title: Multiple effects of pentyl-4-yn-VPA enantiomers: from toxicity to short-term memory enhancement.
abstract: 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.
authors.affiliation: Protein Laboratory, Institute of Molecular Pathology, Panum Institute, University of Copenhagen, Blegdamsvej 3C Bld. 6.2, DK-2200 Copenhagen N, Denmark.
authors.forename: Kamil
authors.initials: K
authors.lastname: Gotfryd
authors.forename: Sylwia
authors.initials: S
authors.lastname: Owczarek
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Boris
authors.initials: B
authors.lastname: Klementiev
authors.forename: Heinz
authors.initials: H
authors.lastname: Nau
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berezin
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bock
authors.forename: Peter S
authors.initials: PS
authors.lastname: Walmod
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016708:Synaptophysin; C513636:pentyl-4-pentynoic acid; D014635:Valproic Acid