RT Journal Article
T1 A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice
A1 Companys Alemany, Júlia
A1 Turcu, Andreea L.
A1 Bellver Sanchis, Aina
A1 Loza García, María Isabel
A1 Brea Floriani, José Manuel
A1 Canudas, Anna M.
A1 Leiva, Rosana
A1 Vázquez, Santiago
A1 Pallàs, Mercè
A1 Griñán Ferré, Christian
K1 NMDAR antagonist
K1 Cognitive decline
K1 Neurodegeneration
K1 Aging
K1 Alzheimer’s disease
K1 Oxidative stress
K1 BDNF
K1 Apoptosis
AB 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
PB MDPI
YR 2020
FD 2020
LK http://hdl.handle.net/10347/23818
UL http://hdl.handle.net/10347/23818
LA eng
NO 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
NO This research was funded by Ministerio de Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI) and Fondo Europeo de Desarrollo Regional (MINECO-FEDER) (Projects SAF2017-82771-R, SAF2016-77703, SAF2015-68749 and SAF2017-90913), Xunta de Galicia (ED431C 2018/21) and Generalitat de Catalunya (2017 SGR 106)
DS Minerva
RD 24 abr 2026