TY - JOUR
T1 - Bis(propyl)-cognitin protects against glutamate-induced neuro-excitotoxicity via concurrent regulation of NO, MAPK/ERK and PI3-K/Akt/GSK3β pathways
AU - Hu, Shengquan
AU - Cui, Wei
AU - Mak, Shinghung
AU - Tang, Jing
AU - Choi, Chunglit
AU - Pang, Yuanping
AU - Han, Yifan
N1 - Funding Information:
This work was supported by grants from the Research Grants Council of Hong Kong ( PolyU5609/09M , PolyU5609/11M and G-U952 ). We sincerely thank Ms. Josephine LEUNG for proofreading our manuscript.
PY - 2013/3
Y1 - 2013/3
N2 - 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 μM) prevented glutamate-induced excitotoxicity 10 times more potently than memantine (IC50, 4.58 μM), 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 GSK3β 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 GSK3β (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/GSK3β 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.
AB - 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 μM) prevented glutamate-induced excitotoxicity 10 times more potently than memantine (IC50, 4.58 μM), 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 GSK3β 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 GSK3β (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/GSK3β 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.
KW - Bis(propyl)-cognitin
KW - Cerebellar granule neuron
KW - Extracellular signal-regulated kinase
KW - Neuroprotection
KW - Nitric oxide
KW - Phosphoinositide 3-kinase
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U2 - 10.1016/j.neuint.2013.01.022
DO - 10.1016/j.neuint.2013.01.022
M3 - Article
C2 - 23357479
AN - SCOPUS:84874595915
SN - 0197-0186
VL - 62
SP - 468
EP - 477
JO - Neurochemistry International
JF - Neurochemistry International
IS - 4
ER -