Structure-activity relationships of steroid and sterol neuromodulators on inflammatory markers in a murine microglial...

Neuroactive steroids are allosteric modulators of GABA_A receptors and are implicated in the etiology and treatment of neuropsychiatric disorders. Existing treatments are helpful but have drawbacks. Neuroactive steroids recently gained attention as rapidly acting antidepressants in postpartum depression and other indications. Unlike other GABA_A receptor modulators, neurosteroids may possess anti-inflammatory actions, potentially contributing to therapeutic benefit. Here we seek to understand neuroactive steroid structure-activity relationships relevant to these anti-inflammatory effects. We used murine microglial BV2 cells challenged with lipopolysaccharide (LPS) as an inflammation model. We investigated structure-activity profile of neuroactive steroids and oxysterol-like compounds on cytokine transcription. LPS increased transcripts for cytokines IL-1β, IL-6 and TNF-α. Both allopregnanolone and its enantiomer significantly suppressed these LPS-induced increases, with no effect in the absence of LPS. CONCLUSIONS: Our results suggest that neuroactive steroids exhibit a distinct structure-activity profile compared with their GABA_A receptor modulation effects. Certain neuroactive steroids may selectively target neuroinflammation. The enantiomer of AlloP could be a tool compound to differentiate anti-inflammatory effects of neuroactive steroids from GABAergic and other enantioselective effects.