Background: The GluN2B subunit of the N-methyl-D-aspartate receptor (NMDAr) modulates many physiological processes including learning, memory, and pain. Excessive increase in NMDAr/GluN2B activity has been associated with various disorders such neuropathic pain and neuronal death following hypoxia. Thus there is an interest in identifying NMDAr antagonists that interact specifically with the GluN2B subunit. Recently based on structural analysis between the GluN2B subunit and conantokin-G, a toxin that interacts selectively with the GluN2B subunit, we designed various peptides that are predicted to act as NMDAr antagonists by interacting with the GluN2B subunit. In this study we tested this prediction for two of these peptides EAR16 and EAR18.
Results: The effects of EAR16 and EAR18 in NMDA-evoked currents were measured in cultured rat embryonic hippocampal neurons and in HEK-293 cells expressing recombinant NMDAr comprised of GluN1a-GluN2A or GluN1a-GluN2B subunits. In hippocampal neurons, EAR16 and EAR18 reduced the NMDA-evoked calcium currents in a dose-dependent and reversible manner with comparable IC50 (half maximal inhibitory concentration) values of 241 and 176 µM, respectively. At 500 µM, EAR16 blocked more strongly the NMDA-evoked currents mediated by the GluN1a-GluN2B (84%) than those mediated by the GluN1a-GluN2A (50%) subunits. At 500 µM, EAR18 blocked to a similar extent the NMDA-evoked currents mediated by the GluN1a-GluN2B (62%) and the GluN1a-GluN2A (55%) subunits.
Conclusions: The newly designed EAR16 and EAR18 peptides were shown to block in reversible manner NMDA-evoked currents, and EAR16 showed a stronger selectivity for GluN2B than for GluN2A.
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http://dx.doi.org/10.1186/s12868-017-0361-4 | DOI Listing |
Alzheimers Res Ther
January 2025
MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.
Background: Fluoroethylnormemantine (FENM), a new Memantine (MEM) derivative, prevented amyloid-β[25-35] peptide (Aβ)-induced neurotoxicity in mice, a pharmacological model of Alzheimer's disease (AD) with high predictive value for drug discovery. Here, as drug infusion is likely to better reflect drug bioavailability due to the interspecies pharmacokinetics variation, we analyzed the efficacy of FENM after chronic subcutaneous (SC) infusion, in comparison with IP injections in two AD mouse models, Aβ-injected mice and the transgenic APP/PSEN1 (APP/PS1) line.
Methods: In Aβ-treated mice, FENM was infused at 0.
Neurosci Lett
December 2024
School of Biomedical Engineering and Sciences, Virginia Tech, Blacksburg, VA, USA; Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA, USA; Veterans Affairs Medical Center, Salem, VA, USA. Electronic address:
Regulation of glutamate through glutamate-glutamine cycling is critical for mediating nervous system plasticity. Blast-induced traumatic brain injury (bTBI) has been linked to glutamate-dependent excitotoxicity, which may be potentiating chronic disorders such as post-traumatic epilepsy. The purpose of this study was to measure changes in the expression of astrocytic and neuronal proteins responsible for glutamatergic regulation at 4-, 12-, and 24 h in the cortex and hippocampus following single blast exposure in a rat model for bTBI.
View Article and Find Full Text PDFbioRxiv
December 2024
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305.
The rich diversity of synapses facilitates the capacity of neural circuits to transmit, process and store information. Here, we used multiplex super-resolution proteometric imaging through array tomography to define features of single synapses in the adult mouse neocortex. We find that glutamatergic synapses cluster into subclasses that parallel the distinct biochemical and functional categories of receptor subunits: GluA1/4, GluA2/3 and GluN1/GluN2B.
View Article and Find Full Text PDFEcotoxicol Environ Saf
December 2024
Department of Pediatrics, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, China; Department of Chinese Medicine, Jinan Geriatric/Rehabilitation Hospital, Jinan 250013, China; Graduate School of Guangzhou University of Chinese Medicine; Guangzhou 510006, China; Department of Proctology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, China. Electronic address:
Subchronic exposure to cyanuric acid (CA) and its structural analogue melamine induces long-term effects on brain and behavior in male rodents. To examine if this exposure induced negative effects on cognitive function in females, we examined the behavioral performance and further attempted to investigate synaptic and neuronal function. CA was intraperitoneal treated with 20 or 40 mg/kg/day to adolescent female rats for 4 consecutive weeks.
View Article and Find Full Text PDFJ Lipid Res
November 2024
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore; Cardiovascular Research Institute, National University Health System, Singapore, Singapore. Electronic address:
Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1, and in Wt mice administered CDCA, stroke infarct area was reduced.
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