin-17
- STAT3:
-
Signal transducer and activator of transcription protein 3
- IFN-γ:
-
Interferon γ
- IL-12:
-
Interleukin-12
- STAT4:
-
Signal transducer and activator of transcription protein 4
- CD40:
-
Cluster of differentiation 40
- STAT1:
-
Signal transducer and activator of transcription protein 1
- NDs:
-
Neurodegenerative diseases
- ND:
-
Neurodegenerative disease
- Aβ-RAGE:
-
Amyloid beta-receptor for advanced glycation end products
- MAPKAP kinase2(MK2)HSP27:
-
MAPK-activated protein kinase-2-heat-shock protein 27
- IL-1β:
-
Interleukin 1beta
- ROS:
-
Reactive oxygen species
- IL-6:
-
Interleukin 6
- JAK2:
-
Janus kinase 2
- SAPK/c:
-
Stress-activated protein kinase/c
- TRIF:
-
Toll/Interleukin-1 receptor-like (TIR) domain-containing adaptor inducing interferon-β
- LPO:
-
Lipoperoxidation
- IRF3:
-
Interferon regulatory factor 3
- MyD88:
-
Myeloid differentiation primary response 88
- TLR4/NOX4:
-
Toll-like receptor 4/NADPH oxidase 4
- TLR2:
-
Toll-like receptor 2
- TRAF6:
-
Tumor necrosis factor receptor (TNFR)-associated factor 6
- PGE2:
-
Prostaglandin E2
- COX-2:
-
Cyclooxygenase 2
- ARE:
-
Antioxidant response element
- p-ERK:
-
Phosphorylated extracellular signal regulated kinase
- PI3K/AKT:
-
Phosphatidylinositol 3-kinase/protein kinase B
- GSK3β:
-
Glycogen synthase kinase -3β
- Keap-1:
-
Kelch-like ECH-associated protein 1
- IFN-β:
-
Interferon β
- HMF:
-
3,5,6,7,8,3’,4’-Heptamethoxyflavone
- TrkA:
-
Tropomyosin receptor kinase A
- NGF:
-
Nerve growth factor
- NQO1:
-
NAD(P)H:quinone oxidoreductase 1
- CAT:
-
Catalase
- SOD1:
-
Superoxide dismutase 1
- CDK5:
-
Cyclin-dependent-like kinase 5
- PAMPs:
-
Pathogen-associated molecular patterns
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Hamsalakshmi gratefully acknowledges the Department of Science and Technology, Govt. of India, New Delhi for granting the INSPIRE fellowship (Application No: DST/INSPIRE/03/2016/000956) to carry out the research. The authors are grateful to Dr. Gopinath Meenakshisundaram, Department of Molecular Nutrition, CSIR, CFTRI, Mysuru, Karnataka, India for his diligent proofreading of this paper and suggestions.
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Hamsalakshmi, Alex, A.M., Arehally Marappa, M. et al. Therapeutic benefits of flavonoids against neuroinflammation: a systematic review. Inflammopharmacol 30, 111–136 (2022). https://doi.org/10.1007/s10787-021-00895-8
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