Multiple effects of pentyl-4-yn-VPA enantiomers: from toxicity to short-term memory enhancement

TY - JOUR

T1 - Multiple effects of pentyl-4-yn-VPA enantiomers: from toxicity to short-term memory enhancement

AU - Gotfryd, Kamil

AU - Owczarek, Sylwia

AU - Hoffmann, Katrin

AU - Klementiev, Boris

AU - Nau, Heinz

AU - Berezin, Vladimir

AU - Bock, Elisabeth

AU - Walmod, Peter S

N1 - Keywords: Analysis of Variance; Animals; Anticonvulsants; Behavior, Animal; Cell Movement; Cells, Cultured; Coculture Techniques; Dose-Response Relationship, Drug; Hippocampus; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Memory, Short-Term; Mice; Neurites; Neurons; Rats; Rats, Wistar; Stereoisomerism; Synapses; Synaptophysin; Time Factors; Valproic Acid

PY - 2006

Y1 - 2006

N2 - 2-n-Pentyl-4-pentynoic acid (PE-4-yn-VPA) is a derivative of the antiepileptic and mood-stabilizing drug valproic acid (VPA). PE-4-yn-VPA exists as R- and S-enantiomers, the latter being more teratogenic. PE-4-yn-VPA also possesses antiepileptic, antiproliferative, and cell-differentiating properties. Moreover, the less teratogenic enantiomer, R-PE-4-yn-VPA, was recently shown to improve learning and memory. We here present a detailed investigation of the enantioselective properties of PE-4-yn-VPA using a range of in vitro and in vivo assays including measurements of cellular growth and migration, neuronal differentiation and survival, intracellular signal transduction, synaptic plasticity and maturation, and short-term memory as determined by the social recognition test. The results show that the enantiomers of PE-4-yn-VPA largely had similar effects in vitro. However, in all in vitro experiments the more teratogenic enantiomer, S-PE-4-yn-VPA, exhibited a stronger potency than R-PE-4-yn-VPA, and only S-PE-4-yn-VPA had a detrimental effect on cell survival. Interestingly, both the R- and S-enantiomer improved learning and memory. In contrast, the beneficial effect of S-PE-4-yn-VPA on memory was lost by time, whereas the effect of R-PE-4-yn-VPA administration was longer lasting, suggesting that the beneficial effect of the S-enantiomer on memory formation may be counteracted by its detrimental effect on neuronal cell survival.

AB - 2-n-Pentyl-4-pentynoic acid (PE-4-yn-VPA) is a derivative of the antiepileptic and mood-stabilizing drug valproic acid (VPA). PE-4-yn-VPA exists as R- and S-enantiomers, the latter being more teratogenic. PE-4-yn-VPA also possesses antiepileptic, antiproliferative, and cell-differentiating properties. Moreover, the less teratogenic enantiomer, R-PE-4-yn-VPA, was recently shown to improve learning and memory. We here present a detailed investigation of the enantioselective properties of PE-4-yn-VPA using a range of in vitro and in vivo assays including measurements of cellular growth and migration, neuronal differentiation and survival, intracellular signal transduction, synaptic plasticity and maturation, and short-term memory as determined by the social recognition test. The results show that the enantiomers of PE-4-yn-VPA largely had similar effects in vitro. However, in all in vitro experiments the more teratogenic enantiomer, S-PE-4-yn-VPA, exhibited a stronger potency than R-PE-4-yn-VPA, and only S-PE-4-yn-VPA had a detrimental effect on cell survival. Interestingly, both the R- and S-enantiomer improved learning and memory. In contrast, the beneficial effect of S-PE-4-yn-VPA on memory was lost by time, whereas the effect of R-PE-4-yn-VPA administration was longer lasting, suggesting that the beneficial effect of the S-enantiomer on memory formation may be counteracted by its detrimental effect on neuronal cell survival.

U2 - 10.1016/j.neuropharm.2006.09.017

DO - 10.1016/j.neuropharm.2006.09.017

M3 - Journal article

C2 - 17095022

SN - 0028-3908

VL - 52

SP - 764

EP - 778

JO - Neuropharmacology

JF - Neuropharmacology

IS - 3

ER -