Poly(ADP-ribosyl)ation enzyme-1 as a target for neuroprotection in acute central nervous system injury.
Poly(ADP-ribose) polymerase 1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. In response to stresses that are toxic to the genome, PARP-1 activity increases substantially, an event that appears crucial for maintaining genomic integrity. Massive PARP-1 activation, however, can deplete the cell of NAD(+) and ATP, ultimately leading to energy failure and cell death. The discovery that cell death may be suppressed by PARP inhibitors or by deletion of the parp-1 gene has prompted a great deal of interest in the process of poly(ADP-ribosyl)ation. Suppression of PARP-1 is capable of protecting against cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The secondary damage of initially surviving neurons in brain stroke accounts for most of the volume of the infarcted area and the subsequent loss of brain function. Microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, which is regulated in turn by PARP-1, proposing that PARP-1 downregulation may therefore be a promising strategy in protecting neurons from this secondary damage, as well. As PARP-1 is now recognised as playing a role also in the regulation of gene transcription, this further increases the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenges the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. PARP(s) might regulate cell fate as essential modulators of death and survival transcriptional programs with relation to NF-kappaB and p53, proposing that inhibitors of poly(ADP-ribosyl)ation could therefore prevent the deleterious consequences of neuroinflammation by reducing NF-kappaB activity.
Skaper
S D
SD
Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, New Frontiers Science Park, Third Avenue, CM19 5AW Harlow, Essex, UK. Stephen_Skaper-1@gsk.com
D000208:Acute Disease; D000818:Animals; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000201:enzymology*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
D018696:Neuroprotective Agents; D011065:Poly(ADP-ribose) Polymerases