VPA Inhibits P19 Neural Differentiation through Redox Dysregulation and Oxidative Stress

Jacob, Benjamin R.; Piorczynski, Ted B.; Hansen, Jason M.

doi:10.1016/j.freeradbiomed.2017.10.298

Cited by 3 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These effects of VPA may prevent the transfer of a one-carbon unit for the relevant cycles to progress, leading to abnormal methylation, phospholipid, polyamines, protein and nucleic acid synthesis [ 180 , 181 ]. It is reported that VPA, via the OCM, may also increase the oxidative stress burden, which will further induce major and minor congenital malformations [ 178 , 182 , 183 , 184 , 185 ]. Pregnant Wistar rats treated with different doses of VPA in mid and late gestational periods revealed alterations in several genes and enzymes of the OCM and folate transporter (folR1) [ 186 ].…”

Section: The Suggested Mechanism Of the Teratogenic Action Of Vpamentioning

confidence: 99%

“…Increased brain oxidative stress induced by prenatal or early postnatal VPA administration was reported by several investigators using the VPA-induced model of autistic-like behavior [ 118 ]. Other investigators have reported VPA as pro-oxidative in humans, animals and cultured cells [ 28 , 139 , 182 , 183 , 184 , 202 ].…”

Section: The Suggested Mechanism Of the Teratogenic Action Of Vpamentioning

confidence: 99%

See 1 more Smart Citation

Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review

Ornoy,

Echefu,

Becker

2023

IJMS

View full text Add to dashboard Cite

Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data.

show abstract

Section: The Suggested Mechanism Of the Teratogenic Action Of Vpamentioning

confidence: 99%

Section: The Suggested Mechanism Of the Teratogenic Action Of Vpamentioning

confidence: 99%

Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review

Ornoy,

Echefu,

Becker

2023

IJMS

View full text Add to dashboard Cite

show abstract

“…It has also been suggested that VPA may cause liver toxicity via the formation of reactive VPA metabolites, inhibition of fatty acid-β oxidation, increased oxidative stress and genetic polymorphisms of certain enzyme genes such as carbomyl phosphate synthetase 1 (CPS1), polymerase gamma (POLG), glutathione S-transferases (GSTs), superoxide dismutase 2 (SOD2), uridine 5'diphospho-glucoronosyltransferase (UGTs) and cytochromes P450 (CYPs) (46,47). It has been highlighted that disturbance to VPA regulation might leads to the formation of toxic metabolites (48) that leads to neurological and mental disorders (49), fetal malformations (50), neuroendocrine dysfunction (51), and impaired hematopeiotic homeostasis (52), among others. Chen et al (2015) found in their study that patients with carnitine deficiency are at higher risk of VPA-induced liver injury (53) and therefore recommended that carnitine supplementation may be beneficial in VPA-induced liver injury to protect the liver from toxins.…”

Section: Vpa and Livermentioning

confidence: 99%

3P's (Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic) of Valproate: What's New?

Ahmad¹

2023

IJPNaCS

View full text Add to dashboard Cite

Valproate (VPA) has been used clinically for more than 40 years and remains one of the most commonly prescribed antiepileptic drugs. With the advances of various scientific disciplines, much new information about this drug has been uncovered. The aim of this review is to summarize new knowledge about the pharmacokinetics, pharmacodynamics, and pharmacogenomics (3Ps) of VPA for future applications and studies. The review was identified nonsystematically using Pubmed, Google Scholar, and open-access search engines, and studies on the pharmacokinetics, pharmacodynamics, and pharmacogenomics of VPA between 2012 and 2022 were included. Recent findings on pharmacokinetic information, including factors associated with serum VPA levels and its interaction with new drugs. On the other hand, VPA was found to have a neuroprotective effect that is beneficial in brain disorders as well as in patients with c stroke. With respect to the lungs, it has been found to reduce the risk of acute respiratory failure. Recent risk data linked VPA use to hepatotoxicity, vitamin D deficiency, prolonged QT interval, and insulin resistance, among others. Various gene polymorphisms such as CYP2C9 and UGT1A6 are some polymorphisms that may cause dose alteration in the population. The compilation of the 3Ps of VPA revealed new drug information indicating the need for further evaluation. These include new uses and benefits, toxicity data including acute and chronic use, and the involvement of genetic polymorphisms in the pharmacokinetics and pharmacodynamics of the drug.

show abstract

Therapeutic and Toxic Effects of Valproic Acid Metabolites

et al. 2023

View full text Add to dashboard Cite

Valproic acid (VPA) and its salts are psychotropic drugs that are widely used in neurological diseases (epilepsy, neuropathic pain, migraine, etc.) and psychiatric disorders (schizophrenia, bipolar affective disorder, addiction diseases, etc.). In addition, the indications for the appointment of valproate have been expanding in recent years in connection with the study of new mechanisms of action of therapeutic and toxic metabolites of VPA in the human body. Thus, VPA is considered a component of disease-modifying therapy for multiple tumors, neurodegenerative diseases (Huntington’s disease, Parkinson’s disease, Duchenne progressive dystrophy, etc.), and human immunodeficiency syndrome. The metabolism of VPA is complex and continues to be studied. Known pathways of VPA metabolism include: β-oxidation in the tricarboxylic acid cycle (acetylation); oxidation with the participation of cytochrome P-450 isoenzymes (P-oxidation); and glucuronidation. The complex metabolism of VPA explains the diversity of its active and inactive metabolites, which have therapeutic, neutral, or toxic effects. It is known that some active metabolites of VPA may have a stronger clinical effect than VPA itself. These reasons explain the relevance of this narrative review, which summarizes the results of studies of blood (serum, plasma) and urinary metabolites of VPA from the standpoint of the pharmacogenomics and pharmacometabolomics. In addition, a new personalized approach to assessing the cumulative risk of developing VPA-induced adverse reactions is presented and ways for their correction are proposed depending on the patient’s pharmacogenetic profile and the level of therapeutic and toxic VPA metabolites in the human body fluids (blood, urine).

show abstract

VPA Inhibits P19 Neural Differentiation through Redox Dysregulation and Oxidative Stress

Cited by 3 publications

References 0 publications

Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review

Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review

3P's (Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic) of Valproate: What's New?

Therapeutic and Toxic Effects of Valproic Acid Metabolites

Contact Info

Product

Resources

About