Progesterone suppresses estrogen receptor-mediated inflammatory pathways following intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a highly fatal neurological disease with few successful treatments. The aim of the current study was to investigate the neuroprotection by progesterone and the related molecular mechanisms following ICH. Mice were treated with progesterone (8 mg/kg), estrogen receptor (ER) agonist-erteberel (10 nmol/2 μL), or ER-β-specific siRNA (si-ER-β, 6 nmol/2 μL). Neurological function, edema in the brain and inflammatory cytokine levels were tested. Progesterone significantly increased neurological function on day 1 to day 7 post-ICH and reduced cerebral water content compared to the control group on day 7. Progesterone also suppressed estrogen receptor beta (ER-β) and decreased inflammatory mediator levels such as prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in ICH-evoked brain tissues and in LPS-stimulated BV-2 microglial cells. These anti-inflammatory effects were inhibited by erteberel, indicating direct interaction with ER-β signaling. Furthermore, progesterone treatment inhibited the expression of Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) p65 via inhibition of ER-β. In summary, our findings show that progesterone is neuroprotective after ICH by modulating the ER-β/TLR4/NF-κB pathway and suggest its therapeutic value for managing post-ICH inflammation.