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. 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. • The neuroactive steroid allopregnanolone (AlloP) inhibited the LPS-induced transcription of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α in BV2 cells. • Ent -allopregnanolone ( ent -AlloP) also inhibited the pro-inflammatory cytokines at similar concentrations. • The anti-inflammatory structure-activity profile did not correlate with functional effects on GABA A receptors. • Oxysterols and variants lacked anti-inflammatory effects in this model.
Shu et al. (Sun,) studied this question.