Valproic acid promotes SOD2 acetylation: a potential mechanism of valproic acid-induced oxidative stress in developing systems

Hansen, Jason M.; Lucas, S. Marc; Ramos, Catania D; Green, Eli J; Nuttall, Dakota J.; Clark, David S.; Marchant, Erik D.; Hancock, Chad R.; Piorczynski, Ted B.

doi:10.1080/10715762.2021.2017913

Cited by 12 publications

(8 citation statements)

References 60 publications

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“…Nevertheless, a growing body of evidence underscores that a pivotal mechanism contributing to VPA-induced NTDs is the perturbation of redox balance and the subsequent generation of excessive ROS. Emerging research suggests that mitigating redox disruptions could potentially lead to a decline in the prevalence of NTDs [ 16 , 18 , 40 ]. Resveratrol and vitamin E could rescue VPA-induced teratogenicity [41] .…”

Section: Discussionmentioning

confidence: 99%

“…VPA induces a surplus generation of reactive oxygen species (ROS) within neuroepithelial cells, triggering apoptosis and consequently impeding the timely closure of the neural tube. This disruption primarily manifests as malformation with exposed brain tissue [ 16 , 18 ]. The imperative lies in the exploration of efficacious prophylactic interventions aimed at mitigating fetal NTDs resulted from VPA administration.…”

Section: Introductionmentioning

confidence: 99%

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Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress

Liang,

Wang,

Zhang

et al. 2023

ABBS

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Neural tube defects (NTDs) represent a developmental disorder of the nervous system that can lead to significant disability in children and impose substantial social burdens. Valproic acid (VPA), a widely prescribed first-line antiepileptic drug for epilepsy and various neurological conditions, has been associated with a 4-fold increase in the risk of NTDs when used during pregnancy. Consequently, urgent efforts are required to identify innovative prevention and treatment approaches for VPA-induced NTDs. Studies have demonstrated that the disruption in the delicate balance between cell proliferation and apoptosis is a crucial factor contributing to NTDs induced by VPA. Encouragingly, our current data reveal that melatonin (MT) significantly inhibits apoptosis while promoting the restoration of neuroepithelial cell proliferation impaired by VPA. Moreover, further investigations demonstrate that MT substantially reduces the incidence of neural tube malformations resulted from VPA exposure, primarily by suppressing apoptosis through the modulation of intracellular reactive oxygen species levels. In addition, the Src/PI3K/ERK signaling pathway appears to play a pivotal role in VPA-induced NTDs, with significant inhibition observed in the affected samples. Notably, MT treatment successfully reinstates Src/PI3K/ERK signaling, thereby offering a potential underlying mechanism for the protective effects of MT against VPA-induced NTDs. In summary, our current study substantiates the considerable protective potential of MT in mitigating VPA-triggered NTDs, thereby offering valuable strategies for the clinical management of VPA-related birth defects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress

Liang,

Wang,

Zhang

et al. 2023

ABBS

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“…VPA administration during pregnancy alone or in combination with other drugs, induces a high number of anomalies, resorption and increased mortality rate. Most of the studies reported on exencephaly and spina bifida occulta as well as spina bifida aperta, thereby mimicking NTD as found in humans [ 6 , 48 , 103 , 114 , 115 , 116 , 125 , 137 , 138 , 139 , 140 , 141 ]. As expected, in addition to the dose relationship of VPA in the pathophysiology of NTD, gestational age is a crucial factor in determining what type of NTD is induced by VPA exposure.…”

Section: Animal Studies On Vpa-induced Teratogenicitymentioning

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%

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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

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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.

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Developmental Toxicology: Introduction and Historical Perspectives

Harris,

Hansen

2024

Reference Module in Biomedical Sciences

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Valproic acid promotes SOD2 acetylation: a potential mechanism of valproic acid-induced oxidative stress in developing systems

Cited by 12 publications

References 60 publications

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress

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

Developmental Toxicology: Introduction and Historical Perspectives

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