RRC ID 1602
Author Tanaka S, Takehashi M, Iida S, Kitajima T, Kamanaka Y, Stedeford T, Banasik M, Ueda K.
Title Mitochondrial impairment induced by poly(ADP-ribose) polymerase-1 activation in cortical neurons after oxygen and glucose deprivation.
Journal J Neurochem
Abstract 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.
Volume 95(1)
Pages 179-90
Published 2005-10-1
DOI 10.1111/j.1471-4159.2005.03353.x
PMID 16181422
MeSH ADP Ribose Transferases / antagonists & inhibitors ADP Ribose Transferases / metabolism* Animals Apoptosis / drug effects Cells, Cultured Cerebral Cortex / drug effects Cerebral Cortex / enzymology* Cerebral Cortex / physiopathology Electrophysiology Enzyme Activation Enzyme Inhibitors / pharmacology Glucose / deficiency* Hypoxia / physiopathology* Intracellular Membranes / metabolism Mitochondria / metabolism* Mitochondrial Proteins / antagonists & inhibitors Mitochondrial Proteins / metabolism NAD / metabolism Neurons / drug effects Neurons / enzymology* Oxygen / pharmacology Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases Proto-Oncogene Proteins c-bcl-2 / metabolism RNA, Small Interfering / pharmacology Rats Rats, Wistar
IF 4.066
Times Cited 42
DNA material AxCANCre (RDB01748)