Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β

Introduction:

Lomerizine, a calcium channel blocker capable of crossing the blood-brain barrier, is clinically used to treat migraines. However, its potential to modulate neuroinflammatory responses has not yet been explored.

Methods:

To evaluate the potential of repurposing lomerizine for treating neuroinflammation, we examined its effects on lipopolysaccharide (LPS)-induced inflammatory responses in three models: BV2 microglial cells, Alzheimer’s disease (AD) excitatory neurons derived from human induced pluripotent stem cells (iPSCs), and LPS-treated wild-type mice.

Results:

In BV2 microglia, lomerizine pretreatment significantly reduced LPS-induced mRNA expression of proinflammatory cytokines and NLRP3 inflammasome components. In vivo, lomerizine pretreatment suppressed LPS-induced increases in Iba-1, GFAP, proinflammatory cytokines, and NLRP3 expression in wild-type mice. Lomerizine posttreatment also attenuated LPS-stimulated expression of proinflammatory cytokines and SOD2 in both BV2 cells and mouse brain tissue. Notably, lomerizine pretreatment reduced LPS-induced tau hyperphosphorylation in both LPS-treated mice and iPSC-derived AD neurons. Mechanistically, lomerizine blocked LPS-induced activation of GSK3α/β and upregulation of DYRK1A, both of which are key regulators of tau phosphorylation.

Discussion:

These findings demonstrate that lomerizine effectively mitigates LPS-induced neuroinflammation and tau hyperphosphorylation, suggesting its potential as a therapeutic agent for neuroinflammatory and tauopathy-related disorders.