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Open AccessArticle

A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice

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Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain
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Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Department de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l’Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain
3
Innopharma Screening Platform, Biofarma Research Group, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, 15701 Santiago de Compostela, Spain
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(3), 284; https://doi.org/10.3390/pharmaceutics12030284
Received: 20 February 2020 / Revised: 9 March 2020 / Accepted: 17 March 2020 / Published: 22 March 2020
(This article belongs to the Section Drug Targeting and Design)
Alzheimer’s disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo efficacy of the RL-208, a new NMDA receptor blocker described recently, with favourable pharmacokinetic properties was evaluated in Senescence accelerated mice prone 8 (SAMP8), a mice model of late-onset AD (LOAD). Oral administration of RL-208 improved cognitive performance assessed by using the three chamber test (TCT), novel object recognition test (NORT), and object location test (OLT). Consistent with behavioural results, RL-208 treated-mice groups significantly changed NMDAR2B phosphorylation state levels but not NMDAR2A. Calpain-1 and Caspase-3 activity was reduced, whereas B-cell lymphoma-2 (BCL-2) levels increased, indicating reduced apoptosis in RL-208 treated SAMP8. Superoxide Dismutase 1 (SOD1) and Glutathione Peroxidase 1 (GPX1), as well as a reduction of hydrogen peroxide (H2O2), was also determined in RL-208 mice. RL-208 treatment induced an increase in mature brain-derived neurotrophic factor (mBDNF), prevented Tropomyosin-related kinase B full-length (TrkB-FL) cleavage, increased protein levels of Synaptophysin (SYN) and Postsynaptic density protein 95 (PSD95). In whole, these results point out to an improvement in synaptic plasticity. Remarkably, RL-208 also decreased the protein levels of Cyclin-Dependent Kinase 5 (CDK5), as well as p25/p35 ratio, indicating a reduction in kinase activity of CDK5/p25 complex. Consequently, lower levels of hyperphosphorylated Tau (p-Tau) were found. In sum, these results demonstrate the neuroprotectant role of RL-208 through NMDAR blockade. View Full-Text
Keywords: NMDAR antagonist; cognitive decline; neurodegeneration; aging; Alzheimer’s disease; oxidative stress; BDNF; apoptosis NMDAR antagonist; cognitive decline; neurodegeneration; aging; Alzheimer’s disease; oxidative stress; BDNF; apoptosis
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Companys-Alemany, J.; Turcu, A.L.; Bellver-Sanchis, A.; Loza, M.I.; Brea, J.M.; Canudas, A.M.; Leiva, R.; Vázquez, S.; Pallàs, M.; Griñán-Ferré, C. A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice. Pharmaceutics 2020, 12, 284.

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