Protein Binding of Valproic Acid in Maternal and Umbilical Cord Serum

Froescher, W.; Gugler, R; Niesen, M.; Hoffmann, Fr.

doi:10.1111/j.1528-1157.1984.tb04183.x

Cited by 25 publications

(4 citation statements)

References 23 publications

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“…To our knowledge, there is no information on the concentrations reached by VPA in the embryonic brain and associated with teratogenic effects following administration of therapeutic doses to the mother. On the other hand, VPA is known to cross the placenta and its levels in umbilical cord serum may be higher than those in maternal serum [71,72]. In the neonate, increases in the serum unbound fraction of VPA have been found to be associated with congenital malformations [73].…”

Section: Discussionmentioning

confidence: 99%

Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis

et al. 2020

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The antiepileptic and mood stabilizer agent valproic acid (VPA) has been shown to exert anti-tumour effects and to cause neuronal damage in the developing brain through mechanisms not completely understood. In the present study we show that prolonged exposure of SH-SY5Y and LAN-1 human neuroblastoma cells to clinically relevant concentrations of VPA caused a marked induction of the protein and transcript levels of the common neurotrophin receptor p75NTR and its co-receptor sortilin, two promoters of apoptotic cell death in response to proneurotrophins. VPA induction of p75NTR and sortilin was associated with an increase in plasma membrane expression of the receptor proteins and was mimicked by cell treatment with several histone deacetylase (HDAC) inhibitors. VPA and HDAC1 knockdown decreased the level of EZH2, a core component of the polycomb repressive complex 2, and upregulated the transcription factor CASZ1, a positive regulator of p75NTR. CASZ1 knockdown attenuated VPA-induced p75NTR overexpression. Cell treatment with VPA favoured proNGF-induced p75NTR/sortilin interaction and the exposure to proNGF enhanced JNK activation and apoptotic cell death elicited by VPA. Depletion of p75NTR or addition of the sortilin agonist neurotensin to block proNGF/sortilin interaction reduced the apoptotic response to VPA and proNGF. Exposure of mouse cerebellar granule cells to VPA upregulated p75NTR and sortilin and induced apoptosis which was enhanced by proNGF. These results indicate that VPA upregulates p75NTR apoptotic cell signalling through an epigenetic mechanism involving HDAC inhibition and suggest that this effect may contribute to the anti-neuroblastoma and neurotoxic effects of VPA.

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Section: Discussionmentioning

confidence: 99%

Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis

et al. 2020

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“…VPA has a higher fetal than maternal concentration due to differences in albumin and free fatty acid concentrations (engendering higher circulating unbound VPA in maternal blood) and increased protein binding in fetal serum [204][205][206][207].…”

Section: Fetal Delivery Of Vpamentioning

confidence: 99%

Valproate and Neuroendocrine Changes in Relation to Women Treated for Epilepsy and Bipolar Disorder: A Review

Reynolds¹,

Sisk²,

Rasgon³

2007

CMC

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Valproic acid (2-n-propylpentanoic acid, VPA) is well-established as a mood-stabilizer for bipolar disorder, in addition to its application as a treatment in neurological disorders such as epilepsy, migraine headaches, and chronic neuropathic pain. Its mechanisms of actions in any of the disorders have not yet been fully elucidated but currently include GABA-ergic inhibitory effects, the suppression of NMDA-mediated excitatory neurotransmission, and possibly effects on monoamines and cerebral glucose metabolism. Given the rising use of VPA by women of reproductive age for various conditions it is increasingly important to understand how VPA affects reproductive and metabolic function in women, yet a number of key issues regarding VPA use in women of reproductive age remain unclear. These include the question of whether VPA use is associated with the development of polycystic ovary syndrome (PCOS)-like features (such as elevated androgen concentrations and/or chronic anovulation). The metabolic effects of VPA use, particularly on insulin sensitivity and weight gain, are also important to understand. Lastly, questions of VPA use during pregnancy and lactation require continued attention. This article reviews the current understanding of VPA's mechanisms of action, effects on the reproductive and metabolic system, and teratogenic qualities, highlighting important future areas of study.

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“…Our epileptic patients did not show an alteration on free-to-bound parameters based upon age which has been shown to influence human free-to-bound phenobarbital levels [35][36][37][38]. We also did not see any effect of multiple anticonvulsant drug therapy on free-to-bound phenobarbital [39,40].…”

Section: Discussionmentioning

confidence: 53%

Free-to-Bound Serum Phenobarbital Levels in Dogs

Peters¹

2013

J Veterinar Sci Technolo

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Monitoring phenobarbital levels in dogs has not traditionally taken free-to-bound serum phenobarbital levels into consideration. This study was designed to evaluate free-to-bound phenobarbital in healthy research dogs during the initiation of therapy with phenobarbital. These findings were compared with the levels obtained during routine therapeutic monitoring of phenobarbital in epileptic dogs. This appears to be the first descriptive study which has looked at free-to-bound phenobarbital in clinical canine patients. During the first week of therapy in healthy canine subjects, the free-to-bound ratio was 0.7 due to the high degree of protein-binding of serum phenobarbital. This was in contrast to the level of protein-binding in epileptic patients receiving phenobarbital chronically, with a free-to-bound ratio of 3.0 ± 2.7. Moreover, during the initiation of therapy with phenobarbital, some of the bound fraction could be displaced with sulfadimethoxine indicating that free-to-bound phenobarbital may have significance during this period. On the other hand, chronic therapy in epileptic dogs leads to reduction in the bound fraction for serum phenobarbital. This leads to a strong, direct correlation of total and free phenobarbital in these patients. This relationship is consistent over a wide range of serum concentrations and does not appear to be affected by the age of the patient, the length of chronic therapy or the presence of other anticonvulsant medications. There was an inverse relationship with total plasma proteins and free phenobarbital concentrations, but it was not statistically significant. Routine monitoring of free-to-bound phenobarbital may not be warranted except under specific conditions.

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Protein Binding of Valproic Acid in Maternal and Umbilical Cord Serum

Cited by 25 publications

References 23 publications

Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis

Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis

Valproate and Neuroendocrine Changes in Relation to Women Treated for Epilepsy and Bipolar Disorder: A Review

Free-to-Bound Serum Phenobarbital Levels in Dogs

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