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

Abstract

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.

Antioxidant, Antiinflammatory, and Antiapoptotic Effects of Rutin in Spleen Toxicity Induced by Sodium Valproate in Rats

“…RUT has different protective effects against oxidative stress-mediated diseases and lipid peroxidation in vitro and in vivo [1]. Metabolomic studies of VPA-induced toxicity have primarily focused on changes in serum and urine metabolites but have not evaluated changes in major organs or tissues [30]. Therefore, the present study was designed to determine the effect of RUT in preventing VPA-induced spleen toxicity in spleen tissue.…”

Predicting Valproate-Induced Liver Injury Using Metabolomic Analysis of Ex Ovo Chick Embryo Allantoic Fluid

“…Several metabolomic studies of VPA-induced toxicity in rodents have evaluated metabolic changes in major organs, mainly using MS-based analytical techniques. Overall, their observations suggest that the toxic mechanism of VPA may involve oxidative stress, inflammation, amino acid metabolism, lipid metabolism, and energy disorder [ 24 ].…”

“…Steatosis was indicated by diacylglycerol and triglyceride (TG) accumulation and carnitine deficiency, while initial toxic responses showed increased levels of S-adenosylmethionine and mono-acetylspermidine in combination with only a moderate increase in TG [ 22 ]. In VPA-exposed rodents, early impairments of β/ω-Ox, glucuronidation, amino acids, and energy-related biochemical pathways were reported [ 23 , 24 ]. In rats exposed to increasing and repeated doses of VPA, significant changes occurred from 100 mg/kg VPA and beyond in two urine biomarkers of hepatotoxicity, 8-hydroxy-2′-deoxyguanosine, and octanoylcarnitine [ 25 ].…”

Recent evaluation about inflammatory mechanisms in nonalcoholic fatty liver disease

“…Lowering dietary linoleic acid levels can reduce the synthesis and/or accumulation of oxidized linoleic acid metabolites in humans. Oxidative metabolites from arachidonic acid and linoleic acid are associated with markers of steatosis, liver injury, and insulin sensitivity, and the relevant oxidative metabolites are more abundant in the plasma of NASH patients than NAFLD patients ( Civelek and Podszun, 2022 ; Gao et al, 2022 ). These data suggest that oxidized linoleic acid metabolites play a crucial role in NASH.…”