Mitochondrial impairment induced by poly(ADP‐ribose) polymerase‐1 activation in cortical neurons after oxygen and glucose deprivation

• Published in: Journal of neurochemistry Vol. 95; no. 1; pp. 179 - 190
• Main Authors: Tanaka, Seigo, Takehashi, Masanori, Iida, Shinya, Kitajima, Takashi, Kamanaka, Yoshihisa, Stedeford, Todd, Banasik, Marek, Ueda, Kunihiro
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.10.2005; Blackwell; Blackwell Publishing Ltd
• Subjects: Adenosine; ADP Ribose Transferases - antagonists & inhibitors; ADP Ribose Transferases - metabolism; Animals; apoptosis; Apoptosis - drug effects; apoptosis‐inducing factor; Biochemistry; Biological and medical sciences; Cells, Cultured; Cerebral Cortex - drug effects; Cerebral Cortex - enzymology; Cerebral Cortex - physiopathology; cerebral ischemia; cytochrome c; Electrophysiology; endonuclease G; Enzyme Activation; Enzyme Inhibitors - pharmacology; Glucose - deficiency; Hypoxia - physiopathology; Inhibitor drugs; Intracellular Membranes - metabolism; Kidneys; Medical sciences; Mitochondria - metabolism; Mitochondrial DNA; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - metabolism; NAD; NAD - metabolism; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Neurology; Neurons; Neurons - drug effects; Neurons - enzymology; Oxygen - pharmacology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Wistar; Renovascular diseases; RNA, Small Interfering - pharmacology; Urinary system involvement in other diseases. Miscellaneous; Rat; Bcl-2 protein; Activation; Glucose; ADP; Mitochondria; cerebral ischemia; cytochrome c; Kidney disease; Oxygen; Deprivation; Urinary system disease; Ischemia reperfusion; Rodentia; Crisis; Substrate; NAD; Vertebrata; Renal Cortical Necrosis; Mammalia; Depletion; Neuron; endonuclease G; apoptosis-inducing factor; ATP; Apoptosis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03353.x

Neuronal cells injured by ischemia and reperfusion to a certain extent are committed to death in necrotic or apoptotic form. Necrosis is induced by gross ATP depletion or ‘energy crisis’ of the cell, whereas apoptosis is induced by a mechanism still to be defined in detail. Here, we investigated this mechanism by focusing on a DNA damage‐sensor, poly(ADP‐ribose) polymerase‐1 (PARP‐1). A 2‐h oxygen and glucose deprivation (OGD) followed by reoxygenation (Reox) induced apoptosis, rather than necrosis, in rat cortical neurons. During the Reox, PARP‐1 was much activated and autopoly(ADP‐ribosyl)ated, consuming the substrate, NAD+. Induction of apoptosis by OGD/Reox was suppressed by overexpression of Bcl‐2, indicating mitochondrial impairment in this induction process. Mitochondrial permeability transition (MPT), or membrane depolarization, and a release of proapoptotic proteins, i.e. cytochrome c, apoptosis‐inducing factor and endonuclease G, from mitochondria were observed during the Reox. These apoptotic changes of mitochondria and the nucleus were attenuated by PARP‐1 inhibitors, 1,5‐dihydroxyisoquinoline and benzamide, and also by small interfering RNA specific for PARP‐1. These results indicated that PARP‐1 plays a principal role in inducing mitochondrial impairment that ultimately leads to apoptosis of neurons after cerebral ischemia.