Abshead
Cortical neurons rapidly die in necrosis due to poor glucose uptake in the low-density (LD) culture under serum-free condition without any supplements. The scanning and transmission electron microscopical analyses characterized the necrosis by membrane disruption, mitochondrial swelling and loss of cytoplasmic electron density. High-glucose treatment delayed the neuronal death by suppressing necrosis, but induced apoptosis through increase in Bax levels, cytochrome c release, caspase-3 activation and DNA ladder formation. Although pyruvate as well as high glucose inhibited necrotic cell death and rapid decrease in cellular ATP levels, possibly related to decreased [3H]-2-deoxy glucose uptake under the serum-free condition, it did not induce apoptosis. Protein kinase C inhibitors blocked these changes related to the cell death mode switch. Several neurotrophic factors did not affect the necrosis, but potentiated high-glucose-induced survival activity, while inhibiting cytochrome c release. All these results suggest that high-glucose treatment causes neuronal cell death mode switch by inhibiting necrosis, while inducing apoptosis, which is prevented by neurotrophic factors.
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Abbreviations
- MCAO:
-
middle cerebral artery occlusion
- GFAP:
-
glial fibrilary acidic protein
- LD:
-
low-density
- MAP-2:
-
microtubule-associated protein-2; TUNEL, terminal deoxyribonucleotidyl transferase-mediated dUTP-biotim mick endlabeling
- GLUT:
-
glucose transporter
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Acknowledgements
We gratefully acknowledge M Niwa and T Suematsu for helps in SEM and TEM studies, T Iwamura (Gifu Pharmaceutical University) for SP600125, JNK inhibitor, and A Yoshida, M Ueda, W Hamabe and M Rikumaru for technical help. We thank Sumitomo Pharmaceutical (Osaka, Japan) for the gift of BDNF. Parts of this study were supported by Grants-in-Aid and Special Coordination Funds from the Ministry of Education, Culture, Sports, Science and Technology.
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Fujita, R., Ueda, H. Protein kinase C-mediated cell death mode switch induced by high glucose. Cell Death Differ 10, 1336–1347 (2003). https://doi.org/10.1038/sj.cdd.4401300
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DOI: https://doi.org/10.1038/sj.cdd.4401300
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