In this study we show that stereoisomers of 3-acetoxy-4′-methoxyflavan are positive modulators of recombinant alpha(1,2,3,5)beta(2)gamma(2L) and alpha(1)beta(2) GABA(A) receptors expressed in Xenopus laevis oocytes. GABA(C) receptors are insensitive to modulation by these compounds. In each case, the enhancement was evident at low micromolar concentrations and occurred independently of the classical high affinity benzodiazepine site, as it could not be blocked by the antagonist flumazenil. Importantly, the compound Fa131 was significantly more efficacious at enhancing GABA-induced currents see more (EC5) at alpha(2)beta(2)gamma(2L) receptors compared to
alpha(1)beta(2)gamma(2L), alpha(3)beta(2)gamma(2L) and alpha(5)beta(2)gamma(2L) receptors (E-max = 21.0 +/- 1.7 times, compared to 8.5 +/- 0.7 times at alpha(1)-, 9.5 +/- 0.6 times at alpha(3)- and 5.2 +/- 0.4 times at alpha(5)-contaning GABA(A) receptors), suggesting a potential use as an anxiolytic. In mice, this agent (1-30 mg/kg i.p.) induced
anxiolytic-like action in two unconditioned models of anxiety: the elevated plus maze and the light/dark paradigms. No sedative or myorelaxant effects were detected using the hole board, actimeter and horizontal wire tests, and only weak barbiturate-potentiating effects on the loss of righting reflex test. Fa131 demonstrated improved segregation of anxiolytic and sedative doses when compared to the non-selective agonist diazepam. Finally, flavan derivatives highlight the potential of targeting non-benzodiazepine VE-821 in vitro Urocanase allosteric sites in the search for new anxioselective drugs. (C) 2008 Elsevier Ltd. All rights reserved.”
“This study aims to clarify sex differences in human biological aging and to explore the gender gaps in health and longevity. Eighty-six men and 93 women who received a 2-day routine
health checkup for 6-7 years beginning in 1992 at the Kyoto Red Cross Hospital were selected. Five candidate biomarkers of aging (forced expiratory volume in 1.0 second per square of height [FEV(1)/Ht(2)], systolic blood pressure [SBP], red blood cells [RBC], albumin [ALBU], and blood urea nitrogen [BUN]) were selected from 29 physiological variables. Individual biological ages (BAS) were estimated from these five biomarkers by a principal component model. From the investigation of the longitudinal changes of individual BAS, it was suggested that (i) beyond 65 years, the rate of aging showed a rapid increase, and (ii) women had relatively lower functional capabilities compared with men, but the rate of aging was slower than that of men, suggesting that these differences might present both disadvantages and advantages for women with regard to health and longevity.”
“The present study investigated the putative pro-cognitive effects of the novel selective PDE9 inhibitor BAY 73-6691.