Authors: Masahiro Okouchi; Naotsuka Okayama; Tak Y. Aw

Source: Current Neurovascular Research, Volume 2, Number 1, January 2005 , pp. 13-22(10)

Publisher: Bentham Science Publishers

Abstract:

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

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1567202052773535

Affiliations: 1: Department of Molecular & Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.

Publication date: 2005-01-01

More about this publication?

• Current Neurovascular Research (CNR) provides a cross platform for the publication of scientifically rigorous research that addresses disease mechanisms of both neuronal and vascular origins in neuroscience. The journal serves as an international forum for the publication of novel and pioneering original work as well as timely neuroscience research reviews in the disciplines of cell developmental disorders, plasticity, and degeneration that bridge the gap between basic science research and clinical discovery. CNR emphasizes the elucidation of disease mechanisms, both cellular and molecular, which can impact the development of unique therapeutic strategies for neuronal and vascular disorders.

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