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Archives of Toxicology Feb 2021Since teratogenicity testing in mammals is a particular challenge from an animal welfare perspective, there is a great need for the development of alternative test...
Since teratogenicity testing in mammals is a particular challenge from an animal welfare perspective, there is a great need for the development of alternative test systems. In this context, the zebrafish (Danio rerio) embryo has received increasing attention as a non-protected embryonic vertebrate in vivo model. The predictive power of zebrafish embryos for general vertebrate teratogenicity strongly depends on the correlation between fish and mammals with respect to both overall general toxicity and more specific endpoints indicative of certain modes-of-action. The present study was designed to analyze the correlation between (1) effects of valproic acid and nine of its analogues in zebrafish embryos and (2) their known neurodevelopmental effects in mice. To this end, zebrafish embryos exposed for 120 h in an extended version of the acute fish embryo toxicity test (FET; OECD TG 236) were analyzed with respect to an extended list of sublethal endpoints. Particular care was given to endpoints putatively related to neurodevelopmental toxicity, namely jitter/tremor, deformation of sensory organs (eyes) and craniofacial deformation, which might correlate to neural tube defects caused by valproic acid in mammals. A standard evaluation of lethal (LC according to OECD TG 236) and sublethal toxicity (EC) merely indicated that four out of ten compounds tested in zebrafish correlate with positive results in mouse in vivo studies. A detailed assessment of more specific effects, however, namely, jitter/tremor, small eyes and craniofacial deformation, resulted in a correspondence of 75% with in vivo mouse data. A refinement of endpoint analysis from an integration of all observations into one LC or EC data (as foreseen by current ecotoxicology-driven OECD guidelines) to a differential evaluation of endpoints specific of selected modes-of-action thus increases significantly the predictive power of the zebrafish embryo model for mammalian teratogenicity. However, for some of the endpoints observed, e.g., scoliosis, lordosis, pectoral fin deformation and lack of movement, further experiments are required for the identification of underlying modes-of-action and an unambiguous interpretation of their predictive power for mammalian toxicity.
Topics: Animals; Ecotoxicology; Embryo, Nonmammalian; Lethal Dose 50; Mice; Models, Biological; Morphogenesis; Neurodevelopmental Disorders; Neurotoxins; Toxicity Tests, Acute; Valproic Acid; Zebrafish
PubMed: 33111190
DOI: 10.1007/s00204-020-02928-7 -
The Lancet. Healthy Longevity Jun 2021Histone deacetylase inhibitors (HDACi) regulate gene expression via epigenetic mechanisms. Accumulating evidence suggests that HDACi exert antiproliferative,... (Review)
Review
Histone deacetylase inhibitors (HDACi) regulate gene expression via epigenetic mechanisms. Accumulating evidence suggests that HDACi exert antiproliferative, antioxidant, antineoplastic, and proapoptotic effects through epigenetic mechanisms. Furthermore, HDACi also exert antithrombotic and antifibrotic effects through regulation of thrombotic and fibrotic transduction mechanisms. One of the oldest HDACi is valproic acid, which was first synthesised in 1882. After the discovery of its anticonvulsant properties for the treatment of epilepsy, the use of valproic acid was extended to other conditions, such as bipolar disorder and migraine. Given the accumulating evidence supporting the role of HDACi in the treatment of multiple medical conditions beyond epilepsy, the interest in novel potential indications for HDACi has been renewed. Considering the pleotropic epigenetic effects of HDACi, future studies could assess their efficacy and safety for cardiovascular disease prevention and treatment; treatment of venous thrombosis, Alzheimer's disease, autoimmune and proinflammatory conditions, chronic thromboembolic pulmonary hypertension, and pulmonary arterial hypertension; and as a coadjuvant therapy for cancer. Adequately designed and powered clinical trials are required to assess the efficacy and safety of HDACi before their clinical repurposing.
Topics: Antineoplastic Agents; Cardiovascular Diseases; Histone Deacetylase Inhibitors; Humans; Longevity; Valproic Acid
PubMed: 36098145
DOI: 10.1016/S2666-7568(21)00061-1 -
Signal Transduction and Targeted Therapy Jan 2024The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with...
The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density (BMD) in both patients and mice. This effect was attributed to VPA-induced elevation in osteoclast formation and activity. Through RNA-sequencing, we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro, and further, a marked upregulation of mature miR-6359 (miR-6359) in vivo was demonstrated using quantitative real-time PCR (qRT-PCR) and miR-6359 fluorescent in situ hybridization (miR-6359-FISH). Specifically, the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils, T lymphocytes, monocytes and bone marrow-derived mesenchymal stem cells (BMSCs) following VPA stimulation, which influenced osteoclast differentiation and bone-resorptive activity. Additionally, VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species (ROS) production by silencing the SIRT3 protein expression, followed by activation of the MAPK signaling pathway, which enhanced osteoclast formation and activity, thereby accelerating bone loss. Currently, there are no medications that can effectively treat VPA-induced bone loss. Therefore, we constructed engineered small extracellular vesicles (E-sEVs) targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif (CGGGAGC) in the 3'-end of the anti-miR-6359 sequence. We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss, but not on ovariectomy (OVX) and glucocorticoid-induced osteoporotic models, deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.
Topics: Female; Humans; Animals; Mice; Valproic Acid; Antagomirs; In Situ Hybridization, Fluorescence; Extracellular Vesicles; MicroRNAs
PubMed: 38246920
DOI: 10.1038/s41392-023-01726-8 -
Journal of Oral & Facial Pain and... 2022To evaluate the efficacy and safety of melatonin for migraine prophylaxis in adults. (Meta-Analysis)
Meta-Analysis
AIMS
To evaluate the efficacy and safety of melatonin for migraine prophylaxis in adults.
METHODS
After a comprehensive literature search in the MEDLINE, Cochrane Database, and International Clinical Trial Registry Platform databases, reviewers extracted data from three relevant articles. PRISMA guidelines were followed in the selection, analysis, and reporting of the findings. Quality assessment was performed using the Cochrane risk of bias assessment tool. A random-effects model was used to estimate the effect size, and meta-regression was performed for variables with a likely influence on effect size. Subgroup analysis was performed based on the comparison used in the included studies.
RESULTS
Melatonin therapy in migraine was associated with a significantly higher responder rate when compared to both placebo and standard therapy (OR = 1.84; 95% CI: 1.08 to 3.14; P = .03). The results of the meta-analyses indicated that melatonin can achieve a significant reduction in frequency of migraine attacks (MD = 1.00; 95% CI: 0.02 to 1.98; P = .04), migraine attack duration (MD = 5.02; 95% CI: 0. 91 to 9.13; P = .02), use of analgesics (MD = 1.43; 95% CI: 0.38 to 2.48; P = .008), and migraine severity (MD = 1.93; 95% CI: 1.23 to 2.63; P < .0001) over placebo, but had no significant effects in comparison to amitriptyline or valproate. There was no significant difference in the occurrence of common adverse drug reactions, such as drowsiness and fatigue, between the melatonin group and the comparison groups.
CONCLUSIONS
Melatonin showed a beneficial prophylactic role in migraine, with a better responder rate in comparison to placebo in reducing migraine severity, mean attack duration, mean attack frequency, and analgesic use, but did not show significant effects in comparison to amitriptyline or valproate.
Topics: Adult; Humans; Melatonin; Migraine Disorders; Valproic Acid; Amitriptyline; Analgesics
PubMed: 36445912
DOI: 10.11607/ofph.3211 -
Environment International Oct 2023Early-life exposure to environmental endocrine disruptors (EDCs) is a potential risk factor for autism spectrum disorder (ASD). Exposure to nonylphenol (NP), a typical...
Early-life exposure to environmental endocrine disruptors (EDCs) is a potential risk factor for autism spectrum disorder (ASD). Exposure to nonylphenol (NP), a typical EDC, is known to cause some long-term behavioural abnormalities. Moreover, these abnormal behaviours are the most frequent psychiatric co-morbidities in ASD. However, the direct evidence for the link between NP exposure in early life and ASD-like behavioural phenotypes is still missing. In the present study, typical ASD-like behaviours induced by valproic acid treatment were considered as a positive behavioural control. We investigated impacts on social behaviours following early-life exposure to NP, and explored effects of this exposure on neuronal dendritic spines, mitochondria function, oxidative stress, and endoplasmic reticulum (ER) stress. Furthermore, primary cultured rat neurons were employed as in vitro model to evaluate changes in dendritic spine caused by exposure to NP, and oxidative stress and ER stress were specifically modulated to further explore their roles in these changes. Our results indicated rats exposed to NP in early life showed mild ASD-like behaviours. Moreover, we also found the activation of ER stress triggered by oxidative stress may contribute to dendritic spine decrease and synaptic dysfunction, which may underlie neurobehavioural abnormalities induced by early-life exposure to NP.
Topics: Rats; Animals; Female; Humans; Autism Spectrum Disorder; Phenols; Valproic Acid; Neurons; Prenatal Exposure Delayed Effects; Disease Models, Animal
PubMed: 37802007
DOI: 10.1016/j.envint.2023.108228 -
Biomedicine & Pharmacotherapy =... Dec 2022Valproic acid (VPA) is a widely used antiepileptic drug, and the herbal extract of Gastrodia elata exerts an anticonvulsant effect. However, few studies have...
Valproic acid (VPA) is a widely used antiepileptic drug, and the herbal extract of Gastrodia elata exerts an anticonvulsant effect. However, few studies have investigated the pharmacokinetic and pharmacodynamic interactions between G. elata extract and VPA. We hypothesize that G. elata extract increases the VPA levels in the brain and enhances the antiepileptic effects of VPA, and this synergistic effect is mediated by transporters at the bloodbrain barrier (BBB). We performed microdialysis on pilocarpine-induced epileptic model rats in vivo to investigate this hypothesis. The results demonstrated that cotreatment with G. elata extract and VPA ameliorated drug-resistant epilepsy by increasing the VPA levels in the brain. In addition, G. elata extract and VPA exerted synergistic anticonvulsive effects to decrease the seizure severity by protecting neurons in the hippocampus and altering the DOPAC and 5-HT levels. However, these phenomena were partially blocked by the organic anion transporter peptide (OATP) inhibitor cyclosporine A (CsA; 20 mg/kg, i.p.), which demonstrated that the increase in the VPA level in the brain was modulated by the transporter OATP. This study provides a comprehensive strategy for assessing the interaction between traditional medicines and conventional antiepileptic drugs in a status epilepticus animal model.
Topics: Animals; Rats; Valproic Acid; Gastrodia; Neuroprotective Agents; Anticonvulsants; Plant Extracts; Organic Anion Transporters
PubMed: 36411625
DOI: 10.1016/j.biopha.2022.113938 -
European Review For Medical and... Dec 2021Non-Hodgkin lymphoma (NHL) is a hematological malignancy with a high rate of relapse and refractory cases. It is believed to be caused by resistance to standard... (Review)
Review
OBJECTIVE
Non-Hodgkin lymphoma (NHL) is a hematological malignancy with a high rate of relapse and refractory cases. It is believed to be caused by resistance to standard treatment modalities. Valproic acid (VPA), previously used as a broad-spectrum anticonvulsant drug, has been proposed for NHL owing to its action of epigenetic modification by inhibiting histone deacetylase. However, VPA studies on NHL are limited. This review describes the rationale behind the use of VPA for NHL treatment, particularly focusing on its molecular mechanism of action.
MATERIALS AND METHODS
This is a narrative review. The literature search strategy for indexed Scopus articles was performed randomly using PubMed and MEDLINE as the primary sources. No specific term was used.
RESULTS
Several mechanisms are responsible for NHL development. VPA can modulate these mechanisms via epigenetic and nonepigenetic modifications. It may also have an impact on the proteins responsible for treatment resistance. The mechanisms of action of VPA in NHL are as follows: the induction of cell cycle arrest via the upregulation of cyclin-dependent protein kinase inhibitors; induction of Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis; inactivation of B-cell lymphoma 6; inhibition of Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt, and nuclear factor kappa B signaling pathways; upregulation of tumor antigen as the primary target of immunotherapy; and strengthening of tumor immunosurveillance.
CONCLUSIONS
Based on its biomolecular mechanism of action, VPA appears to be a promising initial treatment before initiating the standard treatment in patients with NHL to overcome resistance.
Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Drug Resistance, Neoplasm; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Lymphoma, Non-Hodgkin; Signal Transduction; Valproic Acid
PubMed: 34919251
DOI: 10.26355/eurrev_202112_27448 -
Biology Open Jan 2023The mammalian superior colliculus and its non-mammalian homolog, the optic tectum (OT), are midbrain structures that integrate multimodal sensory inputs and guide...
The mammalian superior colliculus and its non-mammalian homolog, the optic tectum (OT), are midbrain structures that integrate multimodal sensory inputs and guide non-voluntary movements in response to prevalent stimuli. Recent studies have implicated this structure as a possible site affected in autism spectrum disorder (ASD). Interestingly, fetal exposure to valproic acid (VPA) has also been associated with an increased risk of ASD in humans and animal models. Therefore, we took the approach of determining the effects of VPA treatment on zebrafish OT development as a first step in identifying the mechanisms that allow its formation. We describe normal OT development during the first 5 days of development and show that in VPA-treated embryos, neuronal specification and neuropil formation was delayed. VPA treatment was most detrimental during the first 3 days of development and did not appear to be linked to oxidative stress. In conclusion, our work provides a foundation for research into mechanisms driving OT development, as well as the relationship between the OT, VPA, and ASD. This article has an associated First Person interview with one of the co-first authors of the paper.
Topics: Humans; Animals; Valproic Acid; Zebrafish; Superior Colliculi; Autism Spectrum Disorder; Neurogenesis; Mammals
PubMed: 36537579
DOI: 10.1242/bio.059567 -
International Journal of Molecular... Aug 2023Eosinophils function in rapid innate immune responses and allergic reactions. Recent research has raised the possibility that the histone deacetylase inhibitor valproic...
Eosinophils function in rapid innate immune responses and allergic reactions. Recent research has raised the possibility that the histone deacetylase inhibitor valproic acid (VPA) may be a promising therapeutic agent for treatment of allergic responses and certain cancers. However, its effects on eosinophils remain unclear. Utilizing the EoL-1 human eosinophil cell line as a model, we investigated the effects of VPA on oxidative stress- and autophagy-mediated immune responses. We found that VPA induced reactive oxidative species (ROS) generation and eosinophil activation without affecting cell viability. Moreover, VPA treatment suppressed the negative regulator of antioxidant transcription factor Nrf2, which is known to activate antioxidant defense. Interestingly, VPA was able to increase autophagic markers, as well as NLRP3 and NLRC4 mRNA activation, in Eol-1 cells in a dose-dependent manner. Collectively, our results indicate that VPA could increase the severity of allergic responses, and if so, it clearly would not be a suitable drug for the treatment of allergic reactions. However, VPA does have the potential to induce autophagy and to regulate the inflammatory responses via inflammasome-driven caspase-1 deactivation in a dose-dependent manner.
Topics: Humans; Valproic Acid; Antioxidants; Oxidative Stress; Inflammation; Autophagy; Hypersensitivity
PubMed: 37686250
DOI: 10.3390/ijms241713446 -
Biomedicine & Pharmacotherapy =... Feb 2023In many countries, valproate is indicated for epilepsy only, whereas its derivative divalproex (DVP) and valpromide (VPM) are indicated for bipolar disorders only. DVP... (Review)
Review
In many countries, valproate is indicated for epilepsy only, whereas its derivative divalproex (DVP) and valpromide (VPM) are indicated for bipolar disorders only. DVP is composed of sodium valproate and valproic acid (VA) in a 1:1 molar ratio and VPM is a prodrug completely hydrolyzed in the gastric tract to VA. Whatever the drug, the absorbed and active substance is the valproate ion. In this article, we reviewed the potential reasons that might justify these different indications. We performed a literature review of comparative studies of efficacy, pharmacokinetic parameters, side effects and costs for VPA, DVP, and VPM. We found only studies comparing VA with DVP. None of the eight efficacy studies found differences in epilepsy or mood disorders. The ten studies of side effects reported a difference in terms of gastrointestinal effects, but inconsistently. The United States (US) summary of product characteristics and kinetic comparison studies reported bioequivalence between DVP and VA, but a longer Tmax for DVP, likely due to its gastro-resistant galenic form. VPM summary of product characteristics and pharmacokinetic studies revealed a lower bioavailability (80% vs. 100% for VA) and a delayed Tmax. There is an additional cost for using DVP or VPM as compared to VA (respectively +177% and +77% in France). The differences in indications between valproate derivatives do not seem justified. Interchangeability between VA and DVP in bipolar disorders seems possible, at identical dosage. VPM would require a closer dosing schedule and a 20% reduction in dosage when switching to valproate.
Topics: Humans; Valproic Acid; Bipolar Disorder; Epilepsy; Drug-Related Side Effects and Adverse Reactions
PubMed: 36521249
DOI: 10.1016/j.biopha.2022.114051