ArticleJournal of neurochemistry2015
Valproic acid induces neuronal cell death through a novel calpain-dependent necroptosis pathway.
Article in Journal of neurochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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The trial behind it
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Who cites it
30 citing papers in PubMed, 54 citations in OpenAlex.
- Review
- In vitro models of valproic acid to assess neurodevelopmental toxicity: A scoping review.Epilepsia · 2025Article
- Prenatal Exposure to Valproic Acid may Alter CD200/CD200R Signaling Pathways in a Rat Model of Autism Spectrum Disorder.Alpha psychiatry · 2025Article
- The Differential Developmental Neurotoxicity of Valproic Acid on Anterior and Posterior Neural Induction of Human Pluripotent Stem Cells.International journal of stem cells · 2025Article
- The multifaceted role of mitochondria in autism spectrum disorder.Molecular psychiatry · 2025Review
- Pre- and Postnatal Valproate Exposure Affects Brain Development.Current topics in behavioral neurosciences · 2025Review
- Indole-3-acetic acid and chenodeoxycholic acid attenuate TLR4/NF-κB signaling and endoplasmic reticulum stress in valproic acid-induced neurotoxicity.Frontiers in pharmacology · 2025Article
- Article
- Role of Necroptosis, a Regulated Cell Death, in Seizure and Epilepsy.Neurochemical research · 2024Review
- Necroptosis in the developing brain: role in neurodevelopmental disorders.Metabolic brain disease · 2023Review
- Calpain: the regulatory point of myocardial ischemia-reperfusion injury.Frontiers in cardiovascular medicine · 2023Review
- The regulation of necroptosis and perspectives for the development of new drugs preventing ischemic/reperfusion of cardiac injury.Apoptosis : an international journal on programmed cell death · 2022Review
- Effects of Low- and High-Dose Valproic Acid and Lamotrigine on the Heart in Female Rats.Cardiovascular toxicology · 2022Article
- GABA Receptor Agonists Protect From Excitotoxic Damage Induced by AMPA in Oligodendrocytes.Frontiers in pharmacology · 2022Article
- The role of necroptosis in disease and treatment.MedComm · 2021Review
- The potential role of necroptosis in clinical diseases (Review).International journal of molecular medicine · 2021Review
- Taurine attenuates valproic acid-induced hepatotoxicity via modulation of RIPK1/RIPK3/MLKL-mediated necroptosis signaling in mice.Molecular biology reports · 2021Article
- Epigenetics modifiers: potential hub for understanding and treating neurodevelopmental disorders from hypoxic injury.Journal of neurodevelopmental disorders · 2020Review
- Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis.Apoptosis : an international journal on programmed cell death · 2020Article
- Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress-Induced Cell Damage: an Involvement of Cathepsin D Inhibition.Neurotoxicity research · 2020Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
A growing body of evidence indicates that valproic acid (VPA), a histone deacetylase inhibitor used to treat epilepsy and mood disorders, has histone deacetylase-related and -unrelated neurotoxic activity, the mechanism of which is still poorly understood. We report that VPA induces neuronal cell death through an atypical calpain-dependent necroptosis pathway that initiates with downstream activation of c-Jun N-terminal kinase 1 (JNK1) and increased expression of receptor-interacting protein 1 (RIP-1) and is accompanied by cleavage and mitochondrial release/nuclear translocation of apoptosis-inducing factor, mitochondrial release of Smac/DIABLO, and inhibition of the anti-apoptotic protein X-linked inhibitor of apoptosis (XIAP). Coinciding with apoptosis-inducing factor nuclear translocation, VPA induces phosphorylation of the necroptosis-associated histone H2A family member H2AX, which is known to contribute to lethal DNA degradation. These signals are inhibited in neuronal cells that express constitutively activated MEK/ERK and/or PI3-K/Akt survival pathways, allowing them to resist VPA-induced cell death. The data indicate that VPA has neurotoxic activity and identify a novel calpain-dependent necroptosis pathway that includes JNK1 activation and RIP-1 expression. A growing body of evidence indicates that valproic acid (VPA) has neurotoxic activity, the mechanism of which is still poorly understood. We report, for the first time, that VPA activates a previously unrecognized calpain-dependent necroptosis cascade that initiates with JNK1 activation and involves AIF cleavage/nuclear translocation and H2AX phosphorylation as well as an altered Smac/DIABLO to XIAP balance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.