Neuroprotective effects of KCL-440, a new poly(ADP-ribose) polymerase inhibitor, in the rat middle cerebral artery occlusion model

Ikeda, Yasuhiko; Hokamura, Kazuya; Kawai, Tadao; Ishiyama, Jun‐ichi; Ishikawa, Kumi; Anraku, Tsuyoshi; Umemura, Takashi; Umemura, Kazuo

doi:10.1016/j.brainres.2005.08.046

Cited by 16 publications

(14 citation statements)

References 27 publications

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“…Inhibition of PARP-1 activity with 3-aminobenzamide (ABA) or 5-aminoisoquinolinone (AIQ) prevented PAR accumulation ( Figure 1b) and enhanced neuronal apoptotic death ( Figure 1c) caused by L-BSO. As our data appear to conflict with other studies, 15,16,21 we wondered whether the intensity of oxidative insult might explain our findings. Neurons were incubated with 50 or 500 mM H 2 O 2 to produce mild or severe oxidative stress, respectively.…”

Section: Resultscontrasting

confidence: 99%

“…15,17,30 This may occur as a consequence of NAD þ depletion, energetic failure and Dc m loss, and has been reported to occur following pro-oxidant insult [11][12][13]31 Because of this it has been suggested that PARP-1 inhibitors might be protective against neuronal damage 15,16 and this has recently been demonstrated in the rat in a model of cerebral infarction induced by middle cerebral artery occlusion. 21 As our data appear to conflict with such studies, we wondered whether the intensity of oxidative insult might explain our findings.…”

Section: Discussionmentioning

confidence: 62%

“…28 This situation may account for the results obtained with PARP-1 inhibitors in the severe model of cerebral infarction in the rat. 21 Interestingly, it has recently been suggested that PARP-1 supports the survival of developing neurons through a mechanism involving CaMK-II-dependent dissociation from PARP-1 of the KIF4, whose Cterminal domain suppresses the activity of PARP-1. 29 Here, we confirmed the involvement of CaMK-II in PARP-1-dependent neuroprotection during the low level stress induced by GCL knockdown.…”

Section: Discussionmentioning

confidence: 99%

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Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress

et al. 2007

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In neurons, DNA is prone to free radical damage, although repair mechanisms preserve the genomic integrity. However, activation of the DNA repair system, poly(ADP-ribose) polymerase (PARP-1), is thought to cause neuronal death through NAD þ depletion and mitochondrial membrane potential (Dw m ) depolarization. Here, we show that abolishing PARP-1 activity in primary cortical neurons can either enhance or prevent apoptotic death, depending on the intensity of an oxidative stress. Only in severe oxidative stress does PARP-1 activation result in NAD þ and ATP depletion and neuronal death. To investigate the role of PARP-1 in an endogenous model of oxidative stress, we used an RNA interference (RNAi) strategy to specifically knock down glutamatecysteine ligase (GCL), the rate-limiting enzyme of glutathione biosynthesis. GCL RNAi spontaneously elicited a mild type of oxidative stress that was enough to stimulate PARP-1 in a Ca 2 þ -calmodulin kinase II-dependent manner. GCL RNAi-mediated PARP-1 activation facilitated DNA repair, although neurons underwent Dw m loss followed by some apoptotic death. PARP-1 inhibition did not prevent Dw m loss, but enhanced the vulnerability of neurons to apoptosis upon GCL silencing. Conversely, mild expression of PARP-1 partially prevented to GCL RNAi-dependent apoptosis. Thus, in the mild progressive damage likely occur in neurodegenerative diseases, PARP-1 activation plays a neuroprotective role that should be taken into account when considering therapeutic strategies. Neurons are prone to acute oxidative stress. 1-4 Furthermore, accumulation of DNA strand breaks is a contributing factor to neurodegeneration during oxidative stress and other conditions such as exposure to alkylating agents 5,6 and aging. 7 To repair damaged DNA, most eukaryotic cells -except yeast -express poly(ADP-ribose) polymerase-1 ((PARP-1); EC 2.4.2.30), 8 a nuclear enzyme that rapidly binds to DNA strand breaks leading to the formation of long, branched poly(ADP-ribose) polymers using NAD þ as substrate. The resulting negatively charged PARP-1 is subsequently dissociated from DNA ends, facilitating the DNA repair process. [8][9][10] Activation of PARP-1 secondary to the acute exposure of neurons and other cell types to pro-oxidant species, such as nitric oxide, peroxynitrite or hydrogen peroxide (H 2 O 2 ) [11][12][13] has been shown to lead to NAD þ depletion and energetic failure, ultimately resulting in cellular death. Moreover, such activation of PARP-1 has been shown to be associated with mitochondrial impairment and apoptotic death, at least in models of oxygen and glucose deprivation in neurons. 14,15 This has led to the suggestion that PARP-1 inhibitors might be neuroprotective. [15][16][17] However, in a model of apoptosis dependent on the use of an essential medium lacking in insulin, it has recently been demonstrated that in neurons 18 DNA repair mechanisms contribute to essential housekeeping functions, maintaining the neuronal genome in a healthy status. Furthermore, these authors showed that in...

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Section: Resultscontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress

et al. 2007

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“…Although involvement of PARP activation in various ischemia models has been thoroughly studied (Ferrer and Planas 2003;Meli et al 2003;Ikeda et al 2005), only circumstantial evidences are available for the role of PARP activation in chronic hypoperfusion-induced neurodegenerative processes (Cozzi et al 2006). Therefore, the aim of the present study was to demonstrate the activation of PARP as a major regulator of cell death in a chronic hypoperfusion-induced neurodegenerative model in rat (BCCAO-induced retinal degeneration), and to evaluate the effect of PARP inhibition (by HO3089) in this model by assessing chronic hypoperfusion-induced morphological changes and determining activation state of critical kinase cascades, such as MAP kinases and PI-3K-Akt.…”

Section: Introductionmentioning

confidence: 99%

Protection Against Chronic Hypoperfusion-Induced Retinal Neurodegeneration by PARP Inhibition via Activation of PI-3-kinase Akt Pathway and Suppression of JNK and p38 MAP Kinases

et al. 2009

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Poly(ADP-ribose) polymerase (PARP) activation is considered as a major regulator of cell death in various pathophysiological conditions, however, no direct information is available about its role in chronic hypoperfusion-induced neuronal death. Here, we provide evidence for the protective effect of PARP inhibition on degenerative retinal damage induced by bilateral common carotid artery occlusion (BCCAO), an adequate chronic hypoperfusion murine model. We found that BCCAO in adult male Wistar rats led to severe degeneration of all retinal layers that was attenuated by a carboxaminobenzimidazol-derivative PARP inhibitor (HO3089) administered unilaterally into the vitreous body immediately following carotid occlusion and then 4 times in a 2-week-period. Normal morphological structure of the retina was preserved and the thickness of the retinal layers was increased in HO3089-treated eyes compared to the BCCAO eyes. For Western blot studies, HO3089 was administered immediately after BCCAO and retinas were removed 4 h later. According to Western blot analysis utilizing phosphorylation-specific primary antibodies, besides activating poly-ADP-ribose (PAR) synthesis, BCCAO induced phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). HO3089 inhibited PAR synthesis, and decreased the phosphorylation of these proapoptotic MAPKs. In addition, HO3089 treatment induced phosphorylation, that is activation, of the protective Akt/glycogen synthase kinase (GSK)-3beta and extracellular signal-regulated kinase (ERK1/2) signaling pathways. These data indicate that PARP activation has a major role in mediating chronic hypoperfusion-induced neuronal death, and inhibition of the enzyme prevents the pathological changes both in the morphology and the kinase signaling cascades involved. These results identify PARP inhibition as a possible molecular target in the clinical management of chronic hypoperfusion-induced neurodegenerative diseases including ocular ischemic syndrome.

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“…Recent experimental data suggest that post-ischemic activation of PARP-1 occurs practically in every cell type of the brain-affected region and significantly contributes to the extension of the final damage. Genetic suppression of either PARP-1 or PARP-2 or administration of appropriate doses of PARP inhibitors within a reasonable time drastically reduces the infarct volume of stroke in rodent models, thus suggesting that PARP inhibitors may reduce strokeinduced neurological damage (Ikeda et al 2005;Koh et al 2004). Further PARP has been implicated in inflammatory responses and as a modulator of AIF-mediated cell death (Hassa and Hottiger 2002;Yu et al 2006).…”

Section: Discussionmentioning

confidence: 98%

Differential PARP Cleavage: An Indication of Heterogeneous Forms of Cell Death and Involvement of Multiple Proteases in the Infarct of Focal Cerebral Ischemia in Rat

Chaitanya

Babu

2009

Cell Mol Neurobiol

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Activation of calpains, cathepsin-b, caspase-3, and granzyme-b correlated with either apoptotic or necrotic cell deaths in cresyl violet staining. The appearance of PARP signature fragments gives a clear idea on the involvement of particular protease in the pathology. Appearance of signature fragments like 89- and 50-kDa indicates the involvement of apoptotic and necrotic cell death in the pathology. Further interaction of AIF and gra-b with PARP also indicates the involvement of non-apoptotic modes of cell death during the pathology of focal cerebral ischemia.

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Neuroprotective effects of KCL-440, a new poly(ADP-ribose) polymerase inhibitor, in the rat middle cerebral artery occlusion model

Cited by 16 publications

References 27 publications

Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress

Poly(ADP-ribose) polymerase-1 protects neurons against apoptosis induced by oxidative stress

Protection Against Chronic Hypoperfusion-Induced Retinal Neurodegeneration by PARP Inhibition via Activation of PI-3-kinase Akt Pathway and Suppression of JNK and p38 MAP Kinases

Differential PARP Cleavage: An Indication of Heterogeneous Forms of Cell Death and Involvement of Multiple Proteases in the Infarct of Focal Cerebral Ischemia in Rat

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