{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:55:22Z","timestamp":1760144122919,"version":"build-2065373602"},"reference-count":95,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Agencia Valenciana de Innovaci\u00f3n, Generalitat Valenciana (Consolidacio Cadena Valor)","award":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"],"award-info":[{"award-number":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"]}]},{"name":"Conseller\u00eda Educaci\u00f3n, Generalitat Valenciana","award":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"],"award-info":[{"award-number":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"]}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n, Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"],"award-info":[{"award-number":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Regional Development Funds (ERDF)","award":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"],"award-info":[{"award-number":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"]}]},{"name":"F. Sarabia Donation","award":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"],"award-info":[{"award-number":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"]}]},{"DOI":"10.13039\/501100003508","name":"Universidad de Valencia, Ayudas para Acciones Especiales","doi-asserted-by":"publisher","award":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"],"award-info":[{"award-number":["CIPROM2021\/082","PI23\/00062","PRV00225","UV-INV_AE-2633839"]}],"id":[{"id":"10.13039\/501100003508","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>(1) Background: Valproic acid (VPA) is one of the frequently prescribed antiepileptic drugs and is generally considered well tolerated. However, VPA neurologic adverse effects in the absence of liver failure are fairly common, suggesting that in the mechanism for the development of VPA-induced encephalopathy, much more is involved than merely the exposure to hyperammonemia (HA) caused by liver insufficiency to perform detoxification. Taking into account the importance of the relationship between an impaired brain energy metabolism and elevated ammonia production, and based on the ability of VPA to interfere with neuronal oxidative pathways, the current study intended to investigate a potential regional ammoniagenic effect of VPA on rats\u2019 brains by determining activities of the enzymes responsible for ammonia production and neutralization. (2) Methods: Rats received a single intraperitoneal injection of VPA (50, 100, 250, 500 mg\/kg). Plasma, the neocortex, the cerebellum, and the hippocampus were collected at 30 min after injection. The levels of ammonia, urea, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured in blood plasma. The activities of glutaminase and glutamate dehydrogenase (GDH) in mitochondria and the activities of AMP deaminase (AMPD), adenosine deaminase (ADA), and glutamine synthetase (GS) in cytosolic fractions isolated from rat brain regions were measured. Ammonia, ALT, and AST values were determined in the mitochondrial and cytosolic fractions. (3) Results: Multi-dose VPA treatment did not significantly affect the plasma levels of ammonia and urea or the ALT and AST liver enzymes. Significant dose-independent increases in the accumulation of ammonia were found only in the cytosol from the cerebellum and there was a strong correlation between the ammonia level and the ADA activity in this brain structure. A significant decrease in the AMPD and AST activities was observed, while the ALT activity was unaffected. Only the highest VPA dose (500 mg\/kg) was associated with significantly less activity of GS compared to the control in all studied brain structures. In the mitochondria of all studied brain structures, VPA caused a dose-independent increases in ammonia levels, a high concentration of which was strongly and positively correlated with the increased GDH and ALT activity, while glutaminase activity remained unchanged, and AST activity significantly decreased compared to the control in all studied brain structures. (4) Conclusions: This study highlights the rat brain region-specific ammoniagenic effects of VPA, which may manifest themselves in the absence of hyperammonemia. Further research should analyze how the responsiveness of the different brain regions may vary in VPA-treated animals that exhibit compromised energy metabolism, leading to increased ammoniagenesis.<\/jats:p>","DOI":"10.3390\/biom14030370","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T05:04:12Z","timestamp":1710911052000},"page":"370","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ammoniagenic Action of Valproate without Signs of Hepatic Dysfunction in Rats: Possible Causes and Supporting Evidence"],"prefix":"10.3390","volume":"14","author":[{"given":"Gubidat","family":"Alilova","sequence":"first","affiliation":[{"name":"Laboratory of Cell Engineering, Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lyudmila","family":"Tikhonova","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Engineering, Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4740-4788","authenticated-orcid":false,"given":"Carmina","family":"Montoliu","sequence":"additional","affiliation":[{"name":"Hospital Clinico Research Foundation, INCLIVA Health Research Institute, 46010 Valencia, Spain"},{"name":"Pathology Department, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3293-652X","authenticated-orcid":false,"given":"Elena","family":"Kosenko","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Engineering, Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1586\/14737175.2.2.151","article-title":"Valproate: A Practical Review of Its Uses in Neurological and Psychiatric Disorders","volume":"2","author":"Kanner","year":"2002","journal-title":"Expert Rev. Neurother."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1081\/CLT-120014645","article-title":"Valproic Acid Toxicity: Overview and Management","volume":"40","author":"Sztajnkrycer","year":"2002","journal-title":"J. Toxicol. Clin. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.clinbiochem.2013.06.012","article-title":"Adverse Drug Reactions Induced by Valproic Acid","volume":"46","author":"Nanau","year":"2013","journal-title":"Clin. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/S0196-0644(05)81955-9","article-title":"Hyperammonemia Secondary to Valproic Acid as a Cause of Lethargy in a Postictal Patient","volume":"22","author":"Kulick","year":"1993","journal-title":"Ann. Emerg. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"673","DOI":"10.2165\/00002018-200326100-00001","article-title":"Do Antiepileptic Drugs Play a Role in Sudden Unexpected Death in Epilepsy?","volume":"26","author":"Walczak","year":"2003","journal-title":"Drug Saf."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1159\/000115687","article-title":"Hyperammonemia and Valproate-Induced Alterations of the State of Consciousness. A Report of 8 Cases","volume":"23","author":"Zaccara","year":"1984","journal-title":"Eur. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"279","DOI":"10.3109\/15563659509018000","article-title":"Life Threatening Intoxication with Sodium Valproate","volume":"33","author":"Andersen","year":"1995","journal-title":"J. Toxicol. Clin. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/0028-3908(85)90028-0","article-title":"Pharmacological Evaluation of Various Metabolites and Analogues of Valproic Acid. Anticonvulsant and Toxic Potencies in Mice","volume":"24","author":"Nau","year":"1985","journal-title":"Neuropharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1152\/physrev.1987.67.2.440","article-title":"Biochemistry and Physiology of Brain Ammonia","volume":"67","author":"Cooper","year":"1987","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/S0002-9343(02)01477-8","article-title":"Correlation between Ammonia Levels and the Severity of Hepatic Encephalopathy","volume":"114","author":"Ong","year":"2003","journal-title":"Am. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF02833598","article-title":"Ammonia: Key Factor in the Pathogenesis of Hepatic Encephalopathy","volume":"6","author":"Butterworth","year":"1987","journal-title":"Neurochem. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.mcna.2008.03.009","article-title":"Hepatic Encephalopathy","volume":"92","author":"Munoz","year":"2008","journal-title":"Med. Clin. N. Am."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.jhep.2010.11.031","article-title":"New Insights on the Mechanisms of Valproate-Induced Hyperammonemia: Inhibition of Hepatic N-Acetylglutamate Synthase Activity by Valproyl-CoA","volume":"55","author":"Aires","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_14","first-page":"270","article-title":"Effects of Sodium Valproate on Mitochondrial Membranes: Electron Paramagnetic Resonance and Transmembrane Protein Movement Studies","volume":"30","author":"Rumbach","year":"1986","journal-title":"Mol. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/0022-510X(83)90174-0","article-title":"Inhibition of Oxidative Phosphorylation in Hepatic and Cerebral Mitochondria of Sodium Valproate-Treated Rats","volume":"61","author":"Rumbach","year":"1983","journal-title":"J. Neurol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1212\/WNL.31.11.1473","article-title":"Inhibitory Effects of Sodium Valproate on Oxidative Phosphorylation","volume":"31","author":"Haas","year":"1981","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1016\/0006-2952(82)90392-6","article-title":"Inhibition by Valproic Acid of Pyruvate Uptake by Brain Mitochondria","volume":"31","author":"Benavides","year":"1982","journal-title":"Biochem. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"172","DOI":"10.4103\/2348-9995.195678","article-title":"Valproate-Induced Hyperammonemic Encephalopathy in an Elderly Patient with Bipolar Disorder","volume":"3","author":"Surendran","year":"2016","journal-title":"J. Geriatr. Ment. Health"},{"key":"ref_19","first-page":"57","article-title":"Valproate-Induced Hyperammonemic Encephalopathy Caused by Free Carnitine Deficiency in a Patient with Bipolar Disorder: A Case Report","volume":"7","author":"Bae","year":"2009","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ajem.2003.12.011","article-title":"Unusual Causes of Hyperammonemia in the ED","volume":"22","author":"Weng","year":"2004","journal-title":"Am. J. Emerg. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S1875-9572(09)60010-3","article-title":"Valproate-Induced Hyperammonemic Encephalopathy","volume":"49","author":"Chou","year":"2008","journal-title":"Pediatr. Neonatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"226","DOI":"10.4103\/0028-3886.16420","article-title":"Valproate-Induced Hyperammonemic Encephalopathy with Normal Liver Function","volume":"53","author":"Rath","year":"2005","journal-title":"Neurol. India"},{"key":"ref_23","first-page":"VD01","article-title":"Valproate Induced Delirium Due to Hyperammonemia in a Case of Acute Mania: A Diagnostic Dilemma","volume":"9","author":"Dixit","year":"2015","journal-title":"J. Clin. Diagn. Res. JCDR"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1177\/106002809302700510","article-title":"Valproate-Induced Coma: Case Report and Literature Review","volume":"27","author":"Duarte","year":"1993","journal-title":"Ann. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1212\/WNL.31.9.1173","article-title":"Valproic Acid and Secondary Hyperammonemia","volume":"31","author":"Rawat","year":"1981","journal-title":"Neurology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1212\/WNL.32.2.206","article-title":"Sodium Valproate-Induced Hyperammonemia without Clinical Hepatic Dysfunction","volume":"32","author":"Zaret","year":"1982","journal-title":"Neurology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.5214\/ans.0972.7531.210210","article-title":"Non-Hyperammonemic Valproate Encephalopathy","volume":"21","author":"Farooq","year":"2014","journal-title":"Ann. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ebcr.2017.04.002","article-title":"Non-Hyperammonaemic Valproate Encephalopathy after 20 Years of Treatment","volume":"8","author":"Isaacs","year":"2017","journal-title":"Epilepsy Behav. Case Rep."},{"key":"ref_29","first-page":"135","article-title":"A Case of Non-Hyperammonemic Valproate-Induced Encephalopathy","volume":"11","author":"Guin","year":"2006","journal-title":"Neurol. Asia"},{"key":"ref_30","first-page":"85","article-title":"Valproate-Induced Non-Hepatic Hyperammonaemic Encephalopathy: A Rare Complication of Chronic Valproate Therapy","volume":"1","author":"Agrawal","year":"2012","journal-title":"Int. J. Clin. Pediatr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1134\/S1819712414030064","article-title":"Antioxidant Defense in the Rat Brain Cortex, Cerebellum, Hippocampus, and Striatum and Its Alterations during Portacaval Shunting","volume":"8","author":"Kaminsky","year":"2014","journal-title":"Neurochem. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/BF00314304","article-title":"Glucose Metabolism as the Site of the Primary Abnormality in Early-Onset Dementia of Alzheimer Type?","volume":"235","author":"Hoyer","year":"1988","journal-title":"J. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/0304-3940(90)90691-2","article-title":"Ammonia Is Endogenously Generated in the Brain in the Presence of Presumed and Verified Dementia of Alzheimer Type","volume":"117","author":"Hoyer","year":"1990","journal-title":"Neurosci. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Cooper, A.J.L., and Jeitner, T.M. (2016). Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain. Biomolecules, 6.","DOI":"10.3390\/biom6020016"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3109\/15376516.2013.821567","article-title":"Toxicity of Valproic Acid in Isolated Rat Liver Mitochondria","volume":"23","author":"Jafarian","year":"2013","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.freeradbiomed.2017.09.023","article-title":"Portacaval Shunting Causes Differential Mitochondrial Superoxide Production in Brain Regions","volume":"113","author":"Kosenko","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","first-page":"654","article-title":"Valproic Acid: Brain and Plasma Levels of the Drug and Its Metabolites, Anticonvulsant Effects and Gamma-Aminobutyric Acid (GABA) Metabolism in the Mouse","volume":"220","author":"Nau","year":"1982","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e8117","DOI":"10.1097\/MD.0000000000008117","article-title":"Sudden Valproate-Induced Hyperammonemia Managed with L-Carnitine in a Medically Healthy Bipolar Patient: Essential Review of the Literature and Case Report","volume":"96","author":"Cattaneo","year":"2017","journal-title":"Medicine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1176\/appi.psy.49.1.82","article-title":"Severe Acute Hyperammonemia after Brief Exposure to Valproate","volume":"49","author":"Eubanks","year":"2008","journal-title":"Psychosomatics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1177\/003693308703200312","article-title":"Fatality Due to Massive Overdose of Sodium Valproate","volume":"32","author":"Connacher","year":"1987","journal-title":"Scott. Med. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1111\/j.1528-1157.1992.tb02355.x","article-title":"Effect of Valproate Dose on Formation of Hepatotoxic Metabolites","volume":"33","author":"Anderson","year":"1992","journal-title":"Epilepsia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.brainres.2006.03.102","article-title":"Behavioral Effects of Short-Term Administration of Lithium and Valproic Acid in Rats","volume":"1093","author":"Tomasiewicz","year":"2006","journal-title":"Brain Res."},{"key":"ref_43","first-page":"444","article-title":"Urea","volume":"Volume VIII","author":"Bergmeyer","year":"1990","journal-title":"Methods of Enzymatic Analysis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0076-6879(85)13033-8","article-title":"Glutaminase from Mammalian Tissues","volume":"Volume 113","author":"Meister","year":"1985","journal-title":"Methods in Enzymology"},{"key":"ref_45","first-page":"216","article-title":"Glutamate Dehydrogenase","volume":"Volume III","author":"Bergmeyer","year":"1984","journal-title":"Methods of Enzymatic Analysis"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0076-6879(85)13030-2","article-title":"Glutamine Synthetase from Mammalian Tissues","volume":"113","author":"Meister","year":"1985","journal-title":"Methods Enzymol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.brainres.2009.10.073","article-title":"AMP Deaminase and Adenosine Deaminase Activities in Liver and Brain Regions in Acute Ammonia Intoxication and Subacute Toxic Hepatitis","volume":"1311","author":"Kaminsky","year":"2010","journal-title":"Brain Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein Measurement with the Folin Phenol Reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_49","first-page":"270","article-title":"Differential Effects of Vigabatrin, Gamma-Acetylenic GABA, Aminooxyacetic Acid, and Valproate on Levels of Various Amino Acids in Rat Brain Regions and Plasma","volume":"349","year":"1994","journal-title":"Naunyn. Schmiedebergs Arch. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0301-0082(82)90010-7","article-title":"Mechanism of Anticonvulsant Action of Valproate","volume":"19","author":"Chapman","year":"1982","journal-title":"Prog. Neurobiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1002\/hep.21357","article-title":"Glutamine: A Trojan Horse in Ammonia Neurotoxicity","volume":"44","author":"Albrecht","year":"2006","journal-title":"Hepatology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1111\/j.1528-1157.1984.tb05638.x","article-title":"Non-Dose-Related Side Effects of Valproate","volume":"25","author":"Jeavons","year":"1984","journal-title":"Epilepsia"},{"key":"ref_53","first-page":"1559325820918445","article-title":"Non-Dose-Dependent Changes in Liver Enzyme Levels of Children With Epilepsy on Treatment With Sodium Valproate","volume":"18","author":"Adedapo","year":"2020","journal-title":"Dose Response Publ. Int. Hormesis Soc."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/j.1528-1157.1993.tb02419.x","article-title":"Valproate (VPA) Metabolites in Various Clinical Conditions of Probable VPA-Associated Hepatotoxicity","volume":"34","author":"Siemes","year":"1993","journal-title":"Epilepsia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.20290","article-title":"Regional Differences in Cerebral Blood Flow and Cerebral Ammonia Metabolism in Patients with Cirrhosis","volume":"40","author":"Ahl","year":"2004","journal-title":"Hepatology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1053\/j.gastro.2010.03.040","article-title":"Hyperammonemia Induces Neuroinflammation That Contributes to Cognitive Impairment in Rats with Hepatic Encephalopathy","volume":"139","author":"Rodrigo","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1007\/BF00964888","article-title":"Acute Effects of Sodium Valproate and Gamma-Vinyl GABA on Regional Amino Acid Metabolism in the Rat Brain: Incorporation of 2-[14C]Glucose into Amino Acids","volume":"7","author":"Chapman","year":"1982","journal-title":"Neurochem. Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Plaitakis, A., Kalef-Ezra, E., Kotzamani, D., Zaganas, I., and Spanaki, C. (2017). The Glutamate Dehydrogenase Pathway and Its Roles in Cell and Tissue Biology in Health and Disease. Biology, 6.","DOI":"10.3390\/biology6010011"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1046\/j.1471-4159.1996.67041584.x","article-title":"Severity of Hyperammonemic Encephalopathy Correlates with Brain Ammonia Level and Saturation of Glutamine Synthetase in Vivo","volume":"67","author":"Kanamori","year":"1996","journal-title":"J. Neurochem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1080\/15563650802178136","article-title":"Valproic Acid Poisoning: An Evidence-Based Consensus Guideline for out-of-Hospital Management","volume":"46","author":"Manoguerra","year":"2008","journal-title":"Clin. Toxicol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1134\/S1819712415020087","article-title":"Ammonia and Enzymes of Ammonia Metabolism in Different Brain Regions in Hyperammonemia","volume":"9","author":"Kosenko","year":"2015","journal-title":"Neurochem. J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/1097-4547(20010101)63:1<20::AID-JNR3>3.0.CO;2-N","article-title":"Differential Vulnerability of Cortical and Cerebellar Neurons in Primary Culture to Oxygen Glucose Deprivation Followed by Reoxygenation","volume":"63","author":"Scorziello","year":"2001","journal-title":"J. Neurosci. Res."},{"key":"ref_63","first-page":"193S","article-title":"Loss of Granule Neurons in the Aging Human Cerebellar Cortex","volume":"40","author":"Renovell","year":"1996","journal-title":"Int. J. Dev. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1046\/j.1471-4159.1994.63020584.x","article-title":"Isolated Cerebral and Cerebellar Mitochondria Produce Free Radicals When Exposed to Elevated Ca2+ and Na+: Implications for Neurodegeneration","volume":"63","author":"Dykens","year":"1994","journal-title":"J. Neurochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1176\/jnp.12.2.193","article-title":"The Role of the Cerebellum in Cognition and Behavior: A Selective Review","volume":"12","author":"Rapoport","year":"2000","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0896-6273(00)80018-5","article-title":"Cerebellar Contributions to Cognition","volume":"16","author":"Fiez","year":"1996","journal-title":"Neuron"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s12311-012-0355-9","article-title":"Consensus Paper: Pathological Role of the Cerebellum in Autism","volume":"11","author":"Fatemi","year":"2012","journal-title":"Cerebellum"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1172\/JCI114877","article-title":"Inactivation of Beef Brain Alpha-Ketoglutarate Dehydrogenase Complex by Valproic Acid and Valproic Acid Metabolites. Possible Mechanism of Anticonvulsant and Toxic Actions","volume":"86","author":"Luder","year":"1990","journal-title":"J. Clin. Investig."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1016\/0006-2952(92)90324-C","article-title":"In Vitro Effects of Valproate and Valproate Metabolites on Mitochondrial Oxidations. Relevance of CoA Sequestration to the Observed Inhibitions","volume":"43","author":"Ponchaut","year":"1992","journal-title":"Biochem. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1111\/j.1528-1157.1991.tb04671.x","article-title":"Effect of Valproate on Human Cerebral Glucose Metabolism","volume":"32","author":"Leiderman","year":"1991","journal-title":"Epilepsia"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.tox.2015.03.001","article-title":"Sodium Valproate Induces Mitochondrial Respiration Dysfunction in HepG2 in Vitro Cell Model","volume":"331","author":"Komulainen","year":"2015","journal-title":"Toxicology"},{"key":"ref_72","first-page":"313","article-title":"Neuroprotective Role of Adenosine in the CNS","volume":"54","author":"Wardas","year":"2002","journal-title":"Pol. J. Pharmacol."},{"key":"ref_73","first-page":"189","article-title":"Adenosine Deaminase, Not Immune to a Mechanistic Rethink in Central Nervous System Disorders?","volume":"37","author":"Hall","year":"2022","journal-title":"Histol. Histopathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1007\/s11064-012-0803-4","article-title":"The Role of Glutamine Synthetase and Glutamate Dehydrogenase in Cerebral Ammonia Homeostasis","volume":"37","author":"Cooper","year":"2012","journal-title":"Neurochem. Res."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Badawy, A.A., Elghaba, R., Soliman, M., Hussein, A.M., AlSadrah, S.A., Awadalla, A., and Abulseoud, O.A. (2020). Chronic Valproic Acid Administration Increases Plasma, Liver, and Brain Ammonia Concentration and Suppresses Glutamine Synthetase Activity. Brain Sci., 10.","DOI":"10.3390\/brainsci10100759"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1046\/j.1471-4159.1994.62031137.x","article-title":"Valproate Increases Glutaminase and Decreases Glutamine Synthetase Activities in Primary Cultures of Rat Brain Astrocytes","volume":"62","author":"Collins","year":"1994","journal-title":"J. Neurochem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/S0021-9258(18)89731-9","article-title":"Preferential Degradation of the Oxidatively Modified Form of Glutamine Synthetase by Intracellular Mammalian Proteases","volume":"260","author":"Rivett","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1016\/S0021-9258(19)41826-7","article-title":"Immunochemical Evidence for Glutamine-Mediated Degradation of Glutamine Synthetase in Cultured Chinese Hamster Cells","volume":"250","author":"Milman","year":"1975","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1042\/bj3150607","article-title":"Effect of Glucose Deprivation on Rat Glutamine Synthetase in Cultured Astrocytes","volume":"315","author":"Rosier","year":"1996","journal-title":"Biochem. J."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/BF00973101","article-title":"Nitroarginine, an Inhibitor of Nitric Oxide Synthetase, Attenuates Ammonia Toxicity and Ammonia-Induced Alterations in Brain Metabolism","volume":"20","author":"Kosenko","year":"1995","journal-title":"Neurochem. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1023\/A:1026339428059","article-title":"Modulation of Glutamine Synthesis in Cultured Astrocytes by Nitric Oxide","volume":"17","author":"Kosenko","year":"1997","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1046\/j.1471-4159.1994.63062172.x","article-title":"Brain ATP Depletion Induced by Acute Ammonia Intoxication in Rats Is Mediated by Activation of the NMDA Receptor and Na+,K(+)-ATPase","volume":"63","author":"Kosenko","year":"1994","journal-title":"J. Neurochem."},{"key":"ref_83","first-page":"598493","article-title":"Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate): Evidence in Humans and Experimental Models","volume":"2013","author":"Sampieri","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/0014-2999(94)00711-F","article-title":"Dose-Dependent Anticonvulsant and Proconvulsant Effects of Nitric Oxide Synthase Inhibitors on Seizure Threshold in a Cortical Stimulation Model in Rats","volume":"274","author":"Rundfeldt","year":"1995","journal-title":"Eur. J. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.freeradbiomed.2014.07.043","article-title":"Valproic Acid Increases NO Production via the SH-PTP1-CDK5-eNOS-Ser(116) Signaling Cascade in Endothelial Cells and Mice","volume":"76","author":"Cho","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_86","first-page":"359","article-title":"Valproic Acid Attenuates Nitric Oxide and Interleukin-1\u03b2 Production in Lipopolysaccharide-Stimulated Iron-Rich Microglia","volume":"8","author":"Mairuae","year":"2018","journal-title":"Biomed. Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1111\/j.1528-1157.2000.tb00245.x","article-title":"Sleep and Epilepsy: A Key Role for Nitric Oxide?","volume":"41","author":"Faradji","year":"2000","journal-title":"Epilepsia"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF02676355","article-title":"Effects of Acute Hyperammonemia in Vivo on Oxidative Metabolism in Nonsynaptic Rat Brain Mitochondria","volume":"12","author":"Kosenko","year":"1997","journal-title":"Metab. Brain Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1139\/O09-008","article-title":"Human GLUD1 and GLUD2 Glutamate Dehydrogenase Localize to Mitochondria and Endoplasmic Reticulum","volume":"87","author":"Mastorodemos","year":"2009","journal-title":"Biochem. Cell Biol. Biochim. Biol. Cell."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S0076-6879(85)13006-5","article-title":"L-Glutamate Dehydrogenase from Bovine Liver","volume":"113","author":"Fisher","year":"1985","journal-title":"Methods Enzymol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/978-1-4615-1989-8_2","article-title":"Brain Metabolism in Encephalopathy Caused by Hyperammonemia","volume":"368","author":"Hawkins","year":"1994","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_92","first-page":"1134","article-title":"Hepatoencephalopathy: The Role of Cerebral Ammonia-Forming Reactions","volume":"21","author":"Alilova","year":"2020","journal-title":"Medline"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1002\/jnr.23908","article-title":"Glutamate Oxidation in Astrocytes: Roles of Glutamate Dehydrogenase and Aminotransferases","volume":"94","author":"McKenna","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0920-1211(01)00308-4","article-title":"The Acute Effect of Valproate on Cerebral Energy Metabolism in Mice","volume":"47","author":"Johannessen","year":"2001","journal-title":"Epilepsy Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"112","DOI":"10.2174\/18715273113126660130","article-title":"Pathogenesis of Alzheimer Disease: Role of Oxidative Stress, Amyloid-\u03b2 Peptides, Systemic Ammonia and Erythrocyte Energy Metabolism","volume":"13","author":"Kosenko","year":"2014","journal-title":"CNS Neurol. Disord. Drug Targets"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/3\/370\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:16:07Z","timestamp":1760105767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/3\/370"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,19]]},"references-count":95,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["biom14030370"],"URL":"https:\/\/doi.org\/10.3390\/biom14030370","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2024,3,19]]}}}