Modulation of Peroxisome Proliferator-Activated Receptor δ Activity Affects Neural Cell Adhesion Molecule and Polysialyltransferase ST8SiaIV Induction by Teratogenic Valproic Acid Analogs in F9 Cell Differentiation

Abstract

It has been suggested that the teratogenic effects of the antiepileptic drug valproic acid (VPA) is reflected in vitro by the differentiation of F9 cells, activation of peroxisome proliferatoractivated receptor ␦ (PPAR␦), and inhibition of histone deacetylases (HDACs). The aim of this study was to identify genes involved in the differentiation of F9 cells induced by VPA, teratogenic VPA derivatives, or the HDAC inhibitor trichostatin A (TSA) and to characterize the role of PPAR␦. Treatment of the cells with teratogenic VPA derivatives or TSA induced differentiation of F9 cells, mRNA, and protein expression of the neural cell adhesion molecule (NCAM) as well as activated the 5Ј-flanking region of the NCAM promoter, whereas nonteratogenic VPA derivatives had no effect at all. The polysialyltransferases [ST8SiaIV (PST1) and ST8SiaII] are responsible for the addition of polysialic acid (PSA) to NCAM. The mRNA expression of PST1 was highly induced by only teratogenic VPA derivatives and TSA. As shown by fluorescence-activated cell sorting analysis the level of PSA was higher after treatment of F9 cells with teratogenic VPA derivatives. It is interesting that overexpression of the PPAR␦ but not PPAR␣ or PPAR␥ in F9 cells resulted in higher induction of NCAM mRNA and protein expression and of PST1 mRNA expression (and a higher PSA level) than in mock-transfected F9 cells. Furthermore, repression of PPAR␦ activity in F9 cells inhibited these effects. We conclude that NCAM and PST1 are molecular markers in F9 cell differentiation caused by treatment with teratogenic VPA compounds or TSA and suggest that in addition to HDAC inhibition PPAR␦ is involved in the signaling pathway.

Modulation of Synaptic Transmission and Analysis of Neuroprotective Effects of Valproic Acid and Derivates in Rat Embryonic Motoneurons

“…Moreover, the ability of PE-4-yn enantiomers to attenuate the age-related decrease in NCAM polysialylation state suggests that it may have a significant advantage in slowing onset of degenerative deficits by enhancing neuroplasticity. It was found that the expression of PSA-NCAM was increased in a concentration dependent manner by both R-and S-PE-4-yn, an observation consistent with the fact, that the racemic mixture of PE-4-yn enantiomers induces the expression of one of the enzymes, PST1, responsible for attaching PSA to NCAM (Lampen et al 2005). This indicates that R-and S-PE-4-yn have largely similar effects in vitro.…”

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

“…In addition, HDAC inhibition is known to enhance NCAM protein expression and the expression of the adult form of polysialyltransferase (PST1) (Lampen et al, 2005). Collectively, these results imply that both the neurobehavioural and neurological deficits induced by in utero exposure to the VPA can be reversed in the adult by use of HDAC inhibitors, such as MS-275.…”

PPAR et interactions des cellules entre elles ou avec la matrice extracellulaire

“…Par ailleurs, il a été récemment montré que l'acide valproï-que, un activateur de PPARβ/δ, tératogène in vivo chez l'homme et la souris, est capable de moduler l'expression de la molécule NCAM (neural cell adhesion molecule) [2]. PPARβ/δ est normalement exprimé dans les cellules F9 de carcinome embryonnaire et son activation par l'acide valproïque induit la différenciation de ces cellules.…”

“…Sa surexpression dans les cellules F9 traitées par l'acide valproïque induit une forte expression du gène codant NCAM, favorisant ainsi l'adhérence et la différenciation des cellules F9. Réciproquement, la répression de l'activité de PPARβ/δ inhibe ces effets [2]. En revanche, l'activation de PPARα ou de PPARγ n'a pas d'effet sur l'expression de NCAM [2].…”

“…Réciproquement, la répression de l'activité de PPARβ/δ inhibe ces effets [2]. En revanche, l'activation de PPARα ou de PPARγ n'a pas d'effet sur l'expression de NCAM [2]. Il est possible que la modulation de l'expression du gène NCAM par PPARβ/δ soit indirecte car aucun élément de réponse ou PPRE (peroxisome proliferator responsive element) aux PPAR n'a été actuellement identifié dans le promoteur du gène NCAM.…”