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Title: | A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice |
Author: | Companys Alemany, Júlia Turcu, Andreea L. Bellver-Sanchis, Aina Loza, María Isabel Brea, José Canudas Teixidó, Anna-Maria Leiva Martínez, Rosana Vázquez Cruz, Santiago Pallàs i Llibería, Mercè, 1964- Griñán Ferré, Christian |
Keywords: | Malalties neurodegeneratives Envelliment Malaltia d'Alzheimer Neurodegenerative Diseases Aging Alzheimer's disease |
Issue Date: | 22-Mar-2020 |
Publisher: | MDPI |
Abstract: | 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 e cacy 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/pharmaceutics12030284 |
It is part of: | Pharmaceutics, 2020, vol. 12, num. 3 |
URI: | http://hdl.handle.net/2445/173853 |
Related resource: | https://doi.org/10.3390/pharmaceutics12030284 |
ISSN: | 1999-4923 |
Appears in Collections: | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) Articles publicats en revistes (Institut de Neurociències (UBNeuro)) Articles publicats en revistes (Institut de Biomedicina (IBUB)) |
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