Zileuton, a 5-Lipoxygenase Inhibitor, Attenuates Haemolysate-Induced BV-2 Cell Activation by Suppressing the MyD88/NF-κB Pathway

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Microglia play a crucial role in neuroinflammation, with M1 polarization contributing to neuronal death in subarachnoid hemorrhage (SAH).
• Zileuton, a 5-lipoxygenase inhibitor, is known to reduce pro-inflammatory cytokines, but its effect on microglial activation in SAH is not well understood.

Purpose of the Study:

• To investigate the inhibitory effects of zileuton on microglial activation induced by SAH.
• To elucidate the underlying mechanisms by which zileuton modulates microglial polarization and neuroinflammation.

Main Methods:

• BV-2 microglial cells were exposed to haemolysate to induce M1 polarization.
• Cells were subsequently treated with varying concentrations of zileuton (5-20 μM).
• Cell viability, polarization status, and expression of key proteins (5-lipoxygenase, TNF-α, IL-10, MyD88, p-NF-κB/NF-κB) were assessed.

Main Results:

• Haemolysate increased BV-2 cell viability and induced M1 polarization.
• High concentrations of zileuton decreased cell viability but shifted polarization from M1 to M2 phenotype.
• Zileuton suppressed 5-lipoxygenase expression, reduced tumor necrosis factor-α, increased interleukin-10, and inhibited the MyD88/NF-κB signaling pathway.

Conclusions:

• Zileuton effectively attenuates SAH-induced neuroinflammation by suppressing M1 microglial activation.
• Phenotype reversal from M1 to M2 microglia is a key mechanism underlying zileuton's therapeutic potential in SAH.
• These findings highlight zileuton as a potential therapeutic agent for managing neuroinflammation in spontaneous subarachnoid hemorrhage.