Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/31772
Title: Bis(propyl)-cognitin protects against glutamate-induced neuro-excitotoxicity via concurrent regulation of NO, MAPK/ERK and PI3-K/Akt/GSK3 beta pathways
Authors: Hu, S
Cui, W
Mak, S
Tang, J
Choi, C
Pang, Y
Han, Y 
Keywords: Bis(propyl)-cognitin
Neuroprotection
Cerebellar granule neuron
Nitric oxide
Extracellular signal-regulated kinase
Phosphoinositide 3-kinase
Issue Date: 2013
Publisher: Pergamon-Elsevier Science Ltd
Source: Neurochemistry international, 2013, v. 62, no. 4, p. 468-477 How to cite?
Journal: Neurochemistry International 
Abstract: We have previously reported that bis(propyl)-cognitin (B3C), similar to memantine (MEM), is an uncompetitive N-methyl-D-aspartate receptor antagonist with fast off-rate property. In the current study, we further demonstrated that in primary cultures of rat cerebellar granule neurons (CGNs), 2 h pretreatment of B3C (IC50, 0.45 mu M) prevented glutamate-induced excitotoxicity 10 times more potently than memantine (IC50, 4.58 mu M), as evidenced by cell viability and lactate dehydrogenase release assays. Additionally, B3C pretreatment could inhibit the increase of intracellular nitric oxide (NO) and the activation of phosphorylated ERK, and reverse the suppression of phosphorylated Akt and GSK3 beta caused by glutamate. Furthermore, the neuroprotection of B3C was abolished by phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. Meanwhile, pharmacological inhibition showed that neither the single specific inhibitors of nitric oxide synthase (L-NMMA), MEK1/2 (U0126) and GSK3 beta (SB415286 and LiCl) nor the combinations of any two of them could fully protect against glutamate-induced apoptosis. However, the co-application of these three inhibitors produced nearly 100% inhibition of glutamate-induced apoptosis. These results taken together suggest that B3C elicits neuroprotection against glutamate-induced neurotoxicity in CGNs via concurrent inhibition of NO, MAPK/ERK pathways and activation of PI3-K/Akt/GSK3 beta pathway. Combining these and our previous publications, it is conjectured that the dimer might be an ideal candidate drug in delaying the course of neurodegeneration related with Alzheimer's disease.
URI: http://hdl.handle.net/10397/31772
ISSN: 0197-0186
DOI: 10.1016/j.neuint.2013.01.022
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