Cell proliferation, migration and CAM-dependent neurite outgrowth as developmental in vitro endpoints for screening teratogenic potential: Application to valproic acid and related analogues of varying potency

Bacon, Christopher L.; Berezin, Vladimir; Bode, Gerrit; Bock, Elisabeth; Bojic, Ursula; Doherty, Patrick; Ehlers, Katharine; Ellerbeck, Ursula; Julien, P.; Kawa, Anna; Maar, Thomas E.; Nau, Heinz; Pirovano, R.; Regan, Ciaran M.; Schousboe, Arne; Spézia, François; Walsh, Frank S.; Williams, E. J.

doi:10.1016/s0887-2333(97)00100-8

Cited by 7 publications

(13 citation statements)

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“…It is the degree of cell cycle arrest that determines the pro‐differentiative effects of these and related compounds, and this is known to be directly indicative of teratogenic potency (Courage‐Maguire et al . 1997; Bacon et al . 1998; Bojic et al .…”

Section: Discussionmentioning

confidence: 99%

“…This potency order suggests that the observed neuritogenic properties of the S‐enantiomer and racemic compound are directly correlated with their ability to arrest the cell cycle in the G1 phase (Courage‐Maguire et al . 1997; Bacon et al . 1998; Bojic et al .…”

Section: Discussionmentioning

confidence: 99%

“…2002). Although the enantioselectivity of the teratogenic action of pentyl‐4‐yn‐VPA has not been reported in vivo , in closely related VPA analogues teratogenicity and anti‐proliferative/pro‐differentiative actions are indeed confined to the S‐enantiomer (Hauck and Nau 1992; Bacon et al . 1998).…”

Section: Discussionmentioning

confidence: 99%

“…This raises concern on the safety profile of this drug and prompts the need to identify whether the distinct pharmacological actions of pentyl‐4‐yn‐VPA can be attributed to the different enantiomeric forms of the drug. Although there are no previous reports of enantioselective actions for pentyl‐4‐yn‐VPA, in similar studies the teratogenic activity of VPA analogues containing a chiral centre has been found to reside in the S‐enantiomer, with the R‐enantiomer inducing no teratogenesis in rodent models (Hauck and Nau 1992; Bacon et al . 1998).…”

mentioning

confidence: 88%

“…1993), and is directly correlated with anti‐proliferative/pro‐differentiative potency in vitro (Courage‐Maguire et al . 1997; Bacon et al . 1998; Bojic et al .…”

mentioning

confidence: 99%

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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

O'Loinsigh

Gherardini

Gallagher

et al. 2003

Journal of Neurochemistry

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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 enantiomerspecific 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 dosedependent 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 88%

“…1993), and is directly correlated with anti‐proliferative/pro‐differentiative potency in vitro (Courage‐Maguire et al . 1997; Bacon et al . 1998; Bojic et al .…”

mentioning

confidence: 99%

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