Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormone in humans, produced by the adrenals, the gonads and the brain. DHEA was previously shown to bind to the nerve growth factor receptor, tropomyosin-related kinase A (TrkA), and to thereby exert neuroprotective effects. Here we show that DHEA reduces microglia-mediated inflammation in an acute lipopolysaccharide-induced neuro-inflammation model in mice and in cultured microglia in vitro. DHEA regulates microglial inflammatory responses through phosphorylation of TrkA and subsequent activation of a pathway involving Akt1/Akt2 and cAMP response element-binding protein. The latter induces the expression of the histone 3 lysine 27 (H3K27) demethylase Jumonji d3 (Jmjd3), which thereby controls the expression of inflammation-related genes and microglial polarization. Together, our data indicate that DHEA-activated TrkA signaling is a potent regulator of microglia-mediated inflammation in a Jmjd3-dependent manner, thereby providing the platform for potential future therapeutic interventions in neuro-inflammatory pathologies.

#4093 Background: We have learned from the questionnaire survey of description and hearing type that the onycholysis and skin toxicity occur in approximately 90% of patients(pts) treated with docetaxel (DTX) on hands and 65% on feet. Besides neurotoxicity and edema, these adverse events cause the worse quality of life (QOL) assessment because of the exposure, public noticed site. According to the report that the Elasto-Gel frozen glove (FG) was effective for the prevention of DTX-induced onycholysis and skin toxicity (Scotte F, JCO 23, 4424-29, 2005), we have planned to reanalyze the efficacy and safety of FG for Japanese breast cancer pts by the multicenter, prospective phase II study.
 Patients and Methods: Patients receiving DTX 75 mg/m2 alone or in combination chemotherapy more than 4 cycles were eligible for this case-control study. Each patient on case group wore an FG for a total of 90 minutes on the both hands. Her feet were not protected. The control data was obtained by the questionnaire survey from the pts who had not used FG during the chemotherapy. Onycholysis and skin toxicity were assessed at each cycle by National Cancer Institute Common Toxicity Criteria and documented by photography. This study had accomplished by multidisciplinary approach by nurses, pharmacists, and doctors. Wilcoxon matched-pairs rank test was used.
 Results: Between March 2006 and May 2007, 70 pts on case and 52 pts on control were evaluated. Median age were similar for each group, 52 [29-74 years] on case and 51 [25-73 years] on control. Onycholysis and skin toxicity were significantly lower in the FG-protected hands compared with the control hands (P = .0001). Onycholysis was grade (G) 0 in 41% v 8%, G1 in 54% v 74%, and G2 to 3 in 4.3% v 18% for the FG-protected hands and the control hands, respectively. For the feet, there was no difference in frequency between pts on case and on control. Skin toxicity was G0 in 76.6% v 44%, G1 in 13.6% v 42%, and G2 to 3 in 4.4% v 14% for the FG-protected hands and the control, respectively. 32 pts (46%) had experienced the deterioration of pigmentation on hands and/or feet, the FG had seemed not to be able to prevent these unfavorable events. Median time to nail and skin toxicity occurrence was not significantly different between the FG-protected and the control hands of feet, respectively. Although one pt (1.4%) experienced discomfort due to cold intolerance, there were no serious adverse events caused by FG.
 Conclusion: FG significantly reduces the nail and skin toxicity associated with DTX and is a safety tool on supportive care management. This should be provided in general practice widely to improve a patient's QOL. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4093.

Acrylamide is a chemical used in various industries and a product following high-temperature cooking of vegetables containing asparagine. Environmental or dietary exposure to acrylamide could impair cognitive function because of its neurotoxicity. Using rat hippocampal slices, we tested whether acrylamide alters induction of long-term potentiation (LTP), a cellular model of learning and memory. We hypothesized that acrylamide impairs cognitive function via activation of pro-inflammatory cytokines because robust upregulation of NLRP3 inflammasome has been reported. Although acrylamide up to 3 mM did not alter basal synaptic transmission, incubation with 10 μM or acute administration of 100 μM acrylamide inhibited induction of LTP. Inhibitors of toll-like receptor 4 (TLR4), and minocycline, an inhibitor of microglial activation, overcame the effects of acrylamide on LTP induction. Furthermore, we observed that acrylamide failed to inhibit LTP after administration of MCC950, an inhibitor of NLRP3, or in the presence of Interleukin-1 receptor antagonist (IL-1Ra). We also found that in vivo acrylamide injection transiently impaired body weight gain and impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by MCC950. These results indicate that cognitive impairment by acrylamide is mediated by mechanisms involving microglia and release of cytokines via NLRP3 activation.

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