作者: Oliveira-Lima, Onésia Cristina ; Ulrich, Henning ; Nunes, Antonio Ítalo Dos Santos ; Silva, Eduardo Rosa ; de Carvalho, Gustavo Almeida ; Chiareli, Raphaela Almeida ; Ortiz-Leoncini, Giovanni ; Pinto, Mauro Cunha Xavier ; da Silva, Eduardo Rosa ; dos Santos Nunes, Antônio Ítalo ; Gomez, Renato Santiago ; Leoncini, Giovanni Ortiz ; Chiarelli, Raphaela Almeida ; Cavalcante, Daniel Pereira

Glycine Transporter Type 1 (GlyT1) inhibition confers neuroprotection against different forms of cerebral damage. This effect occurs through the elevation of synaptic glycine concentrations, which enhances N-methyl-d-aspartate receptor (NMDAR) activation by glutamate. To investigate the neuroprotective mechanism of GlyT1 inhibition, we used the Middle Cerebral Artery Occlusion (MCAO) model in male C57BL/6 mice, aged 10-12 weeks. We administered N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl] sarcosine (NFPS), a GlyT1 inhibitor, 24 h prior to ischemia induction. NFPS pretreatment provided significant neuroprotection in the MCAO model, associated with modulation of pathways related to long-term potentiation. Specifically, GluN2A subunit expression was upregulated, while GluN2B subunit expression was downregulated in cortical areas, correlating with enhanced phosphorylation of CaMKIV and CREB proteins. Coadministration with the GluN2B antagonist Eliprodil or the CREB inhibitor C646 did not affect the neuroprotective effects of NFPS pretreatment, but TCN-201, a specific GluN2A antagonist, disrupted these effects. These findings suggest that GlyT1 inhibition mediates neuroprotection through activation of GluN2A-containing NMDARs and the GluN2A/CaMKIV/CREB signaling cascade, thereby modulating the balance between GluN2A and GluN2B subunits.

2023-12-26·Frontiers in Bioscience-Landmark

GluN2A Mediates PS-Induced Depressive-Like Behavior by Activating CaMKII and Inhibiting Myelinization

Article

作者: Huang, Huimei ; Jiang, Hongli ; Sun, Hongli

BACKGROUNDPrenatal stress (PS) can induce depression in offspring, but the underlying mechanisms are still unknown.OBJECTIVEThe aim of this work was to investigate the mechanism that underlies PS-induced depressive-like behavior in offspring.METHODSA prenatal restraint stress procedure was developed in which pregnant rats at GD14 to GD20 were placed head-first into a well-ventilated bottle three times each day and for 45 min each time. Depressive-like behavior in the male offspring was examined using the sucrose preference test (SPT) and the forced swim test (FST). The level of glutamate and the expression levels of GluN2A, p-CaMKII and myelin basic protein (MBP) in the hippocampus of PS-susceptible (PS-S) offspring were also evaluated. To clarify the mechanism by which PS leads to depression in offspring, the effects of excessive corticosterone were also investigated using an in vitro "injured neuronal" model.RESULTSThe glutamate level in the hippocampus of PS-S male offspring was significantly elevated compared to controls. The expression levels of GluN2A and p-CaMKII were also altered. In addition, the optical density of MBP staining and the expression levels of MBP mRNA and MBP protein were decreased, demonstrating impaired myelinization in the hippocampus. Treatment of PS-S offspring with the GluN2A receptor antagonist NVP-AAM077 resulted in antidepressant-like effects in the FST, as well as rescue of the MBP and p-CaMKII abnormalities.CONCLUSIONSThese findings indicate that GluN2A is a promising target in the development of pharmacotherapies for PS-induced depression.

2018-02-01·Neuroscience

Downregulation of Egr-1 Expression Level via GluN2B Underlies the Antidepressant Effects of Ketamine in a Chronic Unpredictable Stress Animal Model of Depression

Article

作者: Liu, Cai-Cai ; Wang, Hua-Hua ; Sun, Wen-Yao ; Lv, Yi-Dong ; Tian, Liu-Jun ; Zhang, Wei-Jie

Ketamine is a non-competitive antagonist of N-methyl-D-aspartate receptors (NMDARs). Growing evidence suggests that a single dose of ketamine produces a series of rapid and remarkable antidepressant properties. However, the mechanisms remain unclear. In our study, the antidepressant properties of a single dose of ketamine (10 mg/kg, i.p.) in mice exposed to chronic unpredictable stress (CUS) were assessed using the open-field test (OFT) and the forced swimming test (FST). Early growth response 1 (Egr-1) and postsynaptic density protein 95 (PSD-95) mRNA and protein expression levels were examined using qRT-PCR and western blot, respectively. Dendritic spine density in the CA1 region of the hippocampus was detected by Golgi staining. AMPAR currents in hippocampal slices were measured by electrophysiology. Our study showed that CUS induced a significant depression-like behavior accompanied by an upregulation of Egr-1 and downregulations of PSD-95, spine density, and AMPAR currents in the hippocampus, and a single dose of ketamine rapidly restored these changes. Interestingly, a single dose of Ro-25-6981 (an GluN2B antagonist, 10 mg/kg, i.p.) or Egr-1 siRNA, but not NVP AAM077 (an GluN2A antagonist, 10 mg/kg, i.p.), could produce the same antidepressant effects as ketamine. These data demonstrate that ketamine may produce its rapid antidepressant effects by downregulating the expression of Egr-1 via blocking GluN2B in the hippocampus.

100 项与 GluN2A inhibitors( Aptuit) 相关的药物交易

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