Poly(ADP-Ribose) Glycohydrolase Activity Mediates Post-Traumatic Inflammatory Reaction after Experimental Spinal Cord Trauma

Cuzzocrea, Salvatore; Genovese, Tiziana; Mazzon, Emanuela; Crisafulli, Concetta; Min, Wookee; Paola, Rosanna Di; Muià, Carmelo; Li, Jia He; Esposito, Emanuela; Bramantı, Placido; Xu, Weizheng; Massuda, Edmond; Zhang, Jie; Wang, Zhao Qi

doi:10.1124/jpet.106.108076

Cited by 33 publications

(30 citation statements)

References 38 publications

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“…Primary injury to the adult spinal cord is irreversible, whereas secondary degeneration is delayed and therefore amenable to intervention. Accordingly, several studies have shown that therapies targeting various factors involved in the secondary degeneration cascade lead to tissue sparing and improved behavioral outcomes in spinal cord-injured animals [41], [42], [43], [44]. In this report we demonstrate that VP1.15 and S14, PDE7 inhibitors, exerts beneficial effects in a mice model of spinal cord injury.…”

Section: Discussionsupporting

confidence: 50%

PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

et al. 2011

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BackgroundPrimary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation.Methodology/Principal FindingsHere we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5–T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression.Conclusions/SignificanceAll these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI.

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Section: Discussionsupporting

confidence: 50%

PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

et al. 2011

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“…It has been known that both PARG and PARP do play important roles in reticular biological processes [12] where PARP deficiency could reduce arthritis severity in an animal experimental model [22] and diminish tumor necrosis factor-induced inflammatory damage in rheumatoid synovial fibroblasts [23] while, PARG inhibition could prevent septic shock-like syndrome [10] and decrease spinal cord inflammation [24]. Furthermore, some studies have highlighted similar effects on many biological endpoints between PARP and PARG [9][10][11] and their functional similarities [12,[25][26] have been accepted as well.…”

Section: Discussionmentioning

confidence: 99%

RNA Interference of PARG Could Inhibit the Metastatic Potency of Colon Carcinoma Cells via PI3-Kinase/Akt Pathway

Qiao-zhuan¹,

Li²,

Wang³

et al. 2012

Cell Physiol Biochem

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Aims: To investigate the role and mechanism of PARG inhibition of metastatic behavior in colonic carcinoma cells. Methods: We examined the effects of PARG protein knockdown by RNA interference on invasion, migration and matrix adhesion of colon carcinoma cell lines in vitro and using a murine in vivo model of liver metastasis. Metastasis related genes were detected using mRNA and protein levels. Moreover, LY294002, an Akt phosphorylation inhibitor, was used to determine whether the suppression of metastatic behavior of colon carcinoma cells was mediated by Akt phosphorylation that was confirmed by EMSA. Pyrrolidine dithiocarbamate (PDTC) was used as a selective NFĸ-B inhibitor to clarify the relationship between PARG, PARP and NF-ĸB. Results: PARG protein was undetectable following specific shRNA transfection; mRNA and protein levels of PARP were significantly decreased. PARG-shRNA cells showed high levels of phosphorylated Akt with decreased expression of NF-ĸB (both total & nuclear), MMP2 and MMP9. However, no additional changes were noted following inhibition of PI3K/Akt pathway by LY294002 in the PARG-shRNA cells; these cells displayed reduced number of liver metastases when characterized in the murine in vivo model. Conclusion: PARG knockdown, concomitant with inhibition of PARP, suppressed the metastatic potency of colon carcinoma cells by activation of PI3K/Akt signaling pathway.

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“…Accordingly, several studies have shown that therapies targeting various factors involved in the secondary degeneration cascade lead to tissue sparing and improved behavioral outcomes in spinal cord-injured animals (Bao et al, 2003;Cuzzocrea et al, 2006;Glaser et al, 2006). Much of the damage that occurs in the spinal cord following traumatic injury is due to the secondary effects of glutamate excitotoxicity, Ca 2ϩ overload, and oxidative stress, three mechanisms that take part in a spiraling interactive cascade ending in neuronal dysfunction and death (Anderson and Hall, 1993).…”

Section: Discussionmentioning

confidence: 99%

Effects of Palmitoylethanolamide on Signaling Pathways Implicated in the Development of Spinal Cord Injury

Genovese

Esposito

Mazzon

et al. 2008

J Pharmacol Exp Ther

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Activation of peroxisome proliferator-activated receptor (PPAR)-␣, a member of the nuclear receptor superfamily, modulates inflammation and tissue injury events associated with spinal cord trauma in mice. Palmitoylethanolamide (PEA), the naturally occurring amide of palmitic acid and ethanolamine, reduces pain and inflammation through a mechanism dependent on PPAR-␣ activation. The aim of the present study was to evaluate the effect of the PEA on secondary damage induced by experimental spinal cord injury (SCI) in mice. SCI was induced by application of vascular clips to the dura mater via a four-level T 5 -T 8 laminectomy. This resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, and apoptosis. Repeated PEA administration (10 mg/kg i.p.; 30 min before and 1 and 6 h after SCI) significantly reduced: 1) the degree of spinal cord inflammation and tissue injury, 2) neutrophil infiltration, 3) nitrotyrosine formation, 4) proinflammatory cytokine expression, 5) nuclear transcription factor activation-B activation, 6) inducible nitric-oxide synthase expression, and 6) apoptosis. Moreover, PEA treatment significantly ameliorated the recovery of motor limb function. Together, the results indicate that PEA reduces inflammation and tissue injury associated with SCI and suggest a regulatory role for endogenous PPAR-␣ signaling in the inflammatory response associated with spinal cord trauma.Spinal cord injury (SCI) is a highly debilitating pathology (Maegele et al., 2005). Although innovative medical care has improved patient outcome, advances in pharmacotherapy for the purpose of limiting neuronal injury and promoting regeneration have been limited. The complex pathophysiology of SCI may explain the difficulty in finding a suitable therapy. The primary traumatic mechanical injury to the spinal cord causes the death of a number of neurons that cannot be recovered and regenerated. Studies indicate that neurons continue to die for hours following traumatic SCI (Profyris et al., 2004). The events that characterize this successive phase to mechanical injury are called "secondary damage." The secondary damage is determined by a large number of cellular, molecular, and biochemical cascades. A large body of recent data suggests the presence of a local inflammatory response, which amplifies the secondary damage (Blight, 1992).Moreover, evidence has suggested that resident microglia and macrophages originating from blood are two key cell types related to the occurrence of neuronal degeneration in the central nervous system after traumatic injury. In particular, when SCI occurs, microglia in parenchyma is activated, and macrophages in circulation cross the blood-brain barrier (BBB) to act as intrinsic spinal phagocytes. Therefore, these cells can release various neurotrophic peptides such as brainderived neurotrophic factor, glial cell line-derived neurotrophic factor, and laminin, which are excellent substrates for neurite outgrowth.Peroxisome pro...

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Poly(ADP-Ribose) Glycohydrolase Activity Mediates Post-Traumatic Inflammatory Reaction after Experimental Spinal Cord Trauma

Cited by 33 publications

References 38 publications

PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

RNA Interference of PARG Could Inhibit the Metastatic Potency of Colon Carcinoma Cells via PI3-Kinase/Akt Pathway

Effects of Palmitoylethanolamide on Signaling Pathways Implicated in the Development of Spinal Cord Injury

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