Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage.
Poly(ADP-ribose)polymerases (PARPs) are enzymes that are able to catalyze the transfer of ADP-ribose units from NAD to substrate proteins and are particularly abundant in cell nuclei where they play key roles in the maintenance of genomic integrity, control of cell cycle and gene expression. Brain ischemia overactivates PARPs and PARP-deficient mice or animal treated with PARP inhibitors have a drastically reduced brain damage in various stroke models. PARP 'overactivation' occurs not only in neurons but also in astrocytes, microglial cells, endothelia, and infiltrating leukocytes. The ensuing cell death occurs through various molecular mechanisms: a) excessive ATP use for NAD synthesis and inhibition of mitochondrial function with subsequent energy failure (particularly important in neurons); b) apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus (present in neurons, endothelial, and other cells); c) excessive expression of inflammatory mediators (well demonstrated in glial cells) or d) reduced expression of prosurvival factors. Thus PARPs seem to play key roles in postischemic brain damage and are now considered interesting targets for therapies aimed at reducing stroke pathology.
Moroni
Flavio
F
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50135 Firenze, Italy. flavio.moroni@unifi.it
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000502:physiology; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D042783:Endothelial Cells / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D017628:Microglia / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases