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Environmental Toxicology Oct 2023Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by restrictive and repetitive behavior followed by impairment in social,...
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by restrictive and repetitive behavior followed by impairment in social, verbal, and non-verbal interaction and communication. Valproic acid (VPA) is a well-known anti-epileptic drug, but its prenatal exposure to animals causes social impairment, neurotransmitters imbalance, and neuroinflammation with ASD-like phenotypes. Syringic acid (SA) is a polyphenolic compound with anti-inflammatory, anti-apoptotic, antioxidant, and neuromodulator activity. The purpose of study was to investigate the protective effect of Syringic acid (SA) in prenatal VPA-treated rats through behavioral, neuroinflammation, oxidative stress, neurotransmitters, neuronal integrity, and apoptotic marker. Single dose of VPA was administered 600 mg/kg, i.p. on a gestational day (GD) 12th and SA was administrated from PnD 26th to 54th at the dose of 25, 50, and 100 mg/kg, p.o. On PnD 56th behavioral parameters (Pain sensitivity, open field test, narrow beam walks test and social impairment test) were performed and all animals were sacrificed, and brain tissue was isolated for oxidative stress (GSH, CAT, and LPO), neuroinflammation (TNF-α and IL-6) and neurotransmitters (GABA and Glutamate), histopathology (H&E, Nissl), immunohistochemistry (p38 MAPK) analysis. Rat treated with SA dose-dependently prevented behavioral alteration, restored antioxidant enzymes, neurotransmitters level, decreased neuroinflammatory markers, and improved neuronal integrity. Furthermore, immunohistochemistry confirmed the reduced p38 MAPK marker expression by SA in VPA induced autistic behavior.
Topics: Pregnancy; Female; Rats; Animals; Humans; Valproic Acid; Autistic Disorder; Autism Spectrum Disorder; Antioxidants; p38 Mitogen-Activated Protein Kinases; Neuroinflammatory Diseases; Rats, Wistar; Prenatal Exposure Delayed Effects; Disease Models, Animal; Behavior, Animal
PubMed: 37357844
DOI: 10.1002/tox.23876 -
American Journal of Obstetrics &... Jan 2024Risk mitigation for most teratogenic medications relies on risk communication via drug label, and prenatal exposures remain common. Information on the types of and risk...
BACKGROUND
Risk mitigation for most teratogenic medications relies on risk communication via drug label, and prenatal exposures remain common. Information on the types of and risk factors for prenatal exposures to medications with teratogenic risk can guide strategies to reduce exposure.
OBJECTIVE
This study aimed to identify medications with known or potential teratogenic risk commonly used during pregnancy among privately insured persons.
STUDY DESIGN
We used the Merative™ MarketScan® Commercial Database to identify pregnancies with live or nonlive (ectopic pregnancies, spontaneous and elective abortions, stillbirths) outcomes among persons aged 12 to 55 years from 2011 to 2018. Start/end dates of medication exposure and pregnancy outcomes were identified via an adapted algorithm based on validation studies. We required continuous health plan enrollment from 90 days before conception until 30 days after the pregnancy end date. Medications with known or potential teratogenic risk were selected from TERIS (Teratogen Information System) and drug monographs based on the level of risk and quality of evidence (138 with known and 60 with potential risk). We defined prenatal exposure on the basis of ≥1 outpatient pharmacy claim or medical encounter for medication administration during target pregnancy periods considering medication risk profiles (eg, risk only in the first trimester or at a certain dose threshold). Sex hormones and hormone analogs, and abortion and postpartum/abortion hemorrhage treatments were not considered as teratogenic medications because of challenges in separating pregnancy-related indications, nor were opioids (because of complex risk-benefit considerations) or antiobesity medications if their only teratogenic mechanism was weight loss.
RESULTS
Among all pregnancies, the 10 medications with known teratogenic risk and the highest prenatal exposures were sulfamethoxazole/trimethoprim (1988 per 100,000 pregnancy-years), high-dose fluconazole (1248), topiramate (351), lisinopril (144), warfarin (57), losartan (56), carbamazepine (50), valproate (49), vedolizumab (28 since 2015), and valsartan (25). Prevalence of exposure to sulfamethoxazole/trimethoprim decreased from 2346 to 1453 per 100,000 pregnancy-years from 2011 to 2018, but prevalence of exposure to vedolizumab increased 6-fold since its approval in 2015. Prenatal exposures in the first trimester were higher among nonlive pregnancies than among live-birth pregnancies, with the largest difference observed for warfarin (nonlive 370 vs live birth 78), followed by valproate (258 vs 86) and topiramate (1728 vs 674). Prenatal exposures to medications with potential teratogenic risk were most prevalent for low-dose fluconazole (6495), metoprolol (1325), and atenolol (448). The largest first-trimester exposure differences between nonlive and live-birth pregnancies were observed for lithium (242 vs 89), gabapentin (1639 vs 653), and duloxetine (1914 vs 860). Steady increases in hydralazine and gabapentin exposures were observed during the study years, whereas atenolol exposure decreased (561 to 280).
CONCLUSION
Several medications with teratogenic risk for which there are potentially safer alternatives continue to be used during pregnancy. The fluctuating rates of prenatal exposure observed for select teratogenic medications suggest that regular reevaluation of risk mitigation strategies is needed. Future research focusing on understanding the clinical context of medication use is necessary to develop effective strategies for reducing exposures to medications with teratogenic risk during pregnancy.
Topics: Pregnancy; Female; Humans; United States; Teratogens; Valproic Acid; Topiramate; Prenatal Exposure Delayed Effects; Gabapentin; Warfarin; Atenolol; Fluconazole; Sulfamethoxazole; Trimethoprim
PubMed: 38061552
DOI: 10.1016/j.ajogmf.2023.101245 -
World Neurosurgery Feb 2024To systematically evaluate the efficacy of valproic acid (VPA) in rats with spinal cord injury (SCI) to reduce the risk of clinical conversion and provide a valuable... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To systematically evaluate the efficacy of valproic acid (VPA) in rats with spinal cord injury (SCI) to reduce the risk of clinical conversion and provide a valuable reference for future animal and clinical studies.
METHODS
We searched scientific databases, including PubMed, Ovid-Embase, Web of Science, and Scopus databases. The relevant literature was searched from the establishment date of the database to June 28, 2023. The search results were screened, data were extracted, and the quality of the literature was evaluated independently by 2 reviewers.
RESULTS
Among 656 nonduplicated references, 14 articles were included for meta-analysis. The summary results showed that the overall Basso, Beattie and Bresnahan scores of the VPA intervention group were significantly higher than those in the control group at 1-6 weeks after VPA intervention. Subgroup analysis showed that the injury model, administration dose, rat strain, country of study, or follow-up duration had no significant effect on the efficacy of VPA on rats with SCI. In addition, mesh analysis showed that high doses of the VPA group had a better effect on SCI rats, compared with the low dose group and the medium dose group.
CONCLUSIONS
To date, this is the first systematic evaluation of the potential effects of VPA on motor recovery in rats with SCI. We concluded that VPA can promote motor recovery in rats with SCI, and higher doses of VPA seem to be more effective in rats with SCI. However, the limited quality and sample of included studies reduced the application of this meta-analysis. In the future, more high-quality, direct comparative studies are needed to explore this issue in depth.
Topics: Rats; Animals; Valproic Acid; Spinal Cord Injuries; Spinal Cord; Recovery of Function; Disease Models, Animal
PubMed: 37923014
DOI: 10.1016/j.wneu.2023.10.135 -
Clinical and Experimental Pharmacology... Sep 2023Skeletal muscles in animal models of Duchenne muscular dystrophy (DMD) are more susceptible to contraction-induced functional loss, which is not related to fatigue....
Skeletal muscles in animal models of Duchenne muscular dystrophy (DMD) are more susceptible to contraction-induced functional loss, which is not related to fatigue. Valproic acid (VPA) reportedly improves serological and histological markers of damage in dystrophin-deficient murine muscle. Here, we tested whether VPA would reduce the susceptibility to contraction-induced functional loss in two murine DMD models. Adult female mdx (mild) and D2-mdx (severe) DMD murine models were administered VPA (240 mg/kg) or saline for 7 days. Some VPA-treated mdx mice also performed voluntary running in a wheel, which is known to reduce the susceptibility to contraction-induced functional loss; that is, isometric force drop following eccentric contractions. In situ muscle function was assessed before, during and after eccentric contractions. Muscle utrophin and desmin expression were also evaluated using immunoblotting. Interestingly, VPA reduced the isometric force drop following eccentric contractions in both murine models, without change in the relative eccentric maximal force and in the expression of utrophin and desmin. VPA for 7 days combined with voluntary running had no additive effect compared to VPA alone. Furthermore, VPA reduced the absolute isometric maximal force before eccentric contractions in both murine models. The results of our study indicated that VPA in both murine DMD models reduced the susceptibility to contraction-induced functional loss but increased muscle weakness.
Topics: Female; Animals; Mice; Muscular Dystrophy, Duchenne; Valproic Acid; Mice, Inbred mdx; Utrophin; Disease Models, Animal; Desmin; Muscle Contraction; Muscle, Skeletal
PubMed: 37381823
DOI: 10.1111/1440-1681.13804 -
Journal of Breath Research Sep 2023Therapeutic drug monitoring (TDM) of medications with a narrow therapeutic window is a common clinical practice to minimize toxic effects and maximize clinical outcomes....
Therapeutic drug monitoring (TDM) of medications with a narrow therapeutic window is a common clinical practice to minimize toxic effects and maximize clinical outcomes. Routine analyses rely on the quantification of systemic blood concentrations of drugs. Alternative matrices such as exhaled breath are appealing because of their inherent non-invasive nature. This is especially the case for pediatric patients. We have recently showcased the possibility of predicting systemic concentrations of valproic acid (VPA), an anti-seizure medication by real-time breath analysis in two real clinical settings. This approach, however, comes with the limitation of the patients having to physically exhale into the mass spectrometer. This restricts the possibility of sampling from patients not capable or available to exhale into the mass spectrometer located on the hospital premises. In this work, we developed an alternative method to overcome this limitation by collecting the breath samples in customized bags and subsequently analyzing them by secondary electrospray ionization coupled to high-resolution mass spectrometry (SESI-HRMS). A total of= 40 patients (mean ± SD, 11.5 ± 3.5 y.o.) diagnosed with epilepsy and taking VPA were included in this study. The patients underwent three measurements: (i) serum concentrations of total and free VPA, (ii) real-time breath analysis and (iii) off-line analysis of exhaled breath collected in bags. The agreement between the real-time and the off-line breath analysis methods was evaluated using Lin's concordance correlation coefficient (CCC). CCC was computed for ten mass spectral predictors of VPA concentrations. Lin's CCC was >0.6 for all VPA-associated features, except for two low-signal intensity isotopic peaks. Finally, free and total serum VPA concentrations were predicted by cross validating the off-line data set. Support vector machine algorithms provided the most accurate predictions with a root mean square error of cross validation of 29.0 ± 7.4 mg land 3.9 ± 1.4 mg lfor total and free VPA (mean ± SD), respectively. As a secondary analysis, we explored whether exhaled metabolites previously associated with side-effects and response to medication could be rendered by the off-line analysis method. We found that five features associated with side effects showed a CCC > 0.6, whereas none of the drug response-associated peaks reached this cut-off. We conclude that the clinically relevant free fraction of VPA can be predicted by this combination of off-line breath collection with rapid SESI-HRMS analysis. This opens new possibilities for breath based TDM in clinical settings.
Topics: Humans; Adolescent; Child; Female; Valproic Acid; Breath Tests; Algorithms; Body Fluids; Breast Neoplasms
PubMed: 37678210
DOI: 10.1088/1752-7163/acf782 -
Drug Metabolism and Disposition: the... Feb 2024Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is... (Observational Study)
Observational Study
Association of Valproic Acid and Its Main Metabolites' Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring.
Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 μg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 μg/mL versus 4.83 μg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA.
Topics: Humans; Anticonvulsants; Chemical and Drug Induced Liver Injury; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Retrospective Studies; Valproic Acid
PubMed: 38195521
DOI: 10.1124/dmd.123.001539 -
Archives of Razi Institute Aug 2023Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological...
Ginseng is known as the king of all herbs in terms of antioxidant and anti-inflammatory activities and recently has become more involved in the treatment of neurological diseases. In this regard, this study aimed to determine the effects of on pentylenetetrazol-induced epilepsy during the estrus cycle. For this purpose, 30 rats were randomly divided into five groups, namely control (saline), valproic acid (VPA, 75 mg/kg), (50 mg/kg), (100 mg/kg), and (150 mg/kg) with four subgroups (proestrus, estrus, metestrus, and diestrus). Subsequently, the initiation time of myoclonic seizures (ITMS), initiation time of tonic-clonic seizures (ITTS), and seizure duration (SD) were determined. According to the results, ITMS and ITTS significantly increased in the VPA-treated group (<0.05). (100 and 150 mg/kg) administration significantly increased ITMS and ITTS (<0.05). Moreover, the ITMS and ITTS in -treated rats were significantly higher in luteal phases, compared to the follicular phase (<0.05). In addition, pretreatment with VPA significantly decreased SD, compared to the control group (<0.05). A significant decrease in SD was observed in the rats pretreated with (100 and 150 mg/kg) (<0.05). Seizure duration significantly decreased in animals that received in luteal phases, compared to the follicular phase (<0.05). These results suggested that have anticonvulsant effects that are more prominent during the luteal phase than the follicular phase.
Topics: Animals; Female; Rats; Anticonvulsants; Estrus; Ginsenosides; Pentylenetetrazole; Seizures; Valproic Acid
PubMed: 38226383
DOI: 10.32592/ARI.2023.78.4.1359 -
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 -
European Journal of Pharmacology Sep 2023Several reports indicate a plausible role of calcium (Ca) permeable AMPA glutamate receptors (with RNA hypo-editing at the GluA2 Q/R site) and the subsequent...
Several reports indicate a plausible role of calcium (Ca) permeable AMPA glutamate receptors (with RNA hypo-editing at the GluA2 Q/R site) and the subsequent excitotoxicity-mediated neuronal death in the pathogenesis of a wide array of neurological disorders including autism spectrum disorder (ASD). This study was designed to examine the effects of chronic risperidone treatment on the expression of adenosine deaminase acting on RNA 2 (Adar2), the status of AMPA glutamate receptor GluA2 editing, and its effects on oxidative/nitrosative stress and excitotoxicity-mediated neuronal death in the prenatal valproic acid (VPA) rat model of ASD. Prenatal VPA exposure was associated with autistic-like behaviors accompanied by an increase in the apoptotic marker "caspase-3" and a decrease in the antiapoptotic marker "BCL2" alongside a reduction in the Adar2 relative gene expression and an increase in GluA2 Q:R ratio in the hippocampus and the prefrontal cortex. Risperidone, at doses of 1 and 3 mg, improved the VPA-induced behavioral deficits and enhanced the Adar2 relative gene expression and the subsequent GluA2 subunit editing. This was reflected on the cellular level where risperidone impeded VPA-induced oxidative/nitrosative stress and neurodegenerative changes. In conclusion, the present study confirms a possible role for Adar2 downregulation and the subsequent hypo-editing of the GluA2 subunit in the pathophysiology of the prenatal VPA rat model of autism and highlights the favorable effect of risperidone on reversing the RNA editing machinery deficits, giving insights into a new possible mechanism of risperidone in autism.
Topics: Animals; Female; Pregnancy; Rats; Adenosine Deaminase; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Glutamic Acid; Receptors, AMPA; Risperidone; RNA; RNA Editing; Valproic Acid
PubMed: 37460052
DOI: 10.1016/j.ejphar.2023.175916 -
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