Dataset Information

Effects of Poly(ADP-Ribose) Polymerase-1 Inhibition in a Neonatal Rodent Model of Hypoxic-Ischemic Injury.

ABSTRACT:

Background

Hypoxia ischemia (HI) to the developing brain occurs in 1-6 in 1000 live births. Large numbers of survivors have neurological long-term sequelae. However, mechanisms of recovery after HI are not understood and preventive measures or clinical treatments are not effective. Poly(ADP-ribose) polymerase-1 is overactivated in response to ischemia. In neonatal mice HI activates PARP-1 but its role in perinatal brain injury remains uncertain.

Objective

Aim of this study was to explore the effect of TES448 (PARP-1-inhibitor) and hypothermia after an ischemic insult.

Design and methods

10-day-old Wistar rats underwent HI. TES448 was given 10?min, 3?hrs, and 6?hrs after hypoxia. Hypothermia was started 30?min after HI and brains were dissected at P12. Western blotting and histological staining were used to evaluate for degree of injury.

Results

Protein expression of PARP-1 levels was diminished after TES448 treatment. Cresyl violet and TUNEL staining revealed decreased injury in male rat pups following TES448 and combined treatment. Female rats showed increased numbers of TUNEL-positive cells after combined therapy. TES448 inhibited microglia activation after hypoxic-ischemic injury. A cellular response including NeuN, Olig2, and MBP was not affected by PARP-1-inhibition.

Conclusions

Inhibition of PARP-1 and hypothermia lead to an alteration of injury but this effect is sexually dimorphic.

SUBMITTER: Klofers M

PROVIDER: S-EPMC5494065 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Effects of Poly(ADP-Ribose) Polymerase-1 Inhibition in a Neonatal Rodent Model of Hypoxic-Ischemic Injury.

Klöfers Melanie M Kohaut Jules J Bendix Ivo I Herz Josephine J Boos Vinzenz V Felderhoff-Müser Ursula U Dzietko Mark M

BioMed research international 20170615

<h4>Background</h4>Hypoxia ischemia (HI) to the developing brain occurs in 1-6 in 1000 live births. Large numbers of survivors have neurological long-term sequelae. However, mechanisms of recovery after HI are not understood and preventive measures or clinical treatments are not effective. Poly(ADP-ribose) polymerase-1 is overactivated in response to ischemia. In neonatal mice HI activates PARP-1 but its role in perinatal brain injury remains uncertain.<h4>Objective</h4>Aim of this study was to ...[more]

PMID: 28698869

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Project description:BackgroundDespite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors. Particularly, PARP inhibitors are active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated breast related cancer antigens (BRCA) function have HR deficiency, which is also present in a significant proportion of non-BRCA-mutated ovarian cancer ("BRCAness" ovarian cancer). The prevalence of germline BRCA mutations in EOC has historically been estimated to be around 10-15 %. However, recent reports suggest that this may be a gross underestimate, especially in women with high-grade serous ovarian cancer (HGSOC). The emergence of the DNA repair pathway as a rational target in various cancers led to the development of the PARP inhibitors. The concept of tumor-selective synthetic lethality heralded the beginning of an eventful decade, culminating in the approval by regulatory authorities both in Europe as a maintenance therapy and in the United States treatment for advanced recurrent disease of the first oral PARP inhibitor, olaparib, for the treatment of BRCA-mutated ovarian cancer patients. Other PARP inhibitors are clearly effective in this disease and, within the next years, the results of ongoing randomized trials will clarify their respective roles.ConclusionThis review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future. Moreover, combination strategies involving PARP inhibitors are likely to receive increasing attention. The utility of PARP inhibitors combined with cytotoxic chemotherapy is of doubtful value, because of enhanced toxicity of this combination; while, more promising strategies include the combination with antiangiogenic agents, or with inhibitors of the P13K/AKT pathway and new generation of immunotherapy.

Dataset Information

Effects of Poly(ADP-Ribose) Polymerase-1 Inhibition in a Neonatal Rodent Model of Hypoxic-Ischemic Injury.

Background

Objective

Design and methods

Results

Conclusions

Publications

Effects of Poly(ADP-Ribose) Polymerase-1 Inhibition in a Neonatal Rodent Model of Hypoxic-Ischemic Injury.

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