Therapeutic Developments Targeting Toll‐like Receptor‐4‐Mediated Neuroinflammation

Abstract

Toll-like receptors (TLRs) have been shown to play an important role in the immune system, which warrants their remarkable pharmacological potentials. Activation of TLRs requires participation from specific PAMPs (pathogen associated molecular patterns) and accessory proteins such as MD2 (myeloid differentiation protein 2), LBP (lipopolysaccharide binding protein), and CD-14. Assembly of the TLR4-MD2-LPS complex is essential in TLR4 activation. Recent studies have revealed that TLR4 activation is a significant trigger of signal transmission pathways in the nervous system, which could result in chronic pain as well as opioid tolerance and dependence. Researchers of the molecular structure of TLRs and their accessory proteins have opened a door to syntheses of TLRs agonists and antagonists, such as Eritoran. Small molecule modulators of TLR4, such as MD2-I and tricyclic anti-depressants, offer more promising prospects than peptides for their convenient oral usage and lower cost. We mainly discuss the mechanism and clinical prospect of TLR4 agonists and antagonists in this review.

Aromatic‐Turmerone Attenuates LPS‐Induced Neuroinflammation and Consequent Memory Impairment by Targeting TLR4‐Dependent Signaling Pathway

“…This suggests that TLR4 plays a critical role in initiating neuroinflammation. Since then, many compounds with various chemical scaffolds have been reported to modulate TLR4 activation, namely TLR4 antagonists, like TAK‐242 and MD2‐I . Meanwhile, some natural compounds have been suggested to inhibit TLR4 activation as well, such as curcumin and 6‐shoagol.…”

Peripheral immune tolerance alleviates the intracranial lipopolysaccharide injection-induced neuroinflammation and protects the dopaminergic neurons from neuroinflammation-related neurotoxicity

“…Decreased inflammatory cytokines showed the peripheral immune tolerance inducedhypoactive state of PBM. TLR4 serve as the major pattern recognition receptors involved in the detection of LPS so that downregulation of TLR4 expression means diminished inflammatory response of PBM [33,34]. This proves that PBM are the decisive cells in the formation of LPS-induced peripheral immune tolerance.…”

TLR4 in skin cancer: From molecular mechanisms to clinical interventions

“…Based on the emerging role of TLR4 in skin tumorigenesis, the availability of validated pharmacological modulators targeting TLR4 signaling has facilitated a considerable research effort aiming at experimental and investigational therapeutic intervention . Given the complexity underlying TLR4‐dependent signaling, a number of TLR4‐directed modulators have now been identified and are in various stages of preclinical and clinical development as recently reviewed expertly …”

“…A large number of pharmacologically validated TLR4 modulators of natural and synthetic origin is now available, promising to allow for clinical oncologically‐relevant translation in the near future. Numerous specialized reviews have recently provided comprehensive coverage of TLR4 pharmacology . Much emphasis has centered on natural products with TLR4‐antagonistic activity including promiscuous multitarget agents, such as baicalin, curcumin, sulforaphane, andrographolide, and glycyrrhizin, often derived from phytochemical dietary sources that seem amenable to chemopreventive repurposing .…”