The brain cytokine levels are modulated by estrogen following traumatic brain injury: Which estrogen receptor serves as modulator?

• Estrogen reduced the brain levels of pro-inflammatory cytokines.
• Estrogen increased the level of brain IL-10, as an anti-inflammatory mediator.
• Both ERs mediated estrogen effect on the brain cytokine levels.
• Partial agonistic role was not found for ICI.

The present study was designed to explore whether administration of estrogen affects brain cytokine levels in TBI. We also sought determine which one of type of classical estrogen receptors (ERs) is involved. Ovariectomized female rats were divided in to eight groups. Estrogen or vehicle was administered following TBI (E2 and oil groups). Antagonist of ER(ICI 182, 780) or vehicle was also administered following TBI (ICI and DMSO groups). The ICI or vehicle was administered either before induction of TBI and administration of estrogen (ICI+E2 and DMSO+E2 groups). TBI was induced by Marmarou's method. In addition to brain water content, the levels of brain proinflammatory and anti-inflammatory cytokines were measured 24 hours post- TBI. Present results demonstrated that, estrogen reduced TBI- induced brain edema. The antiedema effect of estrogen was attenuated by ICI. The brain measures of IL-1β, IL-6 and TNF-α in TBI were also reduced by estrogen. The anti-inflammatory effect of estrogen was attenuated by ICI. The inhibition level of estrogen by ICI was 53.2%, 12.09% and 48.45% for IL-1β, IL-6 and TNF-α, respectively. Estrogen also elevated IL-10 in TBI. ICI inversely controlled the effect of estrogen on IL-10, by 33.84%. This effect was not observed once ICI was used alone. The estrogen administration following TBI probably results in proinflammatory cytokines reduction, and inversely enhancement of anti-inflammatory cytokines. In our study, the neuroprotective effect of estrogen is proposed to be mediated by both ERα and ERα, and accordingly the inhibition of neuroprotective effect of estrogen by ICI.