Differential enantioselective effects of pentyl-4-yn-valproate on spatial learning in the rat, and neurite outgrowth and cyclin D3 expression in vitro.
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.
O'Loinsigh
Eamon D
ED
Department of Pharmacology, Conway Institute, University College, Dublin, Ireland.
Gherardini
Lisa M
LM
Gallagher
Helen C
HC
Foley
Andrew G
AG
Murphy
Keith J
KJ
Regan
Ciaran M
CM
D000818:Animals; D045744:Cell Line, Tumor; D056743:Cyclin D3; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
C534697:Ccnd3 protein, mouse; C534698:Ccnd3 protein, rat; D056743:Cyclin D3; D016213:Cyclins; C434604:pentyl-4-yn-valproic acid; D014635:Valproic Acid