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

Silva, Monalisa Ribeiro; Correia, Alyne Oliveira; Santos, Gabriel Cabral Alencar dos; Parente, Lucas Leimig Telles; Siqueira, Keicy Parente de; Lima, Danielly Gonçalves Sombra; Moura, Jonathan Almeida; Ribeiro, Ana Elisa da Silva; Costa, Rafael; Lucetti, Daniel Luna; Lucetti, Elaine Cristina Pereira; Neves, Kelly Rose Tavares; Viana, Glauce Socorro de Barros

doi:10.1016/j.pbb.2018.02.001

Cited by 24 publications

(17 citation statements)

References 68 publications

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“…It was reported that treatment with VPA following cerebral ischemia prevented ROS production via the inhibition of HDAC and induction of HSP ( 24 ). Silva et al ( 15 ) suggested that VPA exerted neuroprotective effects by attenuating the increased HDAC and GSK3 immunoreactivity, which are involved in inflammation and brain function in certain areas of the brain of ischemic animals. Inhibition of these enzymes was demonstrated to reduce ischemic cerebral damage by restoring failing mitochondrial bioenergetics and preventing ROS production ( 14 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

“…VPA directly inhibits histone deacetylase (HDAC), causing histone hyperacetylation and heat shock protein (HSP) induction, where HSP induction is correlated with damage resistance. VPA was indicated to exert a neuroprotective effect through these mechanisms in the cerebral ischemia model ( 14 ), it was also indicated that VPA has neuroprotective effects against brain ischemia due to its anti-inflammatory and anti-oxidant activities, as well as against HDAC and glycogen synthase kinase 3 (GSK3) inhibition ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

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Effect of valproic acid on oxidative stress parameters of glutamate‑induced excitotoxicity in SH‑SY5Y cells

Oğuz

Acet

2020

Exp Ther Med

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Glutamate-induced excitotoxicity has been reported to be involved in the pathophysiology of neurodegenerative disorders. It has been proposed that valproic acid (VPA), which is used in epileptic and bipolar disorders, may be protective against excitotoxic insult. The aim of the present study was to investigate the effects of VPA against the glutamate excitotoxicity in the SH-SY5Y human neuroblastoma cell line and determine its anti-oxidant capacity by measuring oxidative and anti-oxidant biochemical parameters. SH-SY5Y human neuroblastoma cells were pre-treated with 1, 5 or 10 mM VPA prior to exposure to 15 mM glutamate. The MTT assay was performed to determine cell viability. To detect oxidative insult in glutamate toxicity and the potential anti-oxidant effect of VPA, the cell catalase (CAT), superoxide dismutase (SOD), malondialdehyde and hydrogen peroxide (H 2 O 2 ) activity was determined. A progressive decline in cell viability was observed with increasing glutamate concentrations (1-50 mM). Treatment with 1 mM VPA was revealed to be effective in increasing the viability of cells exposed to glutamate for 24 h. Oxidative damage, including an increase in H 2 O 2 and MDA, was observed in SH-SY5Y cells treated with glutamate and was reduced by pre-treatment with VPA. CAT activity was decreased following glutamate exposure, but VPA did not prevent this decrease. SOD activity was increased by treatment with VPA alone and was not affected by glutamate exposure. Overall, the present results confirmed the critical role of oxidative stress in glutamate-induced excitotoxicity. They also suggested that VPA may exert an anti-oxidant effect against glutamate-induced excitotoxicity by decreasing oxidative parameters, including H 2 O 2 and MDA, but only had a slight effect on CAT and SOD activity, which have an anti-oxidant capacity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of valproic acid on oxidative stress parameters of glutamate‑induced excitotoxicity in SH‑SY5Y cells

Oğuz

Acet

2020

Exp Ther Med

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“…It alters gene expression and promotes neuroplasticity changes, which in recent years has been suggested to underlie malfunctioning of the neurocircuits related to the psychiatric symptoms [13][14][15] . Inhibition of histone deacetylases (HDACs) and glycogen synthase kinase 3 (Gsk3α and β) are the most prominent mechanisms suspected to be involved in the mood-stabilizing effects of VPA [16][17][18][19] .VPA has been demonstrated to be an inhibitor of HDACs both in vitro and in vivo 20,21 . Chromatin remodeling mediated through HDAC inhibition may lead to transcriptional control of target genes related to neuronal differentiation, protection, and the regulation of behavioral dimensions such as mood and cognitive states 16,17,22 .In conclusion, our findings uncovered an effect of chronic VPA treatment on Ncs-1 expression that is mediated through inhibition of Gsk3.…”

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confidence: 99%

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confidence: 99%

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Contribution of neuronal calcium sensor 1 (Ncs-1) to anxiolytic-like and social behavior mediated by valproate and Gsk3 inhibition

Magno

Tenza-Ferrer

Collodetti

et al. 2020

Sci Rep

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Peripheral biomarker and post-mortem brains studies have shown alterations of neuronal calcium sensor 1 (Ncs-1) expression in people with bipolar disorder or schizophrenia. However, its engagement by psychiatric medications and potential contribution to behavioral regulation remains elusive. We investigated the effect on Ncs-1 expression of valproic acid (VPA), a mood stabilizer used for the management of bipolar disorder. Treatment with VPA induced Ncs-1 gene expression in cell line while chronic administration of this drug to mice increased both Ncs-1 protein and mRNA levels in the mouse frontal cortex. Inhibition of histone deacetylases (HDACs), a known biochemical effect of VPA, did not alter the expression of Ncs-1. In contrast, pharmacological inhibition or genetic downregulation of glycogen synthase kinase 3β (Gsk3β) increased Ncs-1 expression, whereas overexpression of a constitutively active Gsk3β had the opposite effect. Moreover, adeno-associated virus-mediated Ncs-1 overexpression in mouse frontal cortex caused responses similar to those elicited by VPA or lithium in tests evaluating social and mood-related behaviors. These findings indicate that VPA increases frontal cortex Ncs-1 gene expression as a result of Gsk3 inhibition. Furthermore, behavioral changes induced by Ncs-1 overexpression support a contribution of this mechanism in the regulation of behavior by VPA and potentially other psychoactive medications inhibiting Gsk3 activity.The neuronal calcium sensor 1 (Ncs-1) is a Ca 2+ -binding protein that regulates neurotransmitter release 1 , dopamine D2 receptor (D2R) desensitization 2 and neuronal survival 3 , among other functions 4,5 . Alterations in Ncs-1 levels may contribute to psychiatric disorders. Indeed, the expression pattern of Ncs-1 is altered in schizophrenia and bipolar disorder patients 6,7 . In addition, inducible overexpression of Ncs-1 in the brain of rodents enhances exploration and spatial memory acquisition, and increases axonal sprouting 8,9 , whereas loss of Ncs-1 in knockout (KO) mice caused depressive-like, anxiety-like and impaired motivated behaviors 10,11 .Although evidence suggests that Ncs-1 is affected in schizophrenia and bipolar disorder, the effect of psychiatric medications on Ncs-1 remains unexplored. We investigated whether the mood-stabilizing drug valproate (VPA) could contribute to the regulation of brain Ncs-1. VPA is a first-line treatment for depressive and manic phases of bipolar disorder 12 . It alters gene expression and promotes neuroplasticity changes, which in recent years has been suggested to underlie malfunctioning of the neurocircuits related to the psychiatric symptoms [13][14][15] . Inhibition of histone deacetylases (HDACs) and glycogen synthase kinase 3 (Gsk3α and β) are the most prominent mechanisms suspected to be involved in the mood-stabilizing effects of VPA [16][17][18][19] .VPA has been demonstrated to be an inhibitor of HDACs both in vitro and in vivo 20,21 . Chromatin remodeling mediated through HDAC inhibition may lead to transcri...

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Sodium valproate ameliorates memory impairment and reduces the elevated levels of apoptotic caspases in the hippocampus of diabetic mice

Zareie

Gholami

Amirpour-Najafabadi

et al. 2018

Naunyn-Schmiedeberg's Arch Pharmacol

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Learning and memory deficits appear in chronic diabetes and valproic acid has been proved to be beneficial in neurodegenerative diseases. Hence, the current study investigated the effectiveness of chronic valproate treatment for diabetes-induced memory impairment and increased levels of hippocampal apoptotic caspases. This study was conducted in adult male C57B15/J mice. Diabetes, which was induced by alloxan (150 mg/kg; i.p.), was confirmed when fasting blood sugar (FBS) was > 200 mg/dl. Sodium valproate (100 mg/kg; i.p.) was administrated to the diabetic and non-diabetic groups, every 72 h for 2 months. Next, all groups were evaluated for memory performance using the radial maze and shuttle box. After FBS measurement, animals were killed and the hippocampus was extracted and prepared for ELISA to assess caspase levels. Diabetic animals had significantly high FBS and memory impairment 2 months after the alloxan injection. Hippocampal levels of caspases 3, 6, and 8 were significantly higher in the diabetic group than in the control group. However, valproate treatment of diabetic animals significantly improved memory performance in both the radial maze and shuttle box and reduced the elevated levels of hippocampal apoptotic caspases, in comparison with diabetic animals. Chronic administration of valproate seems to have beneficial effects on diabetic neuropathy.

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

Cited by 24 publications

References 68 publications

Effect of valproic acid on oxidative stress parameters of glutamate‑induced excitotoxicity in SH‑SY5Y cells

Effect of valproic acid on oxidative stress parameters of glutamate‑induced excitotoxicity in SH‑SY5Y cells

Contribution of neuronal calcium sensor 1 (Ncs-1) to anxiolytic-like and social behavior mediated by valproate and Gsk3 inhibition

Sodium valproate ameliorates memory impairment and reduces the elevated levels of apoptotic caspases in the hippocampus of diabetic mice

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