GM1 Ganglioside Activates ERK1/2 and Akt Downstream of Trk Tyrosine Kinase and Protects PC12 Cells Against Hydrogen Peroxide Toxicity
- 308 Downloads
Ganglioside GM1 at micro- and nanomolar concentrations was shown to increase the viability of pheochromocytoma PC12 cells exposed to hydrogen peroxide and diminish the accumulation of reactive oxygen species and oxidative inactivation of Na+,K+-ATPase, the effects of micromolar GM1 being more pronounced than those of nanomolar GM1. These effects of GM1 were abolished by Trk receptor tyrosine kinase inhibitor and diminished by MEK1/2, phosphoinositide 3-kinase and protein kinase C inhibitors. Hydrogen peroxide activates Trk tyrosine kinase; Akt and ERK1/2 are activated downstream of this protein kinase. GM1 was found to activate Trk receptor tyrosine kinase in PC12 cells. GM1 (100 nM and 10 µM) increased the basal activity of Akt, but did not change Akt activity in cells exposed to hydrogen peroxide. Basal ERK1/2 activity in PC12 cells was increased by GM1 at a concentration of 10 µM, but not at nanomolar concentrations. Activation of ERK1/2 by hydrogen peroxide was enhanced by GM1 at a concentration of 10 µM and to a lesser extent at a concentration of 100 nM. Thus, the protective and metabolic effects of GM1 ganglioside on PC12 cells exposed to hydrogen peroxide appear to depend on the activation of Trk receptor tyrosine kinase and downstream activation of Akt and ERK1/2.
KeywordsGM1 ganglioside ERK1/2 Akt Activation Protection PC12 cells
The work was supported by Grants from the Russian Fund for Basic Research 13-04-00643. The manuscript does not contain clinical studies or patient data.
Conflict of interest
The authors declare that they have no conflict of interests.
- 2.Li J, OW, Li W, Jiang ZG, Ghanbari HA (2013) Oxidative stress and neurodegenerative disorders. Int J Mol Sci 14:24438–24475Google Scholar
- 3.Hsieh HL, Yang CM (2013) Role of redox signaling in neuroinflammation and neurodegenerative diseases. Biomed Res Int 2013:484613Google Scholar
- 8.Abdul HM, Butterfield DA (2007) Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-l-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implication for Alzheimer’s disease. Free Radic Biol Med 42:371–384PubMedCrossRefPubMedCentralGoogle Scholar
- 12.Avrova NF, Victorov IV, Tyurin VA, Zakharova IO, Sokolova TV, Andreeva NA, Stelmaschuk EV, Tyurina YY, Gonchar VS (1998) Inhibition of glutamate-induced intensification of free radical reactions by gangliosides: possible role in their protective effect in rat cerebellar granule cells and brain synaptosomes. Neurochem Res 23:945–952PubMedCrossRefGoogle Scholar
- 14.Fighera MR, Bonini JS, de Oliveira TG, Frussa-Filho R, Rocha JB, Dutra-Filho CS, Rubin MA, Mello CF (2003) GM1 ganglioside attenuates convulsions and thiobarbituric acid reactive substances production induced by intrastriatal injection of methylmalonic acid. Int J Biochem Cell Biol 35:465–473PubMedCrossRefGoogle Scholar
- 15.Fighera MR, Royes LF, Furian AF, Oliveira MS, Fiorenza NG, Frussa-Filho R, Petry JC, Coelho RC, Mello CF (2006) GM1 ganglioside prevents seizures, Na+, K+-ATP-ase activity inhibition and oxidative stress induced by glutaric acid and pentylenetetrazole. Neurobiol Dis 22:611–623PubMedCrossRefGoogle Scholar
- 18.Gorria M, Huc L, Sergent O, Rebillard A, Gaboriau F, Dimanche-Boitrel MT, Lagadic-Gossmann D (2006) Protective effect of monosialoganglioside GM1 against chemically induced apoptosis through targeting of mitochondrial function and iron transport. Biochem Pharmacol 72:1343–1353PubMedCrossRefGoogle Scholar
- 23.She JQ, Wang M, Zhu DM, Tang M, Chen JT, Wang L, Ruan DY (2009) Monosialoanglioside (GM1) prevents lead-induced neurotoxicity on long-term potentiation, SOD activity, MDA levels, and intracellular calcium levels of hippocampus in rats. Naunyn Schmiedebergs Arch Pharmacol 379:517–524PubMedCrossRefGoogle Scholar
- 25.Ohmi Y, Tajima O, Ohkawa Y, Yamauchi Y, Sugiura Y, Furukawa K, Furukawa K (2011) Gangliosides are essential in the protection of inflammation and neurodegeneration via maintenance of lipid rafts: elucidation by a series of ganglioside-deficient mutant mice. J Neurochem 116:926–935PubMedCrossRefGoogle Scholar
- 26.Geisler FH, Coleman WP, Grieco G, Poonian D; Sygen Study Group (2001) The Sygen multicenter acute spinal cord injury study. Spine 26(24 Suppl.):S87–S98Google Scholar
- 30.Augustinsson LE, Blennow K, Blomstrand C, Bråne G, Ekman R, Fredman P, Karlsson I, Kihlgren M, Lehmann W, Lekman A, Månsson JE, Ramström I, Wallin A, Wikkelsö C, Gottfries CG, Svennerholm L (1997) Intracerebroventricular administration of GM1 ganglioside to presenile Alzheimer patients. Dement Geriatr Cogn Disord 8:26–33PubMedCrossRefGoogle Scholar
- 42.Vassault A (1983) Lactate dehydrogenase: UV-method with pyruvate and NADH. In: Bergmeyer HU (ed) Methods of enzymatic analysis, vol 3. Verlag Chemie, Weinheim, pp 118–126Google Scholar
- 53.Chung H, Seo S, Moon M, Park S (2008) Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. J Endocrinol 198:511–521PubMedCrossRefGoogle Scholar
- 55.Whelan RS, Konstantinidis K, Wei AC, Chen Y, Reyna DE, Jha S, Yang Y, Calvert JW, Lindsten T, Thompson CB, Crow MT, Gavathiotis E, Dorn GW 2nd, O’Rourke B, Kitsis RN (2012) Bax regulates primary necrosis through mitochondrial dynamics. Proc Natl Acad Sci USA 109:6566–6571PubMedCrossRefPubMedCentralGoogle Scholar
- 57.Chan JY, Chang AY, Wang LL, Ou CC, Chan SH (2007) Protein kinase C-dependent mitochondrial translocation of proapoptotic protein Bax on activation of inducible nitric-oxide synthase in rostral ventrolateral medulla mediates cardiovascular depression during experimental endotoxemia. Mol Pharmacol 71:1129–1139PubMedCrossRefGoogle Scholar