Enhanced Poly(ADP-ribosyl)ation after Focal Ischemia in Rat Brain

Tokime, Tomoo; Nozaki, Kazuhiko; Sugino, Toshiyuki; Kikuchi, Hiroe; Hashimoto, Nobuo; Ueda, Kunihiro

doi:10.1097/00004647-199809000-00008

Cited by 111 publications

(72 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…in both experimental TBI and cerebral ischemia (Eliasson et al 1997;Endres et al 1997;Tokime et al 1998;LaPlaca et al 1999). Unique to the present study, protein nitration, a surrogate marker for the presence of the potent PARP-1 activator peroxynitrite, and poly-ADP-ribosylation, a biochemical footprint of PARP-1 activation, were evaluated for 21 days after CCI.…”

Section: Discussionmentioning

confidence: 99%

A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD⁺ depletion and ribosylation of 14‐3‐3γ

Satchell

Zhang

Kochanek

et al. 2003

Journal of Neurochemistry

105

View full text Add to dashboard Cite

Poly(ADP-ribose) polymerase-1 (PARP-1) is a homeostatic enzyme that paradoxically contributes to disturbances in spatial memory acquisition after traumatic brain injury (TBI) in transgenic mice, thought to be related to depletion of its substrate nicotinamide adenine dinucleotide (NAD + ). In this study, systemic administration of the PARP-1 inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP) after TBI preserved brain NAD + levels and dose-dependently reduced poly-ADPribosylation 24 h after injury. While moderate-dose INH2BP improved spatial memory acquisition after TBI; strikingly, both injured-and sham-mice receiving high-dose INH2BP were unable to learn in the Morris-water maze. Poly-ADP-ribosylated peptides identified using a proteomics approach yielded several proteins potentially associated with memory, including structural proteins (tubulin a and b, c-actin, and a-internexin neuronal intermediate filament protein) and 14-3-3c. Nuclear poly-ADP-ribosylation of 14-3-3c was completely inhibited by the dose of INH2BP that produced profound memory disturbances. Thus, partial inhibition of poly-ADP-ribosylation preserves NAD + and improves functional outcome after TBI, whereas more complete inhibition impairs spatial memory acquisition independent of injury, and is associated with ribosylation of 14-3-3c. Keywords: 14-3-3, DNA damage, head injury, 5-iodo-6-amino-1,2-benzopyrone, nicotinamide adenine dinucleotide, poly(ADP-ribose) synthetase. Poly(ADP-ribose) polymerase-1 (PARP-1; E.C.2.4.2.30) is an abundant nuclear protein that is activated by single-strand DNA breaks, produced by a variety of insults including reactive oxygen and nitrogen species, chemical agents, and UV irradiation (Dawson and Dawson 1995;Szabo 1996). Activated PARP-1 utilizes nicotinamide adenine dinucleotide (NAD + ) as a substrate for generating large branching adenosine diphosphate (ADP)-ribose polymers on various proteins including histones, topoisomerases, and PARP-1 itself (Szabo 1998). PARP-1 activation facilitates DNA repair by enabling other enzymes to locate and replace missing base pairs (Szabo et al. 1997;Bauer et al. 2000). Neuronal death and neurologic dysfunction after CNS injury appears to be mediated in part by activation of PARP-1, particularly CNS insults associated with DNA damage and energy failure such as cerebral ischemia (Eliasson et al. 1997;Endres et al. 1998a) and traumatic brain injury (TBI;Whalen et al. 1999;LaPlaca et al. 2001). While disruption of the PARP-1 gene Received December 17, 2002; revised manuscript received January 14, 2003; accepted January 15, 2003. Address correspondence and reprint requests to Robert S. B. Clark, Safar Center for Resuscitation Research, 3434 Fifth Avenue, Pittsburgh, PA 15260, USA. E-mail: clarkrs@ccm.upmc.edu Abbreviations used: 2-AB, 3-aminobenzamide; ADP, adenosine diphosphate; CCI, controlled cortical impact; DMSO, dimethyl sulphoxide; DTT, dithiothreitol; Hsc54, heat shock cognate protein 54; IEF, isoelectric focusing; INH2BP, 5-iodo-6-amino-1,2-benzopyrone; IPG, i...

show abstract

Section: Discussionmentioning

confidence: 99%

A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD⁺ depletion and ribosylation of 14‐3‐3γ

Satchell

Zhang

Kochanek

et al. 2003

Journal of Neurochemistry

105

View full text Add to dashboard Cite

show abstract

“…Although we have not directly monitored NAD ϩ and ATP levels, such depletions occur in other models in which PARP inhibition protects from tissue damage. The protective paradigm of PARP inhibition after DNA damage has been demonstrated for numerous other models of cell death, including cerebral ischemia (10)(11)(12)(13)26), myocardial ischemia (27)(28)(29)(30), N-methyl-D-aspartic acid receptor-mediated excitotoxicity in the lung (31), methamphetamine neurotoxicity (32,33), and MPTP toxicity (34)(35)(36). In all of these cases, a lack of PARP activity, through either genetic disruption or pharmacologic inhibition, provides impressive protection from cell death after DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…As ATP is also consumed in efforts to resynthesize NAD ϩ , cells can die from energy loss. Cerebral ischemic damage is greatly diminished in mice with targeted deletion of PARP (PARP Ϫ͞Ϫ) (10,11) and in animals treated with PARP inhibitors (12,13). A role of PARP activation in pancreatic damage is also suggested by protection through PARP inhibition of pancreatic islet cells from NO-mediated killing (14,15).…”

mentioning

confidence: 99%

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

Pieper

Brat

Krug

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

277

180

View full text Add to dashboard Cite

Streptozotocin (STZ) selectively destroys insulin-producing beta islet cells of the pancreas providing a model of type I diabetes. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme whose overactivation by DNA strand breaks depletes its substrate NAD ؉ and then ATP, leading to cellular death from energy depletion. We demonstrate DNA damage and a major activation of PARP in pancreatic islets of STZ-treated mice. These mice display a 500% increase in blood glucose and major pancreatic islet damage. In mice with homozygous targeted deletion of PARP (PARP ؊͞؊), blood glucose and pancreatic islet structure are normal, indicating virtually total protection from STZ diabetes. Partial protection occurs in PARP ؉͞؊ animals. Thus, PARP activation may participate in the pathophysiology of type I diabetes, for which PARP inhibitors might afford therapeutic benefit.Type I diabetes (insulin-dependent diabetes mellitus) is a chronic metabolic disorder characterized by a loss of pancreatic islet B cell mass, decreased serum insulin, and hyperglycemia. Although the pathogenic mechanisms of this disease have not been fully characterized, genetic, environmental, and autoimmune factors have been postulated. In particular, development of this disorder is postulated to proceed through generation of oxygen radicals during prediabetic pancreatic islet inflammation (1, 2). One possible mechanism is that autoimmune activation of macrophages damages B cells through release of massive amounts of NO after inducible NO synthase activation, as damage elicited when islets are cocultured with macrophages is prevented by inhibition of NO synthase (3).Focal cerebral ischemic damage is also associated with NO release leading to DNA damage elicited by reactive oxygen species, including peroxynitrite formed from NO. Downstream of this DNA damage, the enzyme poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is stimulated. Nuclear PARP is activated by DNA fragments to transfer branched chains of up to 200 ADP ribose groups from NAD ϩ to acceptor proteins in the nucleus, including histones and PARP itself. PARP activation plays a role in DNA repair, particularly the base excision repair process (4-8), in response to moderate amounts of DNA damage. With excessive DNA damage, however, PARP is so highly activated that its substrate NAD ϩ is critically depleted (9). NAD ϩ is an important enzyme in energy metabolism, and its depletion results in lower ATP production. As ATP is also consumed in efforts to resynthesize NAD ϩ , cells can die from energy loss. Cerebral ischemic damage is greatly diminished in mice with targeted deletion of PARP (PARP Ϫ͞Ϫ) (10, 11) and in animals treated with PARP inhibitors (12, 13). A role of PARP activation in pancreatic damage is also suggested by protection through PARP inhibition of pancreatic islet cells from NO-mediated killing (14, 15). Furthermore, in vitro pancreatic islet cells from PARP Ϫ͞Ϫ mice are resistant to NAD ϩ depletion after exposure to either NO or other reactive oxygen intermediates generated th...

show abstract

“…Excessive activation of poly(ADP-ribose) polymerase has been implicated to mediate cell death in different models of ischemia-reperfusion injury 10,40,42 as well as streptozotocininduced diabetes, 32 glutamate-induced neurotoxicity 5,49 and Alzheimer's disease. 27 The common feature in the pathogen- Figure 3 Poly(ADP-ribose) polymer immunohistochemistry on retinal sections to monitor PARP activation after ON transection with or without 3-ABA treatment.…”

Section: Discussionmentioning

confidence: 99%

“…26 However, it has also been demonstrated that excessive PARP activation by various triggers resulting in depletion of NAD + and subsequent cellular ATP depletion ultimately leads to a necrotic-type cell death. 5,32,41,49 There is accumulating evidence that excessive PARP activation plays a key role in mediating ischemia-reperfusion-induced cerebral injury 10,11,38,42 and that infarct volume can be dramatically reduced by PARP inhibition and in PARP knock-out mice. 9,37,38 Cerebral ischemia results in massive activation of N-methyl-D-aspartat (NMDA) receptors via an increase of extracellular glutamate leading to elevated intracellular calcium concentrations, activation of neuronal NO synthase (nNOS), increased NO and ROS formation and ultimately to PARP-activating DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection

2001

View full text Add to dashboard Cite

Excessive activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by free-radical damaged DNA mediates necrotic cell death in injury models of cerebral ischemiareperfusion and excitotoxicity. We recently reported that secondary retinal ganglion cell (RGC) death following rat optic nerve (ON) transection is mainly apoptotic and can significantly but not entirely be blocked by caspase inhibition. In the present study, we demonstrate transient, RGC-specific PARP activation and increased retinal PARP expression early after ON axotomy. In addition, intravitreal injections of 3-aminobenzamide blocked PARP activation in RGCs and resulted in an increased number of surviving RGCs when compared to control animals 14 days after ON transection. These data indicate that secondary degeneration of a subset of axotomized RGCs results from a necrotic-type cell death mediated by PARP activation and increased PARP expression. Furthermore, PARP inhibition may constitute a relevant strategy for clinical treatment of traumatic brain injury. Cell Death and Differentiation (2001) 8, 801 ± 807.

show abstract

Enhanced Poly(ADP-ribosyl)ation after Focal Ischemia in Rat Brain

Cited by 111 publications

References 18 publications

A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD⁺ depletion and ribosylation of 14‐3‐3γ

A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD⁺ depletion and ribosylation of 14‐3‐3γ

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection

Contact Info

Product

Resources

About

Enhanced Poly(ADP-ribosyl)ation after Focal Ischemia in Rat Brain

Cited by 111 publications

References 18 publications

A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD+ depletion and ribosylation of 14‐3‐3γ

A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD+ depletion and ribosylation of 14‐3‐3γ

Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes

Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection

Contact Info

Product

Resources

About

A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD⁺ depletion and ribosylation of 14‐3‐3γ

A dual role for poly‐ADP‐ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD⁺ depletion and ribosylation of 14‐3‐3γ