BackgroundMembers 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.ResultsWe 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.ConclusionsOur 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.

The findings demonstrate an ability of LIV to improve selected biomarkers of bone turnover and gene expression and to reduce osteoclastogenesis. The study indicates a possibility that LIV initiated earlier after SCI and/or continued for a longer duration would increase bone mass.

Postoperative cognitive dysfunction, POCD, afflicts a large number of elderly surgical patients following surgery with general anesthesia. Mechanisms of POCD remain unclear. N-methyl-D-aspartate (NMDA) receptors, critical in learning and memory, that display protein expression changes with age are modulated by inhalation anesthetics. The aim of this study was to identify protein expression changes in NMDA receptor subunits and downstream signaling pathways in aged rats that demonstrated anesthesia-induced spatial learning impairments. Three-month-old and 18-month-old male Fischer 344 rats were randomly assigned to receive 1.8% isoflurane/70 % nitrous oxide (N2O) anesthesia for 4h or no anesthesia. Spatial learning was assessed at 2 weeks and 3 months post-anesthesia in Morris water maze. Hippocampal and cortical protein lysates of 18-month-old rats were immunoblotted for activated caspase 3, NMDA receptor subunits, and extracellular-signal regulated kinase (ERK) 1/2. In a separate experiment, Ro 25-6981 (0.5mg/kg dose) was administered by I.P. injection before anesthesia to 18-month-old rats. Immunoblotting of NR2B was performed on hippocampal protein lysates. At 3 months post-anesthesia, rats treated with anesthesia at 18-months-old demonstrated spatial learning impairment corresponding to acute and long-term increases in NR2B protein expression and a reduction in phospho-ERK1/2 in the hippocampus and cortex. Ro 25-6981 pretreatment attenuated the increase in acute NR2B protein expression. Our findings suggest a role for disruption of NMDA receptor mediated signaling pathways in the hippocampus and cortex of rats treated with isoflurane/ N2O anesthesia at 18-months-old, leading to spatial learning deficits in these animals. A potential therapeutic intervention for anesthesia associated cognitive deficits is discussed.