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Current Neurovascular Research


ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Differential Susceptibility of Naive and Differentiated PC-12 Cells to Methylglyoxal-Induced Apoptosis: Influence of Cellular Redox

Author(s): Masahiro Okouchi, Naotsuka Okayama and Tak Yee Aw

Volume 2, Issue 1, 2005

Page: [13 - 22] Pages: 10

DOI: 10.2174/1567202052773535

Price: $65


Neuropathologies have been associated with neuronal de-differentiation and oxidative susceptibility. To address whether cellular states determines their oxidative vulnerability, we have challenged naive (undifferentiated) and nerve growth factor-induced differentiated pheochromocytoma (PC12) with methylglyoxal (MG), a model of carbonyl stress. MG dose-dependently induced greater apoptosis (24h) in naive (nPC12) than differentiated (dPC12) cells. This enhanced nPC12 susceptibility was correlated with a high basal oxidized cellular glutathione-to-glutathione disulfide (GSH / GSSG) redox and an MG-induced GSH-to-Disulfide (GSSG plus protein-bound SSG) imbalance. The loss of redox balance occurred at 30 min post-MG exposure, and was prevented by N-acetylcysteine (NAC) that was unrelated to de novo GSH synthesis. NAC was ineffective when added at 1h post-MG, consistent with an early window of redox signaling. This redox shift was kinetically linked to decreased BcL-2, increased Bax, and release of mitochondrial cytochrome c which preceded caspase-9 and -3 activation and poly ADP-ribose polymerase (PARP) cleavage (1-2h), consistent with mitochondrial apoptotic signaling. The blockade of apoptosis by cyclosporine A supported an involvement of the mitochondrial permeability transition pore. The enhanced vulnerability of nPC12 cells to MG and its relationship to cellular redox shifts will have important implications for understanding differential oxidative vulnerability in various cell types and their transition states.

Keywords: neurons, gsh/gssg redox state, protein-ssg, mitochondrial signaling, mitochondrial permeability transition pore, naive and differentiated pc12 cells, methylglyoxal-induced apoptosis

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