Time- and Dose-Dependent Neuroprotective Effects of Sex Steroid Hormones on Inflammatory Cytokines after a Traumatic Brain Injury

Following a traumatic brain injury (TBI), excessive release of proinflammatory cytokines is the major cause of cerebral edema and neuronal loss. This study was designed to examine changes in concentrations of some proinflammatory cytokines-including interleukin-1 beta (IL-1 beta), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta (TGF-beta)-in a rat model of TBI in which the animals were treated with different doses of estrogen or progesterone 6 and 24 h after the TBI. Adult female rats were divided into 14 groups. Hormones or vehicle were given intraperitoneally 30 min after a moderate TBI was induced by the Marmarou method. The levels of proinflammatory cytokines in brain were measured at 6 and 24 h after the TBI. A high dose of estrogen (E2) or a low dose of progesterone (P1) increased brain levels of IL-1 beta 52.7% and 79.2% respectively at 6 h after the TBI. By 24h, IL-1 beta levels in the brain were 27.5% and 27% lower following administration of estrogen low dose (E1) or E2, respectively. High-dose administration of progesterone reduced brain levels of IL-6 to 45.9% at 6 h after the TBI, and P1 and E1 treatment significantly decreased IL-6 levels at 24 h. Brain levels of TNF-alpha were 72.5% lower at 6 h after the TBI following P2 treatment and 48.5% higher at 24 hrs following treatment with E2. The levels of TGF-beta were also 3.37 times higher 24 h after the TBI following treatment with E1. Both doses of the hormones tested increases TGF-beta levels 6 h after the TBI. Based on our findings, we conclude that progesterone and estrogen influence the levels of proinflammatory cytokines either at the primary or secondary stages after a TBI. Accordingly, this study suggests a mechanism by which hormones reduce cerebral edema.