Roscovitine, a CDK5 Inhibitor, Alleviates Sevoflurane-Induced Cognitive Dysfunction via Regulation Tau/GSK3β and ERK/PPARγ/CREB Signaling

Liu, Jianhui; Yang, Junjun; Xu, Yaolin; Guo, Gang; Cai, Li; Wu, Haitao; Zhao, Yanhong; Zhang, Xiaoqing

doi:10.1159/000485008

Cited by 31 publications

(21 citation statements)

References 28 publications

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“…For example, downregulation of GFAP expression by PPARγ depends on cyclin‐dependent kinase 5 (CDK5)‐evoked phosphorylation of PPARγ at serine 112. Moreover, activation of CDK5 increases glycogen synthase kinase‐3β and suppresses the activity of extracellular signal‐regulated protein kinase (ERK) 1/2/cyclic AMP response element‐binding protein signaling following sevoflurane exposure (Liu et al, ). Since glycogen synthase kinase‐3β is a cell apoptosis signal (Wang et al, ) and phosphorylated ERK 1/2 (pERK1/2) is a mitogenic kinase, changes in their activities by CDK5 can reduce astrocytic differentiation and GFAP expression (Hilliard et al, ).…”

Section: Expression Of Gfap and Its Regulationmentioning

confidence: 99%

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Liu

et al. 2019

Glia

117

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Glial fibrillary acidic protein (GFAP), a type III intermediate filament, is a marker of mature astrocytes. The expression of GFAP gene is regulated by many transcription factors (TFs), mainly Janus kinase‐2/signal transducer and activator of transcription 3 cascade and nuclear factor κ‐light‐chain‐enhancer of activated B cell signaling. GFAP expression is also modulated by protein kinase and other signaling molecules that are elicited by neuronal activity and hormones. Abnormal expression of GFAP proteins occurs in neuroinflammation, neurodegeneration, brain edema‐eliciting diseases, traumatic brain injury, psychiatric disorders and others. GFAP, mainly in α‐isoform, is the major component of cytoskeleton and the scaffold of astrocytes, which is essential for the maintenance of astrocytic structure and shape. GFAP also has highly morphological plasticity because of its quick changes in assembling and polymerizing states in response to environmental challenges. This plasticity and its corresponding cellular morphological changes endow astrocytes the functions of physical barrier between adjacent neurons and stabilizer of extracellular environment. Moreover, GFAP colocalizes and even molecularly associates with many functional molecules. This feature allows GFAP to function as a platform for direct interactions between different molecules. Last, GFAP involves transportation and localization of other functional proteins and thus serves as a protein transport guide in astrocytes. This guiding role of GFAP involves an elastic retraction and extension cytoskeletal network that couples with GFAP reassembling, transporting, and membrane protein recycling machinery. This paper reviews our current understanding of the expression and functions of GFAP as well as their regulation.

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Section: Expression Of Gfap and Its Regulationmentioning

confidence: 99%

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Liu

et al. 2019

Glia

117

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“…Emerging evidence shows that SEV impairs memory consolidation in rats, possibly through inhibiting phosphorylation of GSK‐3β in the hippocampus . Also, our previous study already showed that SEV anesthesia caused alterations in apoptosis‐related proteins and GSK‐3β phosphorylation, and induced cognitive dysfunction in mice . In addition, it is reported that lithium treatment prevents apoptosis in neonatal rat hippocampus resulting from SEV exposure .…”

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confidence: 92%

Lithium chloride ameliorates cognition dysfunction induced by sevoflurane anesthesia in rats

Wang

Zhang

et al. 2020

FEBS Open Bio

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Postoperative cognitive dysfunction is a common complication in elderly patients after surgeries involving anesthesia, but the underlying mechanisms are poorly understood. Lithium is a conventional treatment for bipolar disorder, which exerts a neuroprotective role in various diseases by inhibiting glycogen synthase kinase‐3β (GSK‐3β) in the brain and spinal cord. However, it is not known whether lithium chloride (LiCl) can protect against cognitive dysfunction induced by sevoflurane (SEV) anesthesia. Here, we examined the effects of LiCl on SEV‐induced cognitive dysfunction in rats and on SEV‐induced neuron apoptosis. We report that anesthesia with SEV significantly impaired memory performance, induced oxidative stress and hippocampal neuron apoptosis, and stimulated GSK‐3β activity. Treatment with LiCl ameliorated SEV‐induced cognitive disorder in rats by inhibiting the GSK‐3β/β‐catenin signaling pathway. In addition, LiCl reduced hippocampal neuron apoptosis and oxidative stress induced by SEV anesthesia. These results suggest that LiCl may have potential for development into a therapeutic agent for treatment of SEV anesthesia‐induced cognitive dysfunction.

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“…Roscovitine reduced basal phosphorylation at AT8 (pSer202/pThr205) but did not affect the OA-induced tau hyperphosphorylation, reflecting its specificity and the selectivity to our cell models. Similarly, several recent studies revealed that inhibiting CDK5 with Roscovitine had neuroprotective properties against neurodegenerative conditions caused by decreasing tau phosphorylation (66, 76, 96). Like LiCl, Roscovitine resulted in opposite effects in the N2a cells by increasing phosphorylation at CP13 (pSer202) and PHF-1 (pSer396/pSer404).…”

Section: Discussionmentioning

confidence: 88%

Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

Yadikar

Torres

Aiello

et al. 2019

Preprint

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26Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of 27 post-translationally modified tau protein in the human brain. Tauopathies are associated with 28 Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. 29Hyperphosphorylation increases tau tendency to aggregate and forms neurofibrillary tangles 30 (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein 31 phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated 32 rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and 33 oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of 34 different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-35 immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), 36 pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation 37 and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric 38 bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl 39 (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) 40 caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX 41 culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator 42 (EGTA) showed conflicting results between the two neuronal cultures.This study provides a 43 comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their 44 efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant 45 further experimentation, possibly including animal models of tauopathies, which may provide a 46 putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative 47 diseases.48

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Roscovitine, a CDK5 Inhibitor, Alleviates Sevoflurane-Induced Cognitive Dysfunction via Regulation Tau/GSK3β and ERK/PPARγ/CREB Signaling

Cited by 31 publications

References 28 publications

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Lithium chloride ameliorates cognition dysfunction induced by sevoflurane anesthesia in rats

Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

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