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Attenuation of Cortical neuron Apoptosis by gangliosides

Attenuation of Cortical neuron Apoptosis by gangliosides -...

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Attenuation of Cortical Neuronal Apoptosis by Gangliosides 1 BO RUM RYU, DENNIS W. CHOI, 2 DEAN M. HARTLEY, 3 ERMINIO COSTA, 4 ILO JOU, and BYOUNG JOO GWAG Department of Pharmacology, Ajou University School of Medicine, Suwon, Kyungkido, Korea (B.R.R., I.J., B.J.G.) Accepted for publication April 10, 1999 This paper is available online at http://www.jpet.org ABSTRACT Addition of the natural gangliosides monosialoganglioside (GM1), disialoganglioside, trisialoganglioside, or tetrasialogan- glioside in the range of 10 to 100 m M, but not asialoganglioside lacking the sialic acid moiety, attenuated cortical neuronal ap- optosis induced by serum deprivation, ionomycin, or cyclo- sporin A but not by protein kinase inhibitors (staurosporine, genistein, lavendustin A, or herbimycin A). Coaddition of 100 nM wortmannin, a selective inhibitor of phosphatidylinositol 3-kinase, but not 1 m M Go6976, a selective protein kinase C inhibitor, blocked the neuroprotective effect of GM1. In contrast to its antiapoptotic effect, GM1 at up to 200 m M did not atten- uate cortical neuronal necrosis induced by exposure to the excitotoxins N- methyl- D -aspartate or kainate. Furthermore, GM1 increased the necrosis induced by oxidative stress (addi- tion of Fe 2 1 or buthionine sulfoximine). These data suggest that neuroprotective effects of natural gangliosides may preferen- tially reflect reduction of neuronal apoptosis rather than necro- sis, and be mediated through mechanisms involving activation of phosphatidylinositol 3-kinase. There has been interest in the ability of the natural gan- gliosides monosialoganglioside (GM1), disialogangliosides (GD1a, GD1b), and trisialoganglioside (GT1b) to protect cen- tral neurons from death induced by a variety of insults. GM1 attenuates neuronal degeneration induced by hippocampal or cortical aspiration (Sofroniew et al., 1986; Sabel et al., 1988), exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri- dine (Hadjiconstantinou and Neff, 1988; Schneider et al., 1992), or ischemia (Seren et al., 1990). In vitro, GM1 or GT1b attenuates excitotoxic neuronal death (Vaccarino et al., 1987; Dawson et al., 1995), and enhances the survival of sympa- thetic neurons and PC12 cells deprived of nerve growth fac- tor (Ferrari et al., 1993). Several mechanisms have been suggested to underlie the neuroprotective effects of ganglio- sides, including inhibition of protein kinase C (PKC) trans- location (Vaccarino et al., 1987), inhibition of nitric oxide synthase (Dawson et al., 1995), and phosphorylation of the nerve growth factor receptor Trk (Ferrari et al., 1995; Rabin and Mocchetti, 1995). Previous studies of the neuroprotective effects of natural gangliosides largely precede field attention to the nature of neuronal death under study, necrosis versus apoptosis. Apo- ptosis was originally recognized by the marked condensation of cytoplasm and nucleus during physiological and patholog- ical processes (Kerr et al., 1972). Internucleosomal DNA frag- mentation (DNA ladders) and death depending on protein synthesis have been coined as functional features of apopto- sis (Wyllie et al., 1984). Target or growth factor deprivation is highly likely to cause neuronal apoptosis. However ischemia,
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