Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 62, Issue 4, Pages 468-477Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2013.01.022
Keywords
Bis(propyl)-cognitin; Neuroprotection; Cerebellar granule neuron; Nitric oxide; Extracellular signal-regulated kinase; Phosphoinositide 3-kinase
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Funding
- Research Grants Council of Hong Kong [PolyU5609/09M, PolyU5609/11M, G-U952]
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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. (C) 2013 Elsevier Ltd. All rights reserved.
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