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Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-d-aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro

  • Pierluigi Valente
    Pierluigi Valente
    Department of Experimental Medicine, University of Genoa, Genoa 16132, Italy
    IRCSS Ospedale Policlinico San Martino, Genoa 16132, Italy
  • Darya Kiryushko
    Darya Kiryushko
    Department of Materials and London Center for Nanotechnology, Imperial College London, London SW7 2AZ, United Kingdom
    Center for Neuroinflammation and Neurodegeneration, Imperial College London, London W12 0NN, United Kingdom
  • Silvio Sacchetti
    Silvio Sacchetti
    Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genoa 16132, Italy
  • Pedro Machado
    Pedro Machado
    Centre for Ultrastructural Imaging, Kings College London, London SE1 1UL, United Kingdom
  • Claire M. Cobley
    Claire M. Cobley
    Department of Physical Chemistry, University of Heidelberg, Heidelberg 69120, Germany
    Max Planck Institute for Intelligent Systems, Stuttgart 70569, Germany
  • Vincenzo Mangini
    Vincenzo Mangini
    Center for Biomolecular [email protected], Istituto Italiano di Tecnologia, Arnesano, Lecce 73010, Italy
  • Alexandra E. Porter
    Alexandra E. Porter
    Department of Materials and London Center for Nanotechnology, Imperial College London, London SW7 2AZ, United Kingdom
  • Joachim P. Spatz
    Joachim P. Spatz
    Department of Physical Chemistry, University of Heidelberg, Heidelberg 69120, Germany
    Max Planck Institute for Medical Research, Heidelberg 69120, Germany
  • Roland A. Fleck
    Roland A. Fleck
    Centre for Ultrastructural Imaging, Kings College London, London SE1 1UL, United Kingdom
  • Fabio Benfenati
    Fabio Benfenati
    Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genoa 16132, Italy
    IRCSS Ospedale Policlinico San Martino, Genoa 16132, Italy
  • , and 
  • Roberto Fiammengo*
    Roberto Fiammengo
    Center for Biomolecular [email protected], Istituto Italiano di Tecnologia, Arnesano, Lecce 73010, Italy
    *Email: [email protected]
Cite this: ACS Nano 2020, 14, 6, 6866–6877
Publication Date (Web):June 8, 2020
https://doi.org/10.1021/acsnano.0c00866
Copyright © 2020 American Chemical Society
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Supporting Info (1)»

Abstract

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N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors controlling fundamental physiological processes in the central nervous system, such as learning and memory. Excessive activation of NMDARs causes excitotoxicity and results in neurodegeneration, which is observed in a number of pathological conditions. Because of their dichotomous role, therapeutic targeting of NMDAR is difficult. However, several lines of evidence suggest that excitotoxicity is predominantly linked to extrasynaptically located NMDARs. Here, we report on a nanoparticle-based strategy to inhibit extrasynaptic NMDARs exclusively and subtype selectively, while allowing synaptic NMDARs activity. We designed gold nanoparticles (AuNPs) carrying conopeptide derivatives conjugated on their poly(ethylene glycol) coating as allosteric NMDAR inhibitors and show that these nanoparticles antagonize exclusively extrasynaptic NMDAR-mediated currents in cultured hippocampal neurons. Additionally, we show that conopeptide-functionalized AuNPs are neuroprotective in an in vitro model of excitotoxicity. By using AuNPs carrying different allosteric inhibitors with distinct NMDAR subtype selectivity such as peptide conantokin-G or peptide conantokin-R, we suggest activation of extrasynaptic GluN2B-containing diheteromeric NMDARs as the main cause of excitotoxicity.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c00866.

  • Peptide sequences (Table S1), preparation procedures for AuNPs 13, TEM micrograph of AuNPs and DLS size distributions (Figure S1, Table S2), and protocol for preparation of hippocampal neuron cultures. Protocol for TEM imaging of neurons treated with AuNPs and reconstruction of very large stitched images (Figure S2). Statistical analysis of the data shown in Figure 5a–c choosing the untreated group as the control group (Table S3) and statistical analysis methods. Treatment of cultured neurons with conopeptide derivatives in solution (Figures S3 and S4). Incubation of neurons with 1.0 nM conopeptide-functionalized AuNPs 13 (no NMDA, Figure S5) (PDF)

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Cited By


This article is cited by 7 publications.

  1. Pierluigi Valente, Darya Kiryushko, Silvio Sacchetti, Pedro Machado, Claire M. Cobley, Vincenzo Mangini, Alexandra E. Porter, Joachim P. Spatz, Roland A. Fleck, Fabio Benfenati, Roberto Fiammengo. Reply to Comment on Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-d-aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro. ACS Nano 2021, 15 (10) , 15409-15417. https://doi.org/10.1021/acsnano.1c05607
  2. Elena Molokanova, Gary B. Braun. Comment on Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-d-Aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro. ACS Nano 2021, 15 (10) , 15402-15408. https://doi.org/10.1021/acsnano.1c01189
  3. Aijie Chen, Yiyuan Kang, Jia Liu, Junrong Wu, Xiaoli Feng, Menglei Wang, Yanli Zhang, Ruolan Wang, Xuan Lai, Longquan Shao. Improvement of synaptic plasticity by nanoparticles and the related mechanisms: Applications and prospects. Journal of Controlled Release 2022, 347 , 143-163. https://doi.org/10.1016/j.jconrel.2022.04.049
  4. Shanshan Zhang, Yuan Zhou, Ruoqi Li, Zhong Chen, Xiang Fan. Advanced drug delivery system against ischemic stroke. Journal of Controlled Release 2022, 344 , 173-201. https://doi.org/10.1016/j.jconrel.2022.02.036
  5. Varun Dhiman, Deepak Pant, Tejpal Dhewa, Anita Padam. A Review on the Antidiabetic and Anticancer Activities of Conus Venom Peptides. Journal of Biologically Active Products from Nature 2021, 11 (5-6) , 413-441. https://doi.org/10.1080/22311866.2021.1944316
  6. Yiu Chung Tse, Moushumi Nath, Amanda Larosa, Tak Pan Wong. Opposing Changes in Synaptic and Extrasynaptic N-Methyl-D-Aspartate Receptor Function in Response to Acute and Chronic Restraint Stress. Frontiers in Molecular Neuroscience 2021, 14 https://doi.org/10.3389/fnmol.2021.716675
  7. Maurizio Villani, Federico Bertoglio, Elisa Restivo, Giovanna Bruni, Stefano Iervese, Carla Renata Arciola, Francesco Carulli, Salvatore Iannace, Fabio Bertini, Livia Visai. Polyurethane-Based Coatings with Promising Antibacterial Properties. Materials 2020, 13 (19) , 4296. https://doi.org/10.3390/ma13194296

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