Identification of cytochrome P450 2E1 as a novel target in neuroinflammation and development of its inhibitor Q11 as a treatment strategy

Abstract

Neuroinflammation is implicated in nearly all pathological processes of central nervous system (CNS) diseases. However, no medications specifically targeting neuroinflammation are clinically available, and conventional anti-inflammatory drugs exhibit limited efficacy. Here, we identified cytochrome P450 2E1 (CYP2E1) as a novel therapeutic target in neuroinflammation. Elevated CYP2E1 levels were observed in hippocampal tissues of mouse and rat neuroinflammation models, as well as in LPS-stimulated primary microglia. Genetic ablation of Cyp2e1 improved spatial learning and memory in neuroinflammatory rats and reduced pro-inflammatory cytokine levels in Cyp2e1-deficient microglia. Furthermore, Q11 (1-(4-methyl-5-thiazolyl) ethanone), a novel CYP2E1 inhibitor developed and synthesized in our laboratory, effectively ameliorated Alzheimer's disease-related spatial learning and memory functions and depression-related anxiety-like behaviors in mice/rats. Mechanistically, Q11 attenuated microglial activation, neuronal damage, oxidative stress, and neuroinflammation by suppressing the PI3K/Akt, STAT1/3, and NF-κB signaling pathways. These findings establish CYP2E1 as a druggable target for neuroinflammation and propose Q11 as a promising candidate for treating neuroinflammation-related diseases.