PI3K-AKT-GSK3β-CREB signaling pathway regulates anxiety-like behavior in rats following alcohol withdrawal

Qiao, Xin; Gai, Hai-Yun; Su, Rui; Deji, Cuola; Cui, Jingjing; Lai, Jianghua; Zhu, Yan

doi:10.1016/j.jad.2018.04.039

Cited by 33 publications

(18 citation statements)

References 46 publications

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“…The discrepancy may be attributable to different efficacies of MEM in different animal models. Previous studies have implicated AKT-GSK3 β signaling in anxiety-like behavior after alcohol withdrawal [53]. In our study, CRS-induced anxiety-like behavior was accompanied by an upregulation of p-AKT levels following both short and long CRS regimens.…”

Section: Discussionsupporting

confidence: 59%

Memantine Differentially Regulates Tau Phosphorylation Induced by Chronic Restraint Stress of Varying Duration in Mice

et al. 2019

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Exposure to chronic psychiatric stress has been linked to Alzheimer’s disease-related tau hyperphosphorylation and abnormalities in glutamate neurotransmission. However, the pathological relationship between glutamatergic dysfunction and tau phosphorylation in the cerebral cortex under chronic psychiatric stress is not fully understood. The present study investigated the effects of memantine (MEM, 5 and 10 mg/kg), an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, on chronic restraint stress- (CRS-) induced tau phosphorylation in mice. CRS administered for 16 or 28 consecutive days (1 h daily) induced significant tau phosphorylation in the brain. MEM treatment suppressed the elevation of phosphorylated tau (P-tau) levels induced by 16-day CRS in a dose-dependent manner. P-tau reduction was accompanied by the attenuation of the upregulation of GSK3β and CDK5 expression and the downregulation of PP2A activity induced by CRS. Additionally, MEM reduced CRS-induced upregulation of NMDA receptor subunit levels (GluN2A, GluN2B) in the frontal cortex. However, MEM markedly enhanced tau phosphorylation in the frontal cortex and other cerebral cortical regions following 28 days of CRS. The stimulatory effect of MEM on CRS-induced tau phosphorylation was correlated with increased activities of AKT, JNK, and GSK3β, inactivation of PP2A, and downregulation of Pin1 and HSP70. Moreover, MEM did not effectively reverse the NMDA receptor upregulation induced by 28-day CRS and even increased GluN2B subunit levels. In contrast to the duration-dependent effects of MEM on P-tau levels, MEM produced an anxiolytic effect in both regimens as revealed by elevated plus maze testing. However, MEM did not affect the body weight reduction induced by CRS. Thus, MEM exerts distinctive effects on CRS-induced tau phosphorylation, which might be related to the expression of GluN2B. The differential effects of MEM on P-tau levels have crucial implications for its clinical application.

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Section: Discussionsupporting

confidence: 59%

Memantine Differentially Regulates Tau Phosphorylation Induced by Chronic Restraint Stress of Varying Duration in Mice

et al. 2019

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“…Aberrant GSK‐3β activation is associated with neurodegeneration and neuroinflammation, and is known to affect transcription factors involved in inflammatory activation (Eldar‐Finkelman & Martinez, 2011; Maixner & Weng, 2013). Among these transcription factors, CREB ‐ a leucine zipper transcription factor that regulates immune‐related genes (Wen, Sakamoto, & Miller, 2010) ‐ is activated by Akt signaling through inhibition of GSK‐3β (Qiao et al, 2018). However, whether mGluR5 PAM regulate microglial activation through Akt/GSK‐3β/CREB signaling has not been examined.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Akt/GSK‐3β/CREB signaling mediates the anti‐inflammatory actions of mGluR5 positive allosteric modulators in microglia and following traumatic brain injury in male mice

Bhat

Henry

Blanchard

et al. 2020

Journal of Neurochemistry

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We have previously shown that treatment with a mGluR5 positive allosteric modulator (PAM) is neuroprotective after experimental traumatic brain injury (TBI), limiting post‐traumatic neuroinflammation by reducing pro‐inflammatory microglial activation and promoting anti‐inflammatory and neuroprotective responses. However, the specific molecular mechanisms governing this anti‐inflammatory shift in microglia remain unknown. Here we show that the mGluR5 PAM, VU0360172 (VuPAM), regulates microglial inflammatory responses through activation of Akt, resulting in the inhibition of GSK‐3β. GSK‐3β regulates the phosphorylation of CREB, thereby controlling the expression of inflammation‐related genes and microglial plasticity. The anti‐inflammatory action of VuPAM in microglia is reversed by inhibiting Akt/GSK‐3β/CREB signaling. Using a well‐characterized TBI model and CX3CR1gfp/+ mice to visualize microglia in vivo, we demonstrate that VuPAM enhances Akt/GSK‐3β/CREB signaling in the injured cortex, as well as anti‐inflammatory microglial markers. Furthermore, in situ analysis revealed that GFP + microglia in the cortex of VuPAM‐treated TBI mice co‐express pCREB and the anti‐inflammatory microglial phenotype marker YM1. Taken together, our data show that VuPAM decreases pro‐inflammatory microglial activation by modulating Akt/GSK‐3β/CREB signaling. These findings serve to clarify the potential neuroprotective mechanisms of mGluR5 PAM treatment after TBI, and suggest novel therapeutic targets for post‐traumatic neuroinflammation. Cover Image for this issue: https://doi.org/10.1111/jnc.15048.

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“…Wortmannin (WT), a potent and selective inhibitor of PI3K, was applied to inhibit the activation of PI3K and thus to prevent the activation of PKB. 11,12 Evidence indicates that WT may decrease inflammatory cytokines in SAP rats and suggests its regulatory mechanisms may involve the suppression of NF-κB and p38MAPK activity. 13 The aims of the study were: 1) to investigate intestinal barrier function through intestinal permeability changes; 2) to study the relationship between PI3K/PKB signal transduction pathway and SAP intestinal injuries by measuring the expression levels of P-PKB and PKB in intestinal tissue; and 3) to observe the role of WT in intestinal injury in SAP rats, as to study its possible mechanism.…”

Section: Introductionmentioning

confidence: 99%

Effect of PI3K/PKB signal pathway inhibitor wortmannin pretreatment on intestinal barrier function in severe acute pancreatitic rats

Tang¹,

Wang²,

Wang³

et al. 2019

Adv Clin Exp Med

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Background. It is well-known that severe acute pancreatitis (SAP) due to infection is mainly caused by intestinal bacterial translocation. The intestinal barrier is tasked with preventing intestinal pathogenic bacteria and toxins from reaching the parenteral tissues through the intestinal wall. Therefore, maintaining intestinal barrier function may be the key to preventing damage from acute pancreatitis (AP). The phosphatidylinositol 3-kinase/protein kinase B pathway (PI3K/PKB) plays a role in AP. However, the exact effect of PI3K/PKB on injury associated with SAP has not yet been found. Objectives. The present study was aimed at investigating the impact of wortmannin (WT), a PI3K/PKB inhibitor, on intestinal barrier function in SAP rats. Material and methods. The rats were divided into 3 groups: 1) the Sham Surgery group (SS), whose duodenum and pancreas were flipped 3 times (n = 18); 2) the pancreatitis group (SAP), who were injected through retrograde pancreatic duct injection with 5% sodium taurocholate (n = 18); and 3) the WSAP intervention group (SAP+WT). Serum alpha-amylase levels, plasma endogenous endotoxin, hematoxylineosin (H&E) staining, intestinal mucosa electron microscopy, intestinal permeability, and expression of p-PKB (phosphorylated protein kinase B) were measured. Results. In our findings under an electron microscope, the SAP group presented cell edema and mitochondrial vacuolated degeneration, sparsely arranged microvilli, tight junction damage, and widening, while the WSAP group exhibited less change and lower pancreas scores (7.4 ±1. 14, 10.2 ±1.48 and 12.0 ±1.58 for 3 h, 6 h and 12 h, respectively) (p < 0.05). Furthermore, the plasma endogenous endotoxin levels and Evans blue content of the WSAP group was significantly lower at all timepoints than in the SAP group (p < 0.05). Western blotting showed that p-PKB expression was lower in the WSAP group than in the SAP group (p < 0.05). Our study suggests that WT relieves intestinal permeability changes in SAP rats and may be dose-dependent. Conclusions. The PI3K/PKB signal pathway may involve SAP-related intestinal injuries and WT may relieve SAP intestinal injuries through the PI3K/PKB pathway.

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PI3K-AKT-GSK3β-CREB signaling pathway regulates anxiety-like behavior in rats following alcohol withdrawal

Cited by 33 publications

References 46 publications

Memantine Differentially Regulates Tau Phosphorylation Induced by Chronic Restraint Stress of Varying Duration in Mice

Memantine Differentially Regulates Tau Phosphorylation Induced by Chronic Restraint Stress of Varying Duration in Mice

Enhanced Akt/GSK‐3β/CREB signaling mediates the anti‐inflammatory actions of mGluR5 positive allosteric modulators in microglia and following traumatic brain injury in male mice

Effect of PI3K/PKB signal pathway inhibitor wortmannin pretreatment on intestinal barrier function in severe acute pancreatitic rats

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