Differential Gene Expression Profile Induced by Valproic Acid (VPA) in Pediatric Epileptic Patients

Floriano-Sánchez, Esaú; Brindis, Fernando; Ortega-Cuéllar, Daniel; Ignacio-Mejía, Iván; Moreno-Arriola, Elizabeth; Romero-Morelos, Pablo; Ceballos-Vasquez, Edgar; Córdova-Espinoza, María Guadalupe; Arregoitia-Sarabia, Cindy Karel; Sandoval-Pacheco, Roberto; Carmona-Aparicio, Liliana; Cárdenas-Rodríguez, Noemi

doi:10.3390/genes9070328

Cited by 12 publications

(12 citation statements)

References 40 publications

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“…In the present study, most of the DEGs were implicated in the immune and inflammatory response, and associated with cytokine-cytokine receptor interactions, as also identified in epileptic patients by Floriano-Sánchez et al (32). Inflammation is increasingly recognized as an important pathogenetic factor in epilepsy.…”

Section: Discussionsupporting

confidence: 81%

“…Subjects aged from 0 to 18 years were enrolled at the Children's Hospital of Fudan University (Shanghai, China) between July 2016 and May 2018. Each patient was evaluated according to the inclusion and exclusion criteria (32). The inclusion criteria were as follows: Pediatric patients diagnosed with epilepsy or an epileptic syndrome and administration of VPA for at least one year.…”

Section: Methodsmentioning

confidence: 99%

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RNA‑seq analysis of blood of valproic acid‑responsive and non‑responsive pediatric patients with epilepsy

Wang

2019

Exp Ther Med

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Epilepsy is the most common chronic neurological disorder, affecting ~70 million individuals worldwide. However, approximately one-third of the patients are refractory to epilepsy medication. Of note, 100% of patients with genetic epilepsy who are resistant to the traditional drug, valproic acid (VPA), are also refractory to the other anti-epileptic drugs. The aim of the present study was to compare the transcriptomes in VPA responders and non-responders, to explore the mechanism of action of VPA and identify possible biomarkers to predict VPA resistance. Thus, RNA-seq was employed for transcriptomic analysis, differentially expressed genes (DEGs) were analyzed using Cuffdiff software and the DAVID database was used to infer the functions of the DEGs. A protein-protein interaction network was obtained using STRING and visualized with Cytoscape. A total of 389 DEGs between VPA-responsive and non-responsive pediatric patients were identified. Of these genes, 227 were upregulated and 162 were downregulated. The upregulated DEGs were largely associated with cytokines, chemokines and chemokine receptor-binding factors, whereas the downregulated DEGs were associated with cation channels, iron ion binding proteins, and immunoglobulin E receptors. In the pathway analysis, the toll-like receptor signaling pathway, pathways in cancer, and cytokine-cytokine receptor interaction were mostly enriched by the DEGs. Furthermore, three modules were identified by protein-protein interaction analysis, and the potential hub genes, chemokine (C-C motif) ligand 3 and 4, chemokine (C-X-C motif) ligand 9, tumor necrosis factor-α and interleukin-1β, which are known to be closely associated with epilepsy, were identified. These specific chemokines may participate in processes associated with VPA resistance and may be potential biomarkers for monitoring the efficacy of VPA.

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Section: Discussionsupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

RNA‑seq analysis of blood of valproic acid‑responsive and non‑responsive pediatric patients with epilepsy

Wang

2019

Exp Ther Med

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“…Experimental and clinical studies show that epilepsy is characterized by many pathogenic mechanisms primarily related to functional alterations in neuronal and neurovascular units and by an imbalance between excitatory (glutamate) and inhibitory ( γ -aminobutyric acid) neurotransmission [7, 8]. Recently, using microarray technology, our group showed that the immune response, inflammation, and oxidative stress (OS) pathways are mainly activated in Mexican epileptic children [9]. Antiepileptic drugs (AEDs) are used to treat epilepsy, and they mainly target ion channels and inhibit neuronal excitability.…”

Section: Introductionmentioning

confidence: 99%

Effects of Valproate Monotherapy on the Oxidant‐Antioxidant Status in Mexican Epileptic Children: A Longitudinal Study

Beltrán-Sarmiento

Arregoitia-Sarabia

Floriano-Sánchez³

et al. 2018

Oxidative Medicine and Cellular Longevity

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Epilepsy is a neurological disorder that can produce brain injury and neuronal death. Several factors such as oxidative stress have been implicated in epileptogenesis. Valproic acid (VPA) is a widely used drug for the treatment of epilepsy, but the mechanisms underlying these benefits are complex and still not fully understood. The objective of this study was to evaluate, for the first time, the effects of VPA on the oxidant-antioxidant status in Mexican epileptic children before and after 6 or 12 months of treatment with VPA by determining the activities of several plasmatic antioxidant enzymes (glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT)) and oxidant marker (malondialdehyde (MDA), hydrogen peroxide (H2O2), 8-hydroxy-2-deoxyguanosine (8-OHdG), and 3-nitrotyrosine (3-NT) levels) profiles. The possible relationships between these markers and some clinicopathological factors were also evaluated. Plasma samples were obtained from the peripheral blood of 16 healthy children and 32 patients diagnosed with epilepsy, and antioxidant/oxidant markers were measured spectrometrically. Significant decreases in all antioxidant enzyme activities, with the exception of GPx, and increases in all oxidant markers in epileptic subjects versus healthy children were observed. Interestingly, all these effects reverted after VPA monotherapy, although the results were different depending on the treatment period (6 or 12 months). These changes were contingent upon brain imaging findings, type of epilepsy, etiology of epilepsy, and the efficacy of 6 months of VPA monotherapy. Significant and positive correlations of GPx and SOD activities and H2O2 and 8-OHdG levels with the age of children at the beginning of treatment were observed. H2O2 levels were also positively correlated with number of seizures before VPA monotherapy. VPA showed significant antioxidant effects decreasing seizure activity, possibly depending on the presence of cerebral structural alterations, treatment time, and age.

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“…It is known that oxidative damage in proteins is a mechanism underlying neurodegeneration [68], and its consequences in epilepsy could be ranged from cell membrane modification to posttranslational modification, specifically alterations in ion channels [66]. In a recent study on epileptic children, our group used microarray technology and observed that epileptic conditions modified the gene expression of many ribosomal proteins and of some GPx and glutathione-S-transferase isoforms and that the principal biological processes with the highest numbers of differentially expressed genes were related to translation, poly(A) RNA and protein binding, and alternative splicing [69]. The above observations confirm that modification of the protein structure and modification of the activity of enzymes related to GSH are the main mechanisms involved in epilepsy progression and that H. inuloides extracts are capable of ameliorating this condition in the epileptic brain.…”

mentioning

confidence: 99%

Dose-Dependent Behavioral and Antioxidant Effects of Quercetin and Methanolic and Acetonic Extracts fromHeterotheca inuloideson Several Rat Tissues following Kainic Acid-InducedStatus Epilepticus

Carmona-Aparicio¹,

Cárdenas-Rodríguez²,

Delgado³

et al. 2019

Oxidative Medicine and Cellular Longevity

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Kainic acid (KA) has been used to study the neurotoxicity induced after status epilepticus (SE) due to activation of excitatory amino acids with neuronal damage. Medicinal plants can protect against damage caused by KA-induced SE; in particular, organic extracts of Heterotheca inuloides and its metabolite quercetin display antioxidant activity and act as hepatoprotective agents. However, it is unknown whether these properties can protect against the hyperexcitability underlying the damage caused by KA-induced SE. Our aim was to study the protective effects (with regard to behavior and antioxidant activity) of administration of natural products methanolic (ME) and acetonic (AE) extracts and quercetin (Q) from H. inuloides at doses of 30 mg/kg (ME30, AE30, and Q30 groups), 100 mg/kg (ME100, AE100, and Q100 groups), and 300 mg/kg (ME300, AE300, and Q300 groups) against damage in brain regions of male Wistar rats treated with KA. We found dose-dependent effects on behavioral and biochemical studies in the all-natural product groups vs. the control group, with decreases in seizure severity (Racine’s scale) and increases in seizure latency (p<0.05 in the ME100, AE100, Q100, and Q300 groups and p<0.01 in the AE300 and ME300 groups); on lipid peroxidation and carbonylated proteins in all brain tissues (p<0.0001); and on GPx, GR, CAT, and SOD activities with all the treatments vs. KA (p≤0.001). In addition, there were strong negative correlations between carbonyl levels and latency in the group treated with KA and in the group treated with methanolic extract in the presence of KA (r=‐0.9919, p=0.0084). This evidence suggests that organic extracts and quercetin from H. inuloides exert anticonvulsant effects via direct scavenging of reactive oxygen species (ROS) and modulation of antioxidant enzyme activity.

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Differential Gene Expression Profile Induced by Valproic Acid (VPA) in Pediatric Epileptic Patients

Cited by 12 publications

References 40 publications

RNA‑seq analysis of blood of valproic acid‑responsive and non‑responsive pediatric patients with epilepsy

RNA‑seq analysis of blood of valproic acid‑responsive and non‑responsive pediatric patients with epilepsy

Effects of Valproate Monotherapy on the Oxidant‐Antioxidant Status in Mexican Epileptic Children: A Longitudinal Study

Dose-Dependent Behavioral and Antioxidant Effects of Quercetin and Methanolic and Acetonic Extracts fromHeterotheca inuloideson Several Rat Tissues following Kainic Acid-InducedStatus Epilepticus

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