Neuroprotective effects of valproic acid on brain ischemia are related to its HDAC and GSK3 inhibitions

Valproic acid (VA) is an antiepileptic that is also used for the treatment of bipolar disorders. The objective was to evaluate the neuroprotective effects of VA on a brain ischemia model. The groups of male Wistar rats were: SO (sham-operated), ischemic and ischemic treated with VA (25, 50 and 100 m...

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Published in:	Pharmacology, biochemistry and behavior Vol. 167; pp. 17 - 28
Main Authors:	Silva, Monalisa Ribeiro, Correia, Alyne Oliveira, dos Santos, Gabriel Cabral Alencar, Parente, Lucas Leimig Telles, de Siqueira, Keicy Parente, Lima, Danielly Gonçalves Sombra, Moura, Jonathan Almeida, da Silva Ribeiro, Ana Elisa, Costa, Roberta Oliveira, Lucetti, Daniel Luna, Lucetti, Elaine Cristina Pereira, Neves, Kelly Rose Tavares, de Barros Viana, Glauce Socorro
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-04-2018
Subjects:	3,4-Dihydroxyphenylacetic Acid - metabolism Animals Brain - metabolism Brain Ischemia - prevention & control Cyclooxygenase 2 Inhibitors - pharmacology Dopamine - metabolism Dose-Response Relationship, Drug Glycogen Synthase Kinases - antagonists & inhibitors GSK3 HDAC Histone Deacetylase Inhibitors - pharmacology Inflammation Lipid Peroxidation Male Neuroprotection Neuroprotective Agents - pharmacology Nitric Oxide Synthase Type II - metabolism Nitrites - metabolism Oxidative stress Rats Valproic acid Valproic Acid - pharmacology Neuroprotection Oxidative stress Inflammation Valproic acid GSK3 HDAC
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Summary:	Valproic acid (VA) is an antiepileptic that is also used for the treatment of bipolar disorders. The objective was to evaluate the neuroprotective effects of VA on a brain ischemia model. The groups of male Wistar rats were: SO (sham-operated), ischemic and ischemic treated with VA (25, 50 and 100 mg/kg, p.o.). After anesthesia with ketamine and xilazine, the animals were subjected to clamping of carotid arteries (30 min) and reperfusion. Except for the carotid clamping, the SO group was submitted to the same procedure. On the 7th day, the animals were behaviorally evaluated, euthanized and had their brain dissected for neurochemical and immunohistochemical assays. The data were analyzed by ANOVA and Tukey as the post hoc test. The results showed that VA reversed partly or completely the behavioral (locomotor activity and memory deficits), neurochemical (striatal DA and DOPAC levels, brain nitrite and lipid peroxidation) and immunohistochemical alterations (iNOS, COX-2, HDAC and GSK3) observed in the untreated ischemic group. VA neuroprotective effects are probably related to its anti-inflammatory and antioxidant properties, as well as to HDAC and GSK3 inhibitory effects. These findings stimulate translational studies focusing on VA as a neuroprotective drug to be potentially used in the clinic for several neurological conditions. [Display omitted] •We confirmed the important Valproic acid neuroprotective properties.•These neuroprotective actions are related to the drug anti-inflammatory activity.•We found that, besides being a HDAC inhibitor, Valproic acid also inhibits the enzyme GSK3.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0091-3057 1873-5177
DOI:	10.1016/j.pbb.2018.02.001