Brain and plasma amino acid concentration in infant rats prenatally exposed to valproic acid

Puig-Lagunes, Ángel Alberto; Rocha, Luísa; Morgado-Valle, Consuelo; Beltran-Parrazal, Luis; López‐Meraz, María Leonor

doi:10.1590/0001-3765202120190861

Cited by 7 publications

(8 citation statements)

References 56 publications

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“…It is the main excitatory neurotransmitter and the precursor of the main inhibitory neurotransmitter, GABA, in the central nervous system. 37 Increased glutamate in this study was consistent with the findings from a previous study by Puig-Lagunes et al 38 Glutamate dehydrogenase (GDH) is a key enzyme in glutamate metabolism and is directly involved in the onset and progression of epilepsy. It is an important regulatory enzyme for maintaining the appropriate balance of glutamate and GABA levels, and it helps regulate neuronal excitability.…”

Section: Discussionsupporting

confidence: 92%

Comprehensive Analysis of Metabolic Changes in Male Mice Exposed to Sodium Valproate Based on GC-MS Analysis

Gao¹,

Jiang²,

Wang³

et al. 2022

DDDT

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Purpose Sodium valproate (VPA) is the most widely used broad-spectrum antiepileptic first-line drug in clinical practice and is effective against various types of epilepsy. However, VPA can induce severe cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity, which limits its use. Metabolomic studies of VPA-induced toxicity have focused primarily on changes in serum and urine metabolites but have not evaluated changes in major organs or tissues. Methods Central target tissues (intestine, lung, liver, hippocampus, cerebral cortex, inner ear, spleen, kidney, heart, and serum) were analyzed using gas chromatography mass spectrometry to comprehensively evaluate VPA toxicity in mouse models. Results Multivariate analyses, including orthogonal projections of the latent structure and Student’s t test, indicated that depending on the matrix used in the study (the intestine, lung, liver, hippocampus, cerebral cortex, inner ear, spleen, kidney, heart or serum) the number of metabolites differed, the lung being the poorest and the kidney the richest in number. Conclusion These metabolites were closely related and were found to participate in 12 key pathways related to amino acid, fatty acid, and energy metabolism, revealing that the toxic mechanism of VPA may involve oxidative stress, inflammation, amino acid metabolism, lipid metabolism, and energy disorder.

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Section: Discussionsupporting

confidence: 92%

Comprehensive Analysis of Metabolic Changes in Male Mice Exposed to Sodium Valproate Based on GC-MS Analysis

Gao¹,

Jiang²,

Wang³

et al. 2022

DDDT

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“…According to a study investigating the prefrontal cortex and the cerebellum of non-human primates, VPA inhibits neurogenesis, disrupts network formation and promotes astrocyte production during embryo development (Zhao et al, 2019). Furthermore, in the HC increased glutamate (Glu) concentrations were reported in rodents (Zieminska et al, 2018) which is consistent with the detection of significantly higher levels of Glu in HC among several brain areas of ASD patients (Puig-Lagunes et al, 2021).…”

Section: Discussionmentioning

confidence: 67%

“…It is interesting though, that in case of males this increase in sEPSC frequency occurred in the 3-month-olds while there were no changes indicating the decreased number of pyramidal cells in the younger animals like in case of female ones. In a study measuring the plasma concentration of 14-day-old rats, it was reported that Glu levels were higher in the HC of female rats exposed to VPA compared to controls but there were no such changes in case of males (Puig-Lagunes et al, 2021). However, other experiments suggest that the concentration of Glu is increased in male HC after VPA-treatment in 31day-old rats as well (Zieminska et al, 2018).…”

Section: Discussionmentioning

confidence: 98%

“…Therefore, it would be beneficial to investigate the interneurons since GABAergic system dysregulation, including decreased number of GABAergic interneurons and impaired GABAergic neurotransmission, has been proposed as a source of E/I imbalance in the HC, as well. To support this idea, the expression of glutamic acid decarboxylase (GAD67), an enzyme responsible for the synthesis of GABA from glutamate (Puig-Lagunes et al, 2021), was measured in different brain areas of VPA-treated young and adolescent male rats. As suspected, significant decrease in the GAD67 levels was found in the HC in all age groups investigated from postnatal day 7 and 72 (Hou et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Alterations of the Hippocampal Networks in Valproic Acid-Induced Rat Autism Model

Bódi

Májer

Kelemen

et al. 2022

Front. Neural Circuits

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Autism Spectrum Disorder (ASD) is one of the most frequently diagnosed neurodevelopmental disorders, characterized among others by impairments in social interactions and repetitive behavior. According to one of the leading hypotheses about its origin, ASD is caused by the imbalance of excitatory and inhibitory circuit activity. ASD-related morphological and functional changes can be observed in several brain regions i.e., in the prefrontal cortex and the hippocampus. It is well-established that prenatal valproic-acid (VPA) exposure of rats on day 12.5 leads to neurodevelopmental alterations with autism-like clinical and behavioral symptoms. The aim of this study was to investigate potential changes in the excitability of neuronal networks and individual neurons of the hippocampus elicited by prenatal VPA treatment. As there are marked sex differences in ASD, offspring of both sexes were systematically tested, using two different age groups, to elucidate eventual differences in neurodevelopment after VPA treatment. Excitatory connections and long-term synaptic plasticity as well as intrinsic excitability of CA1 pyramidal cells were examined. Pregnant female Wistar rats received saline or 500 mg/kg VPA i. p. on gestation day 12.5. Brain slices of 6-week-old and 3-month-old offspring were investigated using extra- and intracellular electrophysiological techniques. Field potential- and whole-cell patch clamp recordings were carried out to measure network excitability and single cell activity in the CA1 region hippocampus. Enhanced excitability of hippocampal networks was detected in the 6-week-old VPA-treated male rats; however, this change could not be observed in 3-month-old males. Intrinsic excitability of single neurons, however, was increased in 3-month-old males. In 6-week-old treated females, the most prominent effect of VPA was an increase in voltage sag, to a similar degree to the neurons of the older age group. In 3-month-old females, a network excitability increase could be demonstrated, in a lesser degree than in younger males. It can be concluded, that VPA treatment had diverse effects on hippocampal excitability depending on the sex and the age of the animals. We found that certain alterations manifested in 6-week-old rats were compensated later, on the other hand, other changes persisted until the age of 3 months.

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“…It is for this reason that the results of the present study are not extensively discussed using neurobehavioral findings of the VPA rodent model of ASD ( Schneider and Przewłocki, 2005 ; Snow et al, 2008 ; Martin and Manzoni, 2014 ). Also, VPA-induced impairment of inhibitory and excitatory neurotransmission takes place in different brain regions, including the cortex, striatum, hippocampus, amygdala, and cerebellum ( Biggs et al, 1992 ; Peichev, 1992 ; Löscher, 1993 ; Olexová et al, 2016 ; Puig-Lagunes et al, 2021 ; Kuo and Liu, 2022 ), which may be associated with a poor behavioral outcome. However, in the model of prenatal exposure to VPA, the offspring is indirectly exposed and these neurochemical findings cannot explain the behavioral characteristics.…”

Section: Discussionmentioning

confidence: 99%

The influence of continuous prenatal exposure to valproic acid on physical, nociceptive, emotional and psychomotor responses during adolescence in mice: Dose-related effects within sexes

Podgorac

Sekulić

Petković

et al. 2022

Front. Behav. Neurosci.

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Clinical findings show that the use of valproic acid (VPA) during pregnancy increases the risk of birth defects and autism spectrum disorder in offspring. Although there is a consensus that monitoring of potential long-term outcomes of VPA exposure is needed, especially in undiagnosed individuals, preclinical studies addressing this issue are rare. The present study examined the effects of continuous intrauterine exposure to a wide dose range of VPA (50, 100, 200, and 400 mg/kg/day) on the physical and behavioral response in peripubertal mice as a rodent model of adolescence. Body weight and the hot plate test [on postnatal days (PND) 25 and 32], the elevated plus-maze test (on PND35), and the open field test (on PND40) served to examine physical growth, the supraspinal reflex response to a painful thermal stimulus and conditional learning, anxiety-like/risk-assessment behavior, as well as novelty-induced psychomotor activity, respectively. VPA exposure produced the following responses: (i) a negative effect on body weight, except for the dose of 100 mg/kg/day in both sexes; (ii) an increase in the percentage of animals that responded to the thermal stimulus above the defined cut-off time interval and the response latency in both sexes; (iii) dose-specific changes within sexes in behavior provoked by a novel anxiogenic environment, i.e., in females less anxiety-like/risk-assessment behavior in response to the lowest exposure dose, and in males more pronounced anxiety-like/risk-assessment behavior after exposure to the highest dose and 100 mg/kg/day; (iv) dose-specific changes within sexes in novelty-induced psychomotor activity, i.e., in females a decrease in stereotypy-like activity along with an increase in rearing, and in males a decrease in stereotypy-like activity only. These findings show that continuous intrauterine exposure to VPA produces maladaptive functioning in different behavioral domains in adolescence and that the consequences are delicate to assess as they are dose-related within sexes.

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Brain and plasma amino acid concentration in infant rats prenatally exposed to valproic acid

Cited by 7 publications

References 56 publications

Comprehensive Analysis of Metabolic Changes in Male Mice Exposed to Sodium Valproate Based on GC-MS Analysis

Comprehensive Analysis of Metabolic Changes in Male Mice Exposed to Sodium Valproate Based on GC-MS Analysis

Alterations of the Hippocampal Networks in Valproic Acid-Induced Rat Autism Model

The influence of continuous prenatal exposure to valproic acid on physical, nociceptive, emotional and psychomotor responses during adolescence in mice: Dose-related effects within sexes

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