Valproic Acid-Mediated Neuroprotection and Neurogenesis After Spinal Cord Injury: From Mechanism to Clinical Potential

Chu, Tianci; Zhou, Hengxing; Lu, Lu; Kong, Xiaohong; Wang, Tianyi; Pan, Bin

doi:10.2217/rme.14.86

Cited by 40 publications

(39 citation statements)

References 78 publications

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“…Interestingly, pharmacological inhibition of HDAC activity alters neuronal differentiation. It has been reported that treatments with trichostatin A (TSA) or valproic acid (VPA) induced neuronal differentiation in adult progenitor cells [46, 57]. VPA treatment also improved the differentiation of sympathoadrenal progenitor cells into catecholaminergic neurons [58].…”

Section: Main Textmentioning

confidence: 99%

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

et al. 2017

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Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer’s disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.

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Section: Main Textmentioning

confidence: 99%

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

et al. 2017

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“…Neuronal loss due to excitotoxicity is a hallmark in epilepsy (Fujikawa, 2005), traumatic brain injury (Algattas and Huang, 2014), as well as in neurodegenerative diseases of the human CNS (Parsons and Raymond, 2014). The substance valproic acid (VPA) is an anticonvulsant and mood-stabilizing drug used for more than 35 years now but has recently gained attention to be neuroprotective in several animal models of acute CNS injury (Chen et al, 2014;Chu et al, 2015;Lu et al, 2013) and neurodegenerative diseases (Chiu et al, 2013). The present study aimed to elucidate the mechanism of neuroprotection by ramified microglia against NMDA-induced excitotoxicity in OHSC.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of microglia neuroprotection: Involvement ofP2X7,TNFα, and valproic acid

Masuch

Shieh

Rooijen

et al. 2015

Glia

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Recently, we have demonstrated that ramified microglia are neuroprotective in N-methyl-D-aspartate (NMDA)-induced excitotoxicity in organotypic hippocampal slice cultures (OHSCs). The present study aimed to elucidate the underlying neuron-glia communication mechanism. It is shown here that pretreatment of OHSC with high concentrations of adenosine 5'-triphosphate (ATP) reduced NMDA-induced neuronal death only in presence of microglia. Specific agonists and antagonists identified the P2X7 receptor as neuroprotective receptor which was confirmed by absence of ATP-dependent neuroprotection in P2X7-deficient OHSC. Microglia replenished chimeric OHSC consisting of wild-type tissue replenished with P2X7-deficient microglia confirmed the involvement of microglial P2X7 receptor in neuroprotection. Stimulation of P2X7 in primary microglia induced tumor necrosis factor α (TNFα) release and blocking TNFα by a neutralizing antibody in OHSC abolished neuroprotection by ATP. OHSC from TNFα-deficient mice show increased exicitoxicity and activation of P2X7 did not rescue neuronal survival in the absence of TNFα. The neuroprotective effect of valproic acid (VPA) was strictly dependent on the presence of microglia and was mediated by upregulation of P2X7 in the cells. The present study demonstrates that microglia-mediated neuroprotection depends on ATP-activated purine receptor P2X7 and induction of TNFα release. This neuroprotective pathway was strengthened by VPA elucidating a novel mechanism for the neuroprotective function of VPA.

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“…In addition to its inhibitory effect on ER stress, VPA was reported to markedly up-regulate AKT expression in a rat traumatic brain injury model [20]. Chu, T et al reported that VPA can counteract secondary damage to functionally rescue SCI in animal models by improving neuroprotection and neurogenesis via inhibition of GSK3β [44]. The correlation between VPA and the AKT and GSK3β pathways also was investigated in our present study.…”

Section: Discussionmentioning

confidence: 54%

Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3β Signaling Pathway

Xie

et al. 2017

IJMS

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Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role in a range of neurological disorders, such as neurodegenerative diseases, spinal cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently, VPA has been reported to exert neurotrophic effects and promote neurite outgrowth, but its molecular mechanism is still unclear. In the present study, we investigated whether VPA inhibited ER stress and promoted neuroprotection and neuronal restoration in SH-SY5Y cells and in primary rat cortical neurons, respectively, upon exposure to thapsigargin (TG). In SH-SY5Y cells, cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and the expression of ER stress-related apoptotic proteins such as glucose‑regulated protein (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase-12/-3 were analyzed with Western blot analyses and immunofluorescence assays. To explore the pathway involved in VPA-induced cell proliferation, we also examined p-AKT, GSK3β, p-JNK and MMP-9. Moreover, to detect the effect of VPA in primary cortical neurons, immunofluorescence staining of β-III tubulin and Anti-NeuN was analyzed in primary cultured neurons exposed to TG. Our results demonstrated that VPA administration improved cell viability in cells exposed to TG. In addition, VPA increased the levels of GRP78 and p-AKT and decreased the levels of ATF6, XBP-1, GSK3β, p-JNK and MMP-9. Furthermore, the levels of the ER stress-induced apoptosis response proteins CHOP, cleaved caspase-12 and cleaved caspase-3 were inhibited by VPA treatment. Meanwhile, VPA administration also increased the ratio of Bcl-2/Bax. Moreover, VPA can maintain neurite outgrowth of primary cortical neurons. Collectively, the neurotrophic effect of VPA is related to the inhibition of ER stress-induced apoptosis in SH-SY5Y cells and the maintenance of neuronal growth. Collectively, our results suggested a new approach for the therapeutic function of VPA in neurological disorders and neuroprotection.

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Valproic Acid-Mediated Neuroprotection and Neurogenesis After Spinal Cord Injury: From Mechanism to Clinical Potential

Cited by 40 publications

References 78 publications

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

Mechanism of microglia neuroprotection: Involvement ofP2X7,TNFα, and valproic acid

Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3β Signaling Pathway

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