Luo_2010_J.Biol.Chem_285_19947

Reference

Title : Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin - Luo_2010_J.Biol.Chem_285_19947
Author(s) : Luo J , Li W , Zhao Y , Fu H , Ma DL , Tang J , Li C , Peoples RW , Li F , Wang Q , Huang P , Xia J , Pang Y , Han Y
Ref : Journal of Biological Chemistry , 285 :19947 , 2010
Abstract : Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and gamma-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [(3)H]MK-801 with a K(i) value of 0.27 mum, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.
ESTHER : Luo_2010_J.Biol.Chem_285_19947
PubMedSearch : Luo_2010_J.Biol.Chem_285_19947
PubMedID: 20404346

Related information

Citations formats

Luo J, Li W, Zhao Y, Fu H, Ma DL, Tang J, Li C, Peoples RW, Li F, Wang Q, Huang P, Xia J, Pang Y, Han Y (2010)
Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin
Journal of Biological Chemistry 285 :19947

Luo J, Li W, Zhao Y, Fu H, Ma DL, Tang J, Li C, Peoples RW, Li F, Wang Q, Huang P, Xia J, Pang Y, Han Y (2010)
Journal of Biological Chemistry 285 :19947