Effects of Histone Deacetylase Inhibitors on the Development of Epilepsy and Psychiatric Comorbidity in WAG/Rij Rats

Citraro, Rita; Leo, Antonio; De, Carmen; Nesci, Valentina; Cantafio, Maria Eugenia Gallo; Amodio, Nicola; Raso, Giuseppina Mattace; Lama, Adriano; Russo, Roberto; Calignano, Antonio; Tallarico, Martina; Russo, Emilio; Sarro, Giovambattista De

doi:10.1007/s12035-019-01712-8

Cited by 65 publications

(44 citation statements)

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“…70,72 Here, NaB counteracts the hepatic histopathological alterations, inflammation, and nitrosative stress related to chronic VPA treatment, highlighting its anti-inflammatory profile. Very recently, these data were published, 73 demonstrating that both VPA and NaB show anti-epileptogenic property, and that their effects on absences increased when co-administered. 20 We also evaluated the effects of VPA alone or in combination with NaB on animal behavior determining seizures and epileptogenesis in WAG/Rij rats.…”

Section: Discussionmentioning

confidence: 97%

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

et al. 2019

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Sodium valproate (VPA), an antiepileptic drug, may cause dose-and time-dependent hepatotoxicity. However, its iatrogenic molecular mechanism and the rescue therapy are disregarded. Recently, it has been demonstrated that sodium butyrate (NaB) reduces hepatic steatosis, improving respiratory capacity and mitochondrial dysfunction in obese mice. Here, we investigated the protective effect of NaB in counteracting VPA-induced hepatotoxicity using in vitro and in vivo models. Human HepG2 cells and primary rat hepatocytes were exposed to high VPA concentration and treated with NaB. Mitochondrial function, lipid metabolism, and oxidative stress were evaluated, using Seahorse analyzer, spectrophotometric, and biochemical determinations.Liver protection by NaB was also evaluated in VPA-treated epileptic WAG/Rij rats, receiving NaB for 6 months. NaB prevented VPA toxicity, limiting cell oxidative and mitochondrial damage (ROS, malondialdehyde, SOD activity, mitochondrial bioenergetics), and restoring fatty acid oxidation (peroxisome proliferator-activated receptor α expression and carnitine palmitoyl-transferase activity) in HepG2 cells, primary hepatocytes, and isolated mitochondria. In vivo, NaB confirmed its activity normalizing hepatic biomarkers, fatty acid metabolism, and reducing inflammation and fibrosis induced by VPA. These data support the protective potential of NaB on VPA-induced liver injury, indicating it as valid therapeutic approach in counteracting this common side effect due to VPA chronic treatment. K E Y W O R D Santiepileptic drug, hepatotoxicity, lipid metabolism, mitochondrial dysfunction, oxidative stress, shortchain fatty acid | 677 PIROZZI et al. | 679 PIROZZI et al. incubated with tert-Butyl hydroperoxide (100 µM) plus H 2 O 2 for 3 hours. The fluorescence measurements were performed with aHTS-7000 Plus plate reader spectrofluorometer (Perkin Elmer, Wellesley, MA, USA) at 485 nm for excitation and 525 nm for emission wavelengths. ROS were quantified as percentage vs control unstimulated cells.

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Section: Discussionmentioning

confidence: 97%

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

et al. 2019

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“…In this study, we apply instrumented home-cage monitoring (Loos et al, 201 015;Robinson et al, 2018;Jankovic et al, 2019) to non-invasively and unobtrusively assess the psychopharmacology of adult and prenatal VPA exposure in C57BL/6J mice. As opposed to VPA injections applied during specific gestational windows (Roullet et al, 2013;Nicolini and Fahnestock, 2018) or administered acutely to demonstrate acute seizure protection (Nau and Loscher, 1982;Watanabe et al, 2010), we apply VPA enterally, dissolved in drinking water (Loscher and Nau, 1982;Frisch et al, 2009;Smeland et al, 2012;De Caro et al, 2019;Citraro et al, 2020). By combining undisturbed recordings of spontaneous behavior with carefully selected provocative maneuvers, we illustrate an ethologically sound approach to ascertain drug-induced changes in specific behavioral domains (e.g., feeding, sheltering, etc.)…”

Section: Introductionmentioning

confidence: 99%

On the Digital Psychopharmacology of Valproic Acid in Mice

et al. 2020

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Antiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anxiety, anger and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity. In this study, we applied instrumented home-cage monitoring to assess how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. Through a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior. At 500-600 mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied to breeder pairs of mice throughout gestation, VPA prolonged the latency to viable litters without affecting litter size. Two-weeks old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior. Together, these data illustrate how automated home-cage assessments of spontaneous behavior capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating such rigorous assessments of psychological tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring.

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“…Thus, rather than aim for a specific plasma or brain concentration, we began by exploring the effects of VPA dissolved in drinking water (o.s.) at a dose range of ~500-600mg/kg/d, previously demonstrated to provide some seizure protection in rodent models [35][36][37][38] . 8-9week old C57BL/6J mice were admitted to BMU home-cage chambers fitted with a single lickometered water source (0.8% sucrose drinking water), an infrared-lucent shelter and food hopper (fitted to sense beam breaks).…”

Section: On the Initiation Of Valproic Acid Therapymentioning

confidence: 99%

“…In this study, we apply instrumented home-cage monitoring 32 to noninvasively and unobtrusively assess the psychopharmacology of adult and prenatal VPA exposure in C57BL/6J mice. As opposed to VPA injections applied during specific gestational windows 25,26 or administered acutely to demonstrate acute seizure protection 33,34 , we apply VPA enterally, dissolved in drinking water [35][36][37][38][39] . By combining undisturbed recordings of spontaneous behavior with standardized provocative maneuvers, we illustrate an ethologically sound approach to ascertain drug-induced changes in specific domains of behavior (e.g., feeding, sheltering, etc.)…”

Section: Introductionmentioning

confidence: 99%

On the Digital Psychopharmacology of Valproic Acid in Mice

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ObjectiveAntiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anger, anxiety and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor developmental delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity.MethodsUsing instrumented home-cage monitoring, we assessed how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. By utilizing a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior.ResultsAt 500-600mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied chronically to breeder pairs of mice, VPA prolonged the latency to viable litters without affecting litter size. Two-week old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior.InterpretationThrough automated home-cage assessments of C57BL/6J mice, we capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating rigorous comprehensive assessments of neuropsychiatric tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring.

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Effects of Histone Deacetylase Inhibitors on the Development of Epilepsy and Psychiatric Comorbidity in WAG/Rij Rats

Cited by 65 publications

References 74 publications

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

On the Digital Psychopharmacology of Valproic Acid in Mice

On the Digital Psychopharmacology of Valproic Acid in Mice

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