Protective effect of ademetionine, cytoflavinum and dihydroquercetin in the liver of rats exposed to toxic effects of valproate sodium

Введение. Вальпроат натрия влияет на метаболизм гамма-аминомасляной кислоты, предотвращая развитие эпилептических приступов. Многие метаболиты вальпроата натрия потенцируют его клинический эффект, однако, именно они могут приводить к развитию хронической интоксикации с поражением печени. Цель - оценка протекторного эффекта адеметионина (гептрала), цитофлавина и дигидрокверцетина у крыс, подвергнутых токсическому влиянию вальпроата натрия (депакина). Методика. Животным контрольной группы вводили вальпроат натрия в токсической дозе 600 мг/кг интрагастрально 1 раз в день в течение 28 сут. Крысам опытных групп вводили вальпроат натрия в той же дозе с одновременным введением адеметионина, цитофлавина или дигидрокверцетина. Животные выводились из эксперимента на 7-, 14-, 21- и 28-е сут. В гомогенате печени определяли стандартными спектрофотометрическими методами концентрацию диеновых конъюгатов, малонового диальдегида, восстановленного глутатиона и активность ферментов метаболизма глутатиона: глутатионредуктазы, глутатионпероксидазы и глутатионтрансферазы. Результаты. При токсическом воздействии вальпроата натрия в ткани печени развивались процессы гиперпероксидации липидов, которые подтверждались значительным повышением уровня диеновых конъюгатов и малонового диальдегида. Концентрация глутатиона снижалась начиная с 14-х сут эксперимента. Активность глутатионредуктазы повышалась к 14-м сут, а затем к 28-м сут практически достигала значений интактных животных. Активность глутатионтрансферазы начинала снижаться с 14-х сут и сохранялась низкой до конца исследования. Активность глутатионпероксидазы повышалась с 14-х сут эксперимента, достигая максимума к 28-м сут. Протекторный эффект адеметионина при токсическом воздействии вальпроата натрия выражался в снижении содержания диеновых конъюгатов и малонового диальдегида. Одновременно происходила активация системы глутатиона: повышалась активность глутатионтрансферазы и глутатионредуктазы. Антиокислительное действие цитофлавина проявлялось в основном на 1-й нед эксперимента: концентрация диеновых конъюгатов и малонового диальдегида снижалась, активность глутатионредуктазы и глутатионтрансферазы повышалась. Дигидрокверцетин также оказывал антиокислительное действие: концентрация диеновых конъюгатов и малонового диальдегида снижалась. Активность глутатионредуктазы и глутатионтрансферазы увеличивалась по сравнению с контрольными животными. Заключение. Вальпроат натрия в токсической дозе приводит к статистически значимому повышению уровня продуктов перекисного окисления липидов и снижению антиокислительной защиты системы глутатиона в печени крыс. Адеметионин, цитофлавин и дигидрокверцетин способствуют восстановлению баланса системы перекисного окисления липидов и антиоксидантной защиты в печени крыс при токсическом влиянии вальпроата натрия. Наиболее перспективным препаратом защиты является адеметионин, так как он наиболее существенно снижает концентрацию диеновых конъюгатов, малонового диальдегид и повышает активность системы глутатиона на протяжении 28 сут эксперимента. Background. Sodium valproate affects metabolism of gamma-aminobutyric acid to prevent the development of epileptic seizures. Many valproic acid metabolites potentiate its clinical effect; however, specifically these metabolites may result in chronic intoxication with liver damage. Aim: To evaluate the protective effect of ademetionine (Heptral), cytoflavin, and dihydroquircetin in rats exposed to the toxic action of sodium valproate (Depakene). Methods. Animals of the control group were administered valproate sodium at a toxic dose of 600 mg/kg, intragastrically. Rats of the experimental group were administered valproate sodium at a dose of 600 mg/kg with simultaneous administration of ademetionine, cytoflavin and dihydroquercetin. The duration of drug administration in all groups was 7 days, 14 days, 21 days, or 28 days. The contents of diene conjugates, malonic dialdehyde, reduced glutathione, and the activity of glutathione reductase, glutathione peroxidase, and glutathione transferase were measured in liver homogenates with standard spectrophotometric methods. Results. Under the toxic effects of valproate sodium in liver tissue, a significant increase in the contents of diene conjugates and malonic dialdehyde was found. The glutathione concentration decreased starting from day 14 of the experiment. The glutathione reductase activity increased by day 14 and practically reached the values of intact animals by day 28. The glutathione transferase activity began decreasing on day 14 and remained low until the end of study. The glutathione peroxidase activity increased starting from day 14 and reached maximum by day 28. The protective effect of ademetionine was manifested by a decrease in the contents of diene conjugates and malonic dialdehyde. There was a simultaneous activation of the glutathione system evident as increased activities of glutathione transferase and glutathione reductase. An antioxidant effect of cytoflavin was manifested mainly at the 1st wk of the experiment. The concentration of diene conjugates and malonic dialdehyde decreased, the activity of glutathione reductase increased, and the activity of glutathione transferase increased. Dihydroquercetin also had an antioxidant effect since the concentration of diene conjugates and malonic dialdehyde decreased. The activity of glutathione reductase and glutathione transferase increased. Conclusion. Sodium valproate significantly increased concentrations of lipid peroxidation products and impaired the glutathione antioxidant defense in the rat liver. Ademetionine, cytoflavin and dihydroquercetin help to restore the balance of lipid peroxidation and antioxidant protection in the rat liver during the toxic effects of valproate sodium. The most effective drug was ademetionine, since within 28 days, it significantly decreased the concentration of diene conjugates and malonic dialdehyde, and it increased the activity of the glutathione system.

Celecoxib added to mood stabilizer for treating acute mania in bipolar disorder: A randomized, double -blind, placebo-controlled trial in IRAN

Background: Inflammatory processes in the brain contribute to the aetiopathogenesis of acute mania. Cyclooxygenase-2 (COX-2) inhibitors, such as Celecoxib, reduce the production of pro-inflammatory cytokines. The purpose of the present investigation was to assess the efficacy of Celecoxib in the treatment of acute mania.Methods: We conducted a double-blind, placebo-controlled trial at the Specialty in-patient Clinic of Ibn-e-Sina Hospital [Mashhad University of Medical Sciences, Iran] from March 2017 to August 2017. The study involved 58 patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria for acute mania screening to participate in the trial were used for the study. Twenty-three patients were assigned to a study group and were given Valproate Sodium 200 mg /BD plus Celecoxib 400 mg/day (200 mg BID). The control group included 22 patients who were given Valproate Sodium 200 mg /BD plus placebo. Patients were assessed by Young Mania Rating Scale (YMRS) at baseline 0, after 9, 18, and 28 days after the medication started. Data were analyzed by using Statistical Package for Social Sciences (SPSS) 11.5., two-way repeated measures analysis of variance, Fisher’s exact test, and T-Test. P≤0.05 was considered to be statistically significant.Results: A total of 58 patients were screened and 45 were randomized. Most of participations in celecoxib group were male (55%) and in placebo group were female (75%). There were no statistically significant differences between the groups regarding number of episode. sex, marital status, past medical history, past psychiatry history and family history P value ≥0.05. A significant difference was observed in the change of scores on Young Mania Rating Scale (YMRS) at week 4 as compared to the baseline in patient groups P: 0.04.Conclusion: This study suggested that Celecoxib can be an effective adjuvant agent in managing patients with acute mania and anti-inflammatory therapies should further be investigated in these patients.Trial registration: Iran clinical trial register: IRCT20200306046708N1

Management of Agitation, Delirium, and Catatonia in Intubated COVID-19 Patients: A Case Series & Rationale for Valproate Sodium Use During Extubation

The complete spectrum of neuropsychiatric effects of SARS-CoV-2 acute respiratory distress syndrome has yet to be fully appreciated, particularly in intubated patients. Manifestations including delirium and catatonia need to be considered in intubated COVID-19 patients. Medications known to exhibit neuroprotective effects, like valproate, can assist in agitation related to sedative withdrawal during extubation. This case series reports on the management of agitation, delirium, and catatonia in COVID-19 patients during and after extubation efforts. We present three cases in which Psychiatry was consulted for agitation in intubated COVID-19 patients. These patients were managed for severe agitation during weaning from extubation as well as for subsequent psychiatric challenges, including catatonia. Patient 1: 26-year-old female with bipolar I with psychotic features who was admitted for acute hypoxic respiratory failure from COVID-19 pneumonia. After an emergency C-section at 31 weeks’ gestation, she was intubated for 9 days and started on valproate 250 mg BID for agitation. She was extubated successfully and discharged home. Patient 2: 42-year-old female with bipolar I and PTSD who was intubated following COVID-19-related acute hypoxic respiratory failure. She received valproate 250mg BID and was extubated successfully. She became catatonic when home quetiapine was resumed and recovered following quetiapine discontinuation and lorazepam. She was discharged on valproic acid and alprazolam. Patient 3: 23-year-old female with bipolar I with psychotic features who was admitted for COVID-19 acute hypoxic respiratory failure and intubated. She received valproate 250 mg BID and was extubated successfully. She became catatonic when risperidone was re-initiated, but recovered following risperidone discontinuation and addition of lorazepam, gabapentin, and duloxetine. Quetiapine was added before discharge. Valproate was effective for managing delirium and agitation during extubation, as evidenced by normalizing Richmond Agitation and Sedation Scale scores. Additionally, valproate aided in managing catatonia post-extubation. This case series reports on the management of agitation in COVID-19 patients during extubation efforts with valproate sodium, due to its ability to manage delirium and catatonia. Valproate is known to exhibit neuroprotective effects, which possibly explains successful management of agitation during the extubation process.

Costus Root Extract Preserves Thyroid Hormones Levels, Thyroglobulin Expression and Thyroid Tissues in Rats Receiving Valproate Sodium

BACKGROUND: Valproate sodium is an anticonvulsant drug. Saussurea lappa (costus) is a medicinal plant rich with antioxidants. This research aimed to assess the protective effect of costus root extract against valproate sodium-induced thyrotoxicity.METHODS: Eighty adult male albino rats were equally divided into four groups; group I: untreated control, group II: rats were given 200 mg/kg BW valproate sodium orally and daily for 8 weeks, group III: rats were given 300 mg/kg BW costus root extract orally and daily for 8 weeks, and group IV: rats were given combination of valproate sodium and costus root extract. After 8 weeks, blood samples were collected to evaluate T3, T4 and thyroid-stimulating hormone (TSH) levels. Thyroid gland samples were handled for light and electron microscopic investigation. The heights of follicular cells, area % of collagen fibers and color intensity of thyroglobulin immunoreaction were statistically analyzed. RESULTS: After being given valproate sodium as an induction, hormonal assay showed significant decrease in serum T3 and T4 and significant increase of TSH. Follicular and cellular alterations were shown by light and electron microscopes. Morphometric study revealed increased follicular cell height and area % of collagen fibers and decreased color intensity of thyroglobulin. In contrast, costus root extract appeared to have a protective role against valproate sodium-induced thyroid injury. Most of the changes induced by valproate sodium were not observed after supplementation with the plant root extract.CONCLUSION: Valproate sodium has serious effects on the function and structure of thyroid gland, and this study shows that costus root extract could have a protective effect against these effects.KEYWORDS: valproate sodium, rat, thyrotoxicity, Saussurea lappa

Valproate Sodium Protects Blood Brain Barrier Integrity in Intracerebral Hemorrhage Mice

Valproate sodium (VPA) is a traditional antiepileptic drug with a neuroprotective role in cerebrovascular disease. After intracerebral hemorrhage (ICH), mechanical compression by hematoma, neuroinflammation, oxidative stress, and cytotoxicity of hematoma lysates caused the destruction of the blood brain barrier (BBB). Targeting BBB is a major therapeutic method for patients with ICH. The purpose of the present study was to explore the role of VPA in preserving BBB integrity in the ICH model and investigate the underlying molecular mechanisms. One hundred and thirty-six adult male CD1 mice were randomly divided into five groups in the study. Mice subjected to ICH were administered intraperitoneally with VPA at 3, 24, and 48 h post-ICH, respectively. Neurobehavioral assessments, BBB permeability, Evans blue fluorescence, hematoma volume, and protein expression were evaluated. The administration of VPA reduced BBB permeability and improved the neurobehavior significantly post-ICH. VPA administration significantly decreased the expression of phosphorylated nuclear factor-kappa B (p-NFκB), matrix metalloproteinases 9 (MMP9), tumor necrosis factorα (TNFα), and interleukin-6 (IL-6), while it enhanced the expression of claudin 5 and occludin in the brain. In conclusion, VPA administration maintained the integrity of BBB after experimental ICH, thus reducing brain edema and improving the neurological outcomes. Therefore, VPA administration might be a new therapeutic method to protect BBB integrity for patients with ICH.