The Role of Wnt/β-Catenin Signaling Pathway in Disrupted Hippocampal Neurogenesis of Temporal Lobe Epilepsy: A Potential Therapeutic Target?

Huang, Cheng; Fu, Xianghui; Zhou, Dong; Li, Jinmei

doi:10.1007/s11064-015-1614-1

Cited by 47 publications

(40 citation statements)

References 130 publications

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“…In fact, therapeutic drugs were used just under pathological condition. It has been reported that simvastatin increase neurogenesis both under pathological and physiological condition [58,59] and has no significant toxicity on neonatal rats [25]. So, we did not design a control group with simvastatin alone in the present study.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 98%

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Wang¹,

Lu²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats. Methods: Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3β both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult. Results: Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3β both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro. Conclusion: We for the first time showed that simvastatin, by upregulating Akt/GSK-3β signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 98%

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Wang¹,

Lu²,

Wang³

et al. 2018

Cell Physiol Biochem

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“…In the central nervous system, it also plays important roles in regulating neurogenesis, neural differentiation, synapse development, and plasticity. Recently, collective data have shown that Wnt/β‐catenin signalling pathway may mediate aberrant neurogenesis and be involved in the epileptogenesis in some epileptic animal models and also human patients . In the present study, to examine the potential role of Wnt signalling pathway in hippocampal neurogenesis, we used the rat model of temporal lobe epilepsy by intracerebral injection of kainic acid, a well‐established model with similar neuropathological and electroencephalographic features that are seen in patients with temporal lobe epilepsy .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, collective data have shown that Wnt/β-catenin signalling pathway may mediate aberrant neurogenesis and be involved in the epileptogenesis in some epileptic animal models and also human patients. 14 In the present study, to examine the potential role of Wnt signalling pathway in hippocampal neurogenesis, we used the rat model of temporal lobe epilepsy by Zhengyi Qu and Fang Su contributed equally intracerebral injection of kainic acid, a well-established model with similar neuropathological and electroencephalographic features that are seen in patients with temporal lobe epilepsy. 15 Our results indicated that the Wnt pathway was activated after kainic acid injection, which may contribute to the structural and functional abnormality of hippocampus in temporal lobe epilepsy.…”

mentioning

confidence: 99%

Wnt/β‐catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid‐induced epilepsy

et al. 2017

Cell Biochemistry & Function

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Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis with massive neuronal loss and severe gliosis. Aberrant neurogenesis has been shown in the epileptogenesis process of temporal lobe epilepsy. However, the molecular mechanisms underlying aberrant neurogenesis remain unclear. The roles of Wnt signalling cascade have been well established in neurogenesis during multiple aspects. Here, we used kainic acid-induced rat epilepsy model to investigate whether Wnt/β-catenin signalling pathway is involved in the aberrant neurogenesis in temporal lobe epilepsy. Immunostaining and western blotting results showed that the expression levels of β-catenin, Wnt3a, and cyclin D1, the key regulators in Wnt signalling pathway, were up-regulated during acute epilepsy induced by the injection of kainic acids, indicating that Wnt signalling pathway was activated in kainic acid-induced temporal lobe epilepsy. Moreover, BrdU labelling results showed that blockade of the Wnt signalling by knocking down β-catenin attenuated aberrant neurogenesis induced by kainic acids injection. Altogether, Wnt/β-catenin signalling pathway mediated hippocampal neurogenesis during epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis. Aberrant neurogenesis has been shown to involve in the epileptogenesis process of temporal lobe epilepsy. In the present study, we discovered that Wnt3a/β-catenin signalling pathway serves as a link between aberrant neurogenesis and underlying remodelling in the hippocampus, leading to temporal lobe epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy.

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“…More recently, bioinformatics and transcriptomic approaches have been used in thalamic neurons [79], or human neural progenitor cells [41], to identify Wnt/ β -catenin target genes involved in neuronal excitation or neurodegenerative diseases, including Alzheimer's disease. In this regard, multiple lines of evidence support a functional role for Wnt/ β -catenin signaling in prevalent neurological disorders related to synaptic dysfunction including autism, Alzheimer's disease, or epilepsy [80–83]. Nevertheless, although these studies have resulted in hundreds of potential novel candidates, the expression of those target genes shows minimal overlap (less than 2%) in different cell backgrounds (Supplementary Figure 3b), likely due to cell-type specific transcriptional and/or translational mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Early Transcriptional Changes Induced by Wnt/β-Catenin Signaling in Hippocampal Neurons

et al. 2016

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Wnt/β-catenin signaling modulates brain development and function and its deregulation underlies pathological changes occurring in neurodegenerative and neurodevelopmental disorders. Since one of the main effects of Wnt/β-catenin signaling is the modulation of target genes, in the present work we examined global transcriptional changes induced by short-term Wnt3a treatment (4 h) in primary cultures of rat hippocampal neurons. RNAseq experiments allowed the identification of 170 differentially expressed genes, including known Wnt/β-catenin target genes such as Notum, Axin2, and Lef1, as well as novel potential candidates Fam84a, Stk32a, and Itga9. Main biological processes enriched with differentially expressed genes included neural precursor (GO:0061364, p-adjusted = 2.5 × 10−7), forebrain development (GO:0030900, p-adjusted = 7.3 × 10−7), and stem cell differentiation (GO:0048863 p-adjusted = 7.3 × 10−7). Likewise, following activation of the signaling cascade, the expression of a significant number of genes with transcription factor activity (GO:0043565, p-adjusted = 4.1 × 10−6) was induced. We also studied molecular networks enriched upon Wnt3a activation and detected three highly significant expression modules involved in glycerolipid metabolic process (GO:0046486, p-adjusted = 4.5 × 10−19), learning or memory (GO:0007611, p-adjusted = 4.0 × 10−5), and neurotransmitter secretion (GO:0007269, p-adjusted = 5.3 × 10−12). Our results indicate that Wnt/β-catenin mediated transcription controls multiple biological processes related to neuronal structure and activity that are affected in synaptic dysfunction disorders.

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The Role of Wnt/β-Catenin Signaling Pathway in Disrupted Hippocampal Neurogenesis of Temporal Lobe Epilepsy: A Potential Therapeutic Target?

Cited by 47 publications

References 130 publications

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Wnt/β‐catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid‐induced epilepsy

Early Transcriptional Changes Induced by Wnt/β-Catenin Signaling in Hippocampal Neurons

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