Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation
Abstract
A wide array of cell signaling mediators and their interactions play vital roles in neuroinflammation associated with ischemia, brain trauma, developmental disorders and age-related neurodegeneration. Along with neurons, microglia and astrocytes are also affected by the inflammatory cascade by releasing pro-inflammatory cytokines, chemokines and reactive oxygen species. The release of pro-inflammatory mediators in response to neural dysfunction may be helpful, neutral or even deleterious to normal cellular survival. Moreover, the important role of NF-κB factors in the central nervous system (CNS) through toll-like receptor (TLR) activation has been well established. This review demonstrates recent findings regarding therapeutic aspects of polyphenolic compounds for the treatment of neuroinflammation, with the aim of regulating TLR4. Polyphenols including flavonoids, phenolic acids, phenolic alcohols, stilbenes and lignans, can target TLR4 signaling pathways in multiple ways. Toll interacting protein expression could be modulated by epigallocatechin-3-gallate. Resveratrol may also exert neuroprotective effects via the TLR4/NF-κB/STAT signaling cascade. Its role in activation of cascade via interfering with TLR4 oligomerization upon receptor stimulation has also been reported. Curcumin, another polyphenol, can suppress overexpression of inflammatory mediators via inhibiting the TLR4-MAPK/NF-κB pathway. It can also reduce neuronal apoptosis via a mechanism concerning the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages. Despite a symphony of in vivo and in vitro studies, many molecular and pharmacological aspects of neuroinflammation remain unclear. It is proposed that natural compounds targeting TLR4 may serve as important pharmacophores for the development of potent drugs for the treatment of neurological disorders.
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The TLR4/MyD88/NF-kappaB pathway is well recognized for its role in the inflammatory signaling pathway.
“The TLR4/MyD88/NF-κB pathway is well recognized for its role in the inflammatory signaling pathway [68].”
From Neuroprotective Effects of Sodium Butyrate by Restoring Gut Microbiota and Inhibiting TLR4 Signaling in Mice with MPTP-Induced Parkinson’s Disease (2023) · cites this paper as [68]
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- Authors
- Rahimifard, M., Maqbool, F., Moeini-Nodeh, S., Niaz, K., Abdollahi, M., Braidy, N., Nabavi, S. M., & Nabavi, S. F.
- Affiliations
- Pharmaceutical Sciences Research Center (IR)
- UNSW Sydney (AU)
- Baqiyatallah University of Medical Sciences (IR)
- Corresponding author
- Abdollahi, Mohammad
- Nabavi, Seyed Mohammad
- ORCID
- Venue
- Ageing Research Reviews
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 36
- Pages
- 11-19
- ISSN
- 1568-1637 (ISSN-L)
- OpenAlex
- W2589764628
- Cited by
- 481
- References
- 110
- Citations by year
- 2026: 28 · 2025: 50 · 2024: 57 · 2023: 70 · 2022: 70 · 2021: 61 · 2020: 58 · 2019: 40 · 2018: 34 · 2017: 13
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Ageing Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Keywords
- neuroinflammation, TLR4 signaling, polyphenols, NF-κB, TLR4, resveratrol, epigallocatechin gallate, curcumin, MyD88, MAPK signaling, neuroprotection, microglia, astrocytes, flavonoids, phenolic acids, stilbenes, lignans, neurodegeneration
- MeSH terms
- Animals, Astrocytes, Cell Survival, Humans, Inflammation, Neurons, Signal Transduction, Drug Delivery Systems, Microglia, Inflammation Mediators, Toll-Like Receptor 4, Polyphenols
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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