NGF-Dependent activation of TrkA pathway: A mechanism for the neuroprotective effect of troxerutin in D-galactose-treated mice.
D-galactose-(D-gal)-treated mouse, with cognitive impairment, has been used for neurotoxicity investigation and anti-neurotoxicity pharmacology research. In this study, we investigated the mechanism underlying the neuroprotective effect of troxerutin. The results showed that troxerutin improved behavioral performance in D-gal-treated mice by elevating Cu, Zn-superoxide dismutases (Cu, Zn-SOD) activity and decreasing reactive oxygen species levels. Furthermore, our results showed that troxerutin significantly promoted nerve growth factor (NGF) mRNA expression which resulted in TrkA activation. On one hand, NGF/TrkA induced activation of Akt and ERK1/2, which led to neuronal survival; on the other hand, NGF/TrkA mediated CaMKII and CREB phosphorylation and increased PSD95 expression, which improved cognitive performance. However, the neuroprotective effect of troxerutin was blocked by treatment with K252a, an antagonist for TrkA. No neurotoxicity was observed in mice treated with K252a or troxerutin alone. In conclusion, administration of troxerutin to D-gal-injected mice attenuated cognitive impairment and brain oxidative stress through the activation of NGF/TrkA signaling pathway.
Lu
Jun
J
Xuzhou Normal University, Jiangsu Province, China.
Wu
Dong-mei
DM
Hu
Bin
B
Zheng
Yuan-lin
YL
Zhang
Zi-feng
ZF
Wang
Yong-jian
YJ
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D003072:Cognition Disorders / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005690:Galactose / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D051528:Guanylate Kinases; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives* / Q000627:therapeutic use; D026121:Indole Alkaloids / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D020932:Nerve Growth Factor / Q000235:genetics / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism
D002227:Carbazoles; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D004791:Enzyme Inhibitors; D006896:Hydroxyethylrutoside; D026121:Indole Alkaloids; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C005865:troxerutin; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; D013482:Superoxide Dismutase; D050882:CREB-Binding Protein; D020917:Receptor, trkA; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051528:Guanylate Kinases; D005690:Galactose
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