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VA

valproate semisodium (Depakote ER / divalproex ER)

✓ Approved

AbbVie, Inc. · SCN1A · Small Molecule

What is valproate semisodium?

valproate semisodium is a small molecule developed by AbbVie, Inc.. It is approved for therapeutic indications via oral (po).

Drug Profile

Brand NamesDepakote ER, divalproex ER
CompanyAbbVie, Inc.
Drug ClassSmall Molecule
Molecular TargetSCN1A, SCN2A, SCN3A
RouteOral (PO)
StatusApproved
Sources: ClinicalTrials.gov, AbbVie, Inc.

Mechanism of Action

Molecular Targets

valproate semisodium acts on 3 molecular targets:

SCN1Asodium voltage-gated channel alpha subunit 1 (DEE6B, FEB3)
SCN2Asodium voltage-gated channel alpha subunit 2 (Na(v)1.2, BFNIS)
SCN3Asodium voltage-gated channel alpha subunit 3 (Nav1.3, NAC3)
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Therapeutic Indications

valproate semisodium is developed for 3 unique indications across 3 therapeutic areas.

Therapeutic AreaConditionPhase
Nervous system disordersGeneralised tonic-clonic seizure✓ Approved
Psychiatric disordersBipolar disorder✓ Approved
Surgical and medical proceduresMigraine prophylaxis✓ Approved

Related Research Articles

PubMedTherapeutic drug monitoring2026-10-16

Gender-Based Differences in the Effects of Valproate on Dose-Corrected Plasma Concentrations of Quetiapine and Its Metabolites: A Retrospective Cohort Study.

Luo Kang K, Zhou Honghai H, Chen Xingxing X, Zhang Xiaogang X et al.

This retrospective study aimed to investigate the effects of valproate on the concentration-to-dose (C/D) ratio of quetiapine and N-desalkylquetiapine. Multiple linear regression analysis was used to identify independent factors influencing the C/D values of quetiapine and N-desalkylquetiapine, and the results were compared. Subgroup analyses were based on sex and age. Valproate independently influenced the C/D ratios of quetiapine and N-desalkylquetiapine in a multivariate linear regression model adjusted for covariates. The Mann-Whitney U test indicated that the valproate combination group experienced a 16.85% reduction in the C/D ratio for quetiapine and a 23.68% reduction in the C/D ratio for N-desalkylquetiapine compared with the nonvalproate combination group, with significant differences (P < 0.001). Plasma N-desalkylquetiapine C/D ratios were negatively correlated with valproate dose (rs = -0.151). The subgroup analysis indicated no significant interactions between age and valproate, or between sex and valproate, on the C/D ratios of N-desalkylquetiapine (P-interaction >0.05); however, a significant interaction was observed between sex and valproate on the C/D ratio of quetiapine (P-interaction = 0.007). The Mann-Whitney U test revealed that concomitant valproate use significantly reduced the C/D ratio of quetiapine in females aged <40 and ≥40 years (all P < 0.05), but not in males (all P > 0.05). This study presents a novel finding that valproate significantly decreases the quetiapine C/D ratio, specifically in females. Furthermore, valproate also significantly decreases the N-desalkylquetiapine C/D ratio, an effect not specific to any population.

PMID 42885966
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PubMedJournal of clinical medicine2026-10-16

Male Reproductive Disorders Associated with Antiseizure Medications: Evidence from Meta-Analysis and FAERS Pharmacovigilance Study.

Na Heejin H, Choi Boyoon B, Oh Se-Hoon SH, Jo In-Je IJ et al.

Background/Objectives: Antiseizure medications (ASMs) are widely used in the management of epilepsy; however, their effects on male reproductive function in humans remain incompletely characterized. This study aimed to evaluate drug-specific associations between ASMs and male reproductive disorders through a meta-analysis of observational clinical studies and FDA Adverse Event Reporting System (FAERS)-based pharmacovigilance analyses. Methods: Clinical studies involving men with epilepsy receiving ASMs, untreated men with epilepsy, and healthy controls were systematically reviewed and quantitatively synthesized. FAERS reports from the first quarter of 2019 to the second quarter of 2026 (2019Q1-2026Q2) were analyzed using reporting odds ratios (RORs) and information components (ICs), with disproportionality signals identified by either method. Results: The meta-analysis included 20 clinical studies involving 1530 participants. Valproate was associated with adverse effects on reproductive hormones, sperm parameters, and sexual function, whereas carbamazepine and phenytoin were primarily associated with alterations in reproductive hormone levels. In the pharmacovigilance analysis, valproate showed a significant disproportionality signal for male reproductive disorders (IC025 1.792). Conclusions: The findings indicate that male reproductive effects are not uniform across ASMs but exhibit distinct drug-specific patterns. Valproate was associated with alterations across multiple reproductive domains, whereas carbamazepine and phenytoin were associated predominantly with reproductive hormone alterations. Reproductive health should be considered when selecting and monitoring long-term ASM therapy in men, and prospective studies are needed to further characterize the reproductive safety profiles of individual ASMs.

PMID 42882028
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PubMedCells2026-10-16

TRPs-NCX2 Axis Jointly Preserves Pancreatic Beta Cell Susceptibility/Sensitivity to Elevated Glucose.

Sagintayev Adlet A, Oflaz Furkan E FE, Kanlinuro Andra A, van Amsterdam Savina S et al.

Background: For appropriate glucose sensing, pancreatic beta-cells essentially establish a constant mitochondria-directed endoplasmic reticulum (ER) Ca2+ leak via phosphorylated presenilin-1 (PS1). In the current work, we investigated how cells maintain the ER Ca2+ content during this continuous Ca2+ leak. Methods: Ca2+ imaging for ER, cytosolic and subplasmalemmal Ca2+, high resolution respirometry, and ELISA for insulin secretion were used. Results: A novel ER Ca2+ refilling mechanism driven by reverse-mode NCX2, which is fueled by local Na+ influxes through TRPC3 and TRPV4 channels that are independent of STIM-ORAI1 was found in pancreatic rodent and human beta cell lines. Disrupting this TRPs-NCX2 axis reduces subplasmalemmal Ca2+ levels, abolishes glucose-induced cytosolic Ca2+ oscillations, suppresses glucose-triggered elevation in mitochondrial energetics, and impairs first-phase insulin secretion. Conclusions: We identified a novel, ORAI1-independent "TRPs-NCX2" relay that couples Na+ influx via TRPC3 and TRPV4 to NCX2 reverse mode to maintain ER Ca2+ stores during physiological basal ER Ca2+ leakage, which is fundamental to beta-cell responsiveness to elevated glucose.

PMID 42882464
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PubMedCells2026-10-16

Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.

Niinuma Sara Anjum SA, Takemoto Ashleigh Suzu-Nishio AS, Khalil William Junior WJ, Butler Alexandra E AE et al.

Pancreatic β-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic reticulum (ER) and mitochondria strongly influences β-cell fate. The two organelles are physically coupled at mitochondria-associated membranes (MAMs), contact sites that synchronize ER Ca2+ release with mitochondrial Ca2+ uptake and adenosine triphosphate (ATP) production, and that help regulate redox balance, autophagy, mitophagy and the unfolded protein response. This review draws together evidence on three questions. First, which stresses converge on the β-cell: ER stress, oxidative stress and dysregulated autophagy and mitophagy. Second, how ER-mitochondria crosstalk sustains β-cell health through Ca2+ handling and the proteins that maintain MAM integrity, including inositol 1,4,5-trisphosphate (IP3) receptors, voltage-dependent anion channel 1 (VDAC1), mitofusin 2 (Mfn2) and the ER stress sensors IRE1α and PERK. Third, how glucolipotoxic and inflammatory stress remodels these contacts and pushes communication towards a maladaptive state marked by mitochondrial Ca2+ overload, ROS accumulation, defective organelle quality control, cellular senescence and apoptosis. We contrast rodent and human data, where MAM composition and glucotoxic responses diverge, and consider therapeutic strategies, such as incretin-based agents and the mitochondrial-derived peptide MOTS-c, that target this interface to preserve β-cell function in diabetes.

PMID 42882431
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PubMedAnimals : an open access journal from MDPI2026-10-16

Chronic Energy Restriction Is Associated with Impaired Follicular Development and Hepatic Bile Acid Remodeling in Mice.

Zhu Wenjun W, Li Jiahao J, Cheng Xiaochan X, Zhang Hengyu H et al.

Chronic energy restriction (ER) can impair female reproductive function, but the peripheral metabolic mechanisms by which sustained energy deficiency disrupts follicular development remain poorly understood. This study aimed to determine whether hepatic bile acid (BA) remodeling contributes to the link between systemic energy availability and ovarian dysfunction. A chronic ER mouse model was established by reducing energy intake by 50% for 44 days. Multi-omics approaches, including hepatic transcriptomics, untargeted metabolomics, and targeted BA metabolomics, were integrated with ovarian functional analyses. ER significantly reduced ovarian weight, impaired follicular development, and decreased circulating concentrations of reproductive hormones. Hepatic transcriptomic and metabolomic analyses revealed extensive metabolic remodeling, with marked enrichment of BA-related pathways and increased expression of CYP7A1, suggesting increased hepatic BA synthetic capacity. Targeted BA profiling demonstrated elevated hepatic and circulating BA levels, including increased concentrations of several farnesoid X receptor (FXR)-activating BAs. Furthermore, ovarian FXR expression was increased, accompanied by decreased expression of key steroidogenic regulators, including SRB1, StAR, CYP11A1, and HSD3B1, consistent with reduced ovarian steroidogenic activity. These findings suggest that altered BA metabolism and increased ovarian FXR expression may contribute to reproductive dysfunction under chronic ER.

PMID 42882994
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PubMedInternational journal of molecular sciences2026-10-16

Diosgenin Alleviates Neuropathic Pain Associated with Alterations in Spinal Mitochondrial and ER Stress-Related Factors in CCI Mice.

Rahman Md Mahbubur MM, Yoon Taesu T, Yum Seung Hoon SH, Shim Ye Won YW et al.

Neuropathic pain is difficult to treat as current therapies are often insufficient and provide incomplete relief. However, the mechanisms of chronic nerve injury are poorly addressed. In the present study, we explored the therapeutic effects of natural steroidal saponin diosgenin and its possible spinal mechanisms in a mouse model of chronic constriction injury (CCI)-induced neuropathic pain. C57BL/6 mice underwent CCI and were orally administered diosgenin once daily from three days after surgery. Diosgenin significantly alleviated CCI-induced mechanical allodynia and thermal hyperalgesia and enhanced motor performance in paw withdrawal, open-field, and rotarod tests. These effects were associated with the restoration of mitochondrial homeostasis as evidenced by the increased mitochondrial fusion, decreased fission and activation of NRF2 signaling. Diosgenin also suppressed spinal endoplasmic reticulum (ER) stress, mitochondria apoptotic signaling and the expression of pro-inflammatory cytokines, and pain-related neuropeptides. Mechanistically, the inhibition of spinal NRF2 proteins and the pharmacological induction of ER stress reduced the analgesic effect of diosgenin, highlighting the critical involvement of these pathways in its therapeutic efficacy. Altogether, diosgenin alleviated neuropathic pain in CCI mice that were pharmacologically associated with the restoration of spinal mitochondrial function and ER stress suppression. Therefore, diosgenin could be a promising natural steroidal therapeutic candidate in alleviating neuropathic pain.

PMID 42883869
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