Poly(ADP‐Ribose) Polymerase‐1 in Acute Neuronal Death and Inflammation

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that is activated primarily by DNA damage. Upon activation, the enzyme hydrolyzes NAD(+) to nicotinamide and transfers ADP ribose units to a variety of nuclear proteins, including histones and PARP-1 itself. This process is important in facilitating DNA repair. However, excessive activation of PARP-1 can lead to significant decrements in NAD(+), and ATP depletion, and cell death (suicide hypothesis). In response to cellular damage by oxygen radicals or excitotoxicity, a rapid and strong activation of PARP-1 occurs in neurons. Excessive PARP-1 activation is implicated in a variety of insults, including cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The use of PARP inhibitors has, therefore, been proposed as a protective therapy in decreasing excitotoxic neuronal cell death, as well as ischemic and other tissue damage. Excitotoxic brain lesions initially result in the primary destruction of brain parenchyma and subsequently in secondary damage of neighboring neurons hours after the insult. This secondary damage of initially surviving neurons accounts for most of the volume of the infarcted area and the loss of brain function after a stroke. One major component of secondary neuronal damage is the migration of macrophages and microglial cells toward the sites of injury, where they produce large quantities of toxic cytokines and oxygen radicals. Recent evidence indicates that this 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. Studies demonstrating an important role for PARP-1 in the regulation of gene transcription have further increased the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenge the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. The hypothesis that PARPs might regulate cell fate as essential modulators of death and survival transcriptional programs is discussed with relation to nuclear factor kappaB and p53.

The Therapeutic Effects of PJ34 [N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide.HCl], a Selective Inhibitor of Poly(ADP-Ribose) Polymerase, in Experimental Allergic Encephalomyelitis Are Associated with Immunomodulation

“…PARP inhibition in EAE is therefore manifested in a reduction in most aspects of CNS inflammation including the loss of BBB integrity. However, PARP activation has also been implicated in neurotoxicity (Virá g and Szabó, 2002;Skaper, 2003). Consequently, inhibiting PARP may also be beneficial in EAE by maintaining neuronal cell viability thus preventing functional deficits as well as reducing the release of new autostimulatory antigens.…”

“…PARP activity has been implicated in neurotoxicity and in the pathogenesis of cerebral ischemia and other neurodegenerative disorders (Love et al, 1999;Mandir et al, 1999;Ha and Snyder, 2000;Skaper, 2003). Poly(ADP-ribose) residues are present in CNS tissues from animals with EAE (Scott et al, 2001a).…”

Selenium Attenuates ROS-Mediated Apoptotic Cell Death of Injured Spinal Cord through Prevention of Mitochondria Dysfunction; <i>in Vitro</i> and<i> in Vivo</i> Study

“…Therefore, it may also negatively influence cell metabolism and survival. PARP activity is generally thought to contribute to neuronal cell death under a variety of neurological conditions [36], including traumatic brain injury [37,38] and SCI [39], as a consequence of energy failure or via the modification of the activity of various proteins by poly (ADP-ribosylation) [40]. Selenite effectively blocks PARP-mediated apoptotic cell death in lesion sites (Fig.…”

NADH hyperoxidation correlates with enhanced susceptibility of aged rats to hypoxia

“…PARP is a nuclear enzyme, which scans for deoxyribonucleic acid (DNA) damage (Skaper, 2003) caused by free radicals (Yabuki et al, 1997). Following activation (as early as 15min after transient ischemia (Narasimhan et al, 2003)), PARP hydrolyses its substrate, nicotinamide adenine dinucleotide (NAD + ) to nicotinamide and transfers poly(ADP-ribose) chains to a variety of other nuclear proteins.…”