Abstract
Addition of the natural gangliosides monosialoganglioside (GM1), disialoganglioside, trisialoganglioside, or tetrasialoganglioside in the range of 10 to 100 μM, but not asialoganglioside lacking the sialic acid moiety, attenuated cortical neuronal apoptosis induced by serum deprivation, ionomycin, or cyclosporin 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 μM Go6976, a selective protein kinase C inhibitor, blocked the neuroprotective effect of GM1. In contrast to its antiapoptotic effect, GM1 at up to 200 μM did not attenuate cortical neuronal necrosis induced by exposure to the excitotoxins N-methyl-d-aspartate or kainate. Furthermore, GM1 increased the necrosis induced by oxidative stress (addition of Fe2+ or buthionine sulfoximine). These data suggest that neuroprotective effects of natural gangliosides may preferentially reflect reduction of neuronal apoptosis rather than necrosis, and be mediated through mechanisms involving activation of phosphatidylinositol 3-kinase.
Footnotes
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Send reprint requests to: Dr. Byoung Joo Gwag, Department of Pharmacology, Ajou University School of Medicine, Suwon, Kyungkido, Korea 442–749. E-mail: bjgwag{at}madang.ajou.ac.kr
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↵1 This work was supported by National Institute of Neurological Disorders and Stroke Grant NS 30337 (D.W.C.) and Korea Science and Engineering Foundation Grant 971-0704-021–2 (B.J.G.).
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↵2 Current address: Department of Neurology and Center for the Study of Nervous System Injury, Box 8111, Washington University School of Medicine, St. Louis, MO 63110.
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↵3 Current address: Center of Neurologic Diseases, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, MA 02115.
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↵4 Current address: Psychiatric Institute, University of Illinois Medical School, Chicago, IL 60612.
- Abbreviations:
- GM1
- monosialoganglioside
- BDNF
- brain-derived neurotrophic factor
- BSO
- buthionine sulfoximine
- GD1a
- disialoganglioside 1a
- GQ1b
- tetrasialoganglioside 1b
- GT1b
- trisialoganglioside 1b
- NMDA
- N-methyl-d-aspartate
- PI3-K
- phosphatidylinositol 3-kinase
- PKC
- protein kinase C
- MEM
- minimum essential medium
- DIV
- days in vitro
- LDH
- lactate dehydrogenase
- Received September 8, 1998.
- Accepted April 10, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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Attenuation of Cortical Neuronal Apoptosis by Gangliosides
