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Differential enantioselective effects of pentyl‐4‐yn‐valproate on spatial learning in the rat, and neurite outgrowth and cyclin D3 expression in vitro
Author(s) -
D. O'Loinsigh Eamon,
Gherardini Lisa M.,
Gallagher Helen C.,
Foley Andrew G.,
Murphy Keith J.,
Regan Ciaran M.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02158.x
Subject(s) - neurite , in vitro , cyclin , microbiology and biotechnology , chemistry , cyclin d1 , neuroscience , enantioselective synthesis , cancer research , biology , biochemistry , cell cycle , apoptosis , catalysis
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 m m , 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.