title: NGF-Dependent activation of TrkA pathway: A mechanism for the neuroprotective effect of troxerutin in D-galactose-treated mice.
abstract: 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.
authors.affiliation: Xuzhou Normal University, Jiangsu Province, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Dong-mei
authors.initials: DM
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Yuan-lin
authors.initials: YL
authors.lastname: Zheng
authors.forename: Zi-feng
authors.initials: ZF
authors.lastname: Zhang
authors.forename: Yong-jian
authors.initials: YJ
authors.lastname: Wang
mesh_terms: 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
chemical_list: 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
references.citation: Behav Brain Res. 2006 Aug 10;171(2):251-60
references.pmid: 16707173
references.citation: J Control Release. 2006 Jul 20;113(3):189-207
references.pmid: 16790290
references.citation: Behav Pharmacol. 1999 Dec;10(8):723-30
references.pmid: 10780287
references.citation: Free Radic Biol Med. 2001 Dec 1;31(11):1448-55
references.pmid: 11728817
references.citation: J Pharmacol Sci. 2007 Aug;104(4):329-34
references.pmid: 17666865
references.citation: Free Radic Biol Med. 1998 Jun;24(9):1477-84
references.pmid: 9641266
references.citation: J Neurochem. 2006 Jun;97(6):1634-58
references.pmid: 16805774
references.citation: Nat Neurosci. 1998 Nov;1(7):602-9
references.pmid: 10196568
references.citation: J Neurosci Res. 2006 Aug 15;84(3):647-54
references.pmid: 16710848
references.citation: Brain Behav Immun. 2009 Feb;23(2):193-203
references.pmid: 18835350
references.citation: Clin Sci (Lond). 2006 Feb;110(2):167-73
references.pmid: 16411893
references.citation: Cell. 1994 Jun 3;77(5):627-38
references.pmid: 8205613
references.citation: Neurol Res. 2005 Jul;27(5):552-6
references.pmid: 15978184
references.citation: Nat Med. 2005 May;11(5):551-5
references.pmid: 15852017
references.citation: Pharmacol Res. 2003 Aug;48(2):209-15
references.pmid: 12798674
references.citation: Brain Res Mol Brain Res. 2000 Mar 10;76(1):36-46
references.pmid: 10719213
references.citation: Neuron. 2000 Jan;25(1):11-4
references.pmid: 10707967
references.citation: Neurobiol Aging. 2008 Oct;29(10):1533-46
references.pmid: 17478013
references.citation: Behav Brain Res. 2005 Feb 28;157(2):245-51
references.pmid: 15639175
references.citation: Free Radic Biol Med. 2000 May 1;28(9):1405-20
references.pmid: 10924859
references.citation: J Neurosci. 2001 Feb 1;21(3):1047-55
references.pmid: 11157090
references.citation: Neuropsychobiology. 2002;46(4):186-9
references.pmid: 12566935
references.citation: Neurobiol Learn Mem. 2008 Jul;90(1):19-27
references.pmid: 18316211
references.citation: Science. 1987 Sep 4;237(4819):1154-62
references.pmid: 3306916
references.citation: Prog Neurobiol. 2004 Feb;72(2):111-27
references.pmid: 15063528
references.citation: Biochem Pharmacol. 2007 Oct 1;74(7):1078-90
references.pmid: 17692828
references.citation: J Biol Chem. 1999 Jun 18;274(25):17748-56
references.pmid: 10364217
references.citation: Biogerontology. 2003;4(1):15-8
references.pmid: 12652185
references.citation: Acta Pharmacol Sin. 2002 Jul;23(7):587-90
references.pmid: 12100749
references.citation: Yao Xue Xue Bao. 2002 Jan;37(1):1-4
references.pmid: 12579889
references.citation: J Neurosci. 2003 Jun 15;23(12):5354-60
references.pmid: 12832561
references.citation: J Neurosci. 1999 May 1;19(9):3535-44
references.pmid: 10212313
references.citation: J Neurochem. 2001 Jan;76(1):1-10
references.pmid: 11145972
references.citation: J Neurosci. 2000 Nov 1;20(21):8177-87
references.pmid: 11050141
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2008 Jul;148(1):1-5
references.pmid: 18400562
references.citation: FEBS Lett. 2006 Dec 11;580(28-29):6730-40
references.pmid: 17134702
references.citation: Ann N Y Acad Sci. 1998 Nov 20;854:435-42
references.pmid: 9928450
references.citation: Genes Dev. 2000 Dec 1;14(23):2919-37
references.pmid: 11114882
references.citation: Biochim Biophys Acta. 1998 Dec 8;1436(1-2):127-50
references.pmid: 9838078
references.citation: Nature. 1991 Mar 14;350(6314):158-60
references.pmid: 1706478
references.citation: Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5862-6
references.pmid: 1712109
references.citation: Neuron. 1992 Dec;9(6):1067-79
references.pmid: 1281417
references.citation: EMBO J. 1999 Feb 1;18(3):664-74
references.pmid: 9927426
references.citation: Neurosignals. 2006-2007;15(1):1-12
references.pmid: 16825799
references.citation: Neuroscience. 2006 Nov 3;142(4):1281-92
references.pmid: 16938401
references.citation: Life Sci. 2007 Apr 24;80(20):1897-905
references.pmid: 17391708
references.citation: Psychoneuroendocrinology. 2006 Aug;31(7):805-11
references.pmid: 16707226
references.citation: Science. 1991 Apr 26;252(5005):554-8
references.pmid: 1850549
references.citation: Neurobiol Learn Mem. 2010 Feb;93(2):157-64
references.pmid: 19766199
references.citation: EMBO J. 1996 Dec 2;15(23):6541-51
references.pmid: 8978681
references.citation: J Neurosci. 1991 Jul;11(7):1889-906
references.pmid: 1648601
references.citation: Brain Behav Immun. 2008 Nov;22(8):1156-9
references.pmid: 18620042
references.citation: Neuropsychobiology. 2002;46(1):27-32
references.pmid: 12207144
references.citation: Mol Cell Neurosci. 2005 Jun;29(2):162-72
references.pmid: 15911341
references.citation: Biogerontology. 2007 Jun;8(3):373-81
references.pmid: 17473993
references.citation: Biomed Environ Sci. 2003 Sep;16(3):267-75
references.pmid: 14631832
references.citation: Annu Rev Neurosci. 2001;24:677-736
references.pmid: 11520916
references.citation: Neuron. 1998 Oct;21(4):869-83
references.pmid: 9808472
references.citation: Nature. 2007 Jul 26;448(7152):439-44
references.pmid: 17611497
references.citation: Biogerontology. 2004;5(5):317-25
references.pmid: 15547319
references.citation: Mech Ageing Dev. 1999 May 17;108(3):239-51
references.pmid: 10405984
references.citation: J Neurol Sci. 2009 Feb 15;277(1-2):58-64
references.pmid: 19007942
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2915-9
references.pmid: 16476997
references.citation: Int Immunopharmacol. 2009 Jan;9(1):91-6
references.pmid: 19000936
references.citation: Biochim Biophys Acta. 2008 Oct;1783(10):1700-6
references.pmid: 18501717
references.citation: J Biol Chem. 2000 Jul 7;275(27):20685-92
references.pmid: 10748101
references.citation: Genes Dev. 1999 Nov 15;13(22):2905-27
references.pmid: 10579998
references.citation: J Pharmacol Exp Ther. 2002 Jan;300(1):213-9
references.pmid: 11752119
references.citation: Int J Neuropsychopharmacol. 2008 Sep;11(6):851-76
references.pmid: 18205981