An important consideration in traumatic brain injury (TBI) in females is the influence of hormones on recovery. Recent studies in both cerebral ischemia and TBI have demonstrated an attenuation in both damage and neurologic recovery following hormonal treatment. However, the ability of endogenous hormone levels to provide neuropathological protection after fluid percussion (FP) brain injury has not been studied. The purpose of this experiment was to determine whether endogenous circulating hormones in the female rat could provide neuroprotection compared to males and ovariectomized female animals. Sixty-four Sprague-Dawley rats underwent a moderate (1.7–2.2 atm) right parasagittal FP injury. Intact females (i.e., nonovariectomized) were subjected to injury either during the proestrous (TBI-FP, n = 18) phase of their cycle or nonproestrous (TBI-FNP, n = 19) phase. A separate group of females were ovariectomized (TBI-OVX, n = 10) 10 days prior to FP injury in order to reduce hormone levels. Male animals were also traumatized (TBI-M, n = 17). Appropriate sham controls (Sham-FP, n = 2; Sham-FNP, n = 2; Sham-OVX, n = 2; Sham-M, n = 2) also underwent all aspects of surgery except for the actual FP injury. All groups were sacrificed 3 days following TBI for analysis. Both intact female groups had significantly (p < 0.05) smaller cortical contusions compared to male animals. In addition to this finding, the TBI-FNP group was significantly (p < 0.04) different from the ovariectomized female animals. Ovariectomized rats had larger areas of damage compared to intact females. The TBI-OVX group's cortical contusion volume was similar to male animals. These results provide evidence for endogenous hormonal histopathological protection following parasagittal FP brain injury. The use of hormone therapy after TBI warrants continued exploration.

Background: Members of the mammalian nucleotide binding domain, leucine-rich repeat (LRR)-containing receptor (NLR) family of proteins are key modulators of innate immunity regulating inflammation. Our previous work has shown that among the members of this family, NLRP1/NALP1, present in neurons, plays a crucial role in inflammasome formation and the production of the inflammatory cytokines interleukin (IL) -1β and IL-18 after various types of central nervous system injury.Results: We investigated whether age-related cognitive decline may involve a heightened inflammatory response associated with activation of the NLRP1 inflammasome in the hippocampus. Young (3 months) and aged (18 months) male Fischer 344 rats were tested in a spatial acquisition task via Morris water maze. Following behavioral testing, hippocampal lysates were assayed for expression of NLRP1 inflammasome components and inflammatory cytokines. Hippocampal lysates from aged rats showed significantly higher levels of NLRP1 inflammasome constituents, caspase-1, caspase-11, the purinergic receptor P2X7, pannexin-1 and X-linked inhibitor of apoptosis (XIAP) than lysates from younger animals. Following treatment with probenecid, an inhibitor or pannexin-1, aged animals demonstrated reduction in inflammasome activation and improvement in spatial learning performance.Conclusions: Our behavioral findings are consistent with increases in IL-1β and IL-18 that have been previously shown to correlate with spatial learning deficits. Probenecid reduced activated caspase-1 and ameliorated spatial learning deficits in aged rats. Thus, aging processes stimulate activation of the NLRP1 inflammasome and secretion of IL-1β and IL-18 that may contribute to age-related cognitive decline in the growing elderly population. Moreover, probenecid may be potentially useful as a therapy to improve cognitive outcomes in the aging population.