title: 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.
authors.affiliation: Toxicology and Disease Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mahban
authors.initials: M
authors.lastname: Rahimifard
authors.affiliation: Toxicology and Disease Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; International Campus, Tehran University of Medical Sciences, (IC-TUMS), Tehran, Iran.
authors.forename: Faheem
authors.initials: F
authors.lastname: Maqbool
authors.affiliation: Toxicology and Disease Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Shermineh
authors.initials: S
authors.lastname: Moeini-Nodeh
authors.affiliation: Toxicology and Disease Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; International Campus, Tehran University of Medical Sciences, (IC-TUMS), Tehran, Iran.
authors.forename: Kamal
authors.initials: K
authors.lastname: Niaz
authors.affiliation: Toxicology and Disease Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; International Campus, Tehran University of Medical Sciences, (IC-TUMS), Tehran, Iran. Electronic address: Mohammad.Abdollahi@UToronto.Ca.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abdollahi
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Australia.
authors.forename: Nady
authors.initials: N
authors.lastname: Braidy
authors.affiliation: Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran. Electronic address: Nabavi208@gmail.com.
authors.forename: Seyed Mohammad
authors.initials: SM
authors.lastname: Nabavi
authors.affiliation: Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
authors.forename: Seyed Fazel
authors.initials: SF
authors.lastname: Nabavi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D059808:Polyphenols / Q000008:administration & dosage* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D059808:Polyphenols; D051197:Toll-Like Receptor 4
keywords: Central nervous system; NF-κB; Neuroinflammation; Polyphenol; Toll-like receptor 4