ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Previously, we demonstrated the racemic form of the valproate (VPA) analogue, 2-n-pentyl-4-pentynoic acid ([±]pentyl-4-yn-VPA), to be neuritogenic in vitro and to enhance cognition in vivo. To determine the enantioselectivity of these effects, the racemate and purified enantiomers of [±]pentyl-4-yn-VPA (84 mg/kg, i.p.) were administered to rodents 20 min prior to multi-session water maze training. The racemate and R-enantiomer significantly reduced escape latencies during water maze learning and enhanced its recall in a probe trial 3 days later. In contrast, S-pentyl-4-yn-VPA did not influence these behavioural parameters. The enantiomer-specific effects of [±]pentyl-4-yn-VPA were further discriminated in vitro using neuro 2A neuroblastoma and C6 glioma cell lines. In neuro 2A, the S-enantiomer induced profound neurite outgrowth at concentrations up to 0.5 mm, with the R-enantiomer and racemate being less neuritogenic. Immunoblot analysis of cyclin D3 expression in C6 glioma indicated the racemate and S-pentyl-4-yn-VPA to induce dose-dependent up-regulation of this protein, similar to that associated with G1-phase cell cycle arrest mediated by VPA, whereas R-pentyl-4-yn-VPA was without effect. These results indicate that the cognition-enhancing effects of pentyl-4-yn-VPA are due to the actions of the R-enantiomer, and that cyclin D3 up-regulation and associated anti-proliferative and pro-differentiative actions are predominantly associated with the S-enantiomer.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1111/j.1471-4159.2004.02158.x
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