Influence of PARP-1 Polymorphisms in Patients after Traumatic Brain Injury

Sarnaik, Ajit; Conley, Yvette P.; Okonkwo, David O.; Barr, Taura L.; Fink, Ericka L.; Szabó, Csaba; Kochanek, Patrick M.; Clark, Robert S. B.

doi:10.1089/neu.2009.1171

Cited by 38 publications

(26 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Evidence for sex-differences in PARP activation is also seen interrogating CSF from both adult and pediatric patients after severe TBI. Similar to the cerebral ischemia studies described above, PARP appears to have a greater role in males compared with females after brain injury [85][86]. Also consistent with the cerebral ischemia studies described above, and what appears to be the only major identified cell death pathway demonstrating female proclivity, release of cytochrome c into CSF (consistent but not pathognomonic of apoptosis) is higher in girls versus boys after severe TBI.…”

Section: Sex-based Disparity After Traumatic Brain In-jurysupporting

confidence: 76%

Unmasking Sex-Based Disparity in Neuronal Metabolism

Manole

Tehranian-DePasquale²,

Du³

et al. 2011

CPD

View full text Add to dashboard Cite

Both classic and emerging literature point to sex-based disparity in neuronal metabolism. While detectable under baseline conditions, this phenomenon appears to be exaggerated or sometimes unmasked in neurons by cellular stress. A complex sex-dependent response to nutrient deprivation, excitotoxicity, oxidative/nitrositive stress, oxygen-glucose deprivation, and chemical toxicity has been observed in neurons in vitro, as well as after various insults including ischemic or traumatic brain injury in vivo. Importantly, sex-based disparity in response to diverse therapeutics has been seen in neurons in culture, contemporary animal models of brain injury, and in human disease. These have clear implications for pharmacological design of therapeutics targeting central nervous system diseases involving both males and females, and preclinical testing of promising agents.

show abstract

Section: Sex-based Disparity After Traumatic Brain In-jurysupporting

confidence: 76%

Unmasking Sex-Based Disparity in Neuronal Metabolism

Manole

Tehranian-DePasquale²,

Du³

et al. 2011

CPD

View full text Add to dashboard Cite

show abstract

“…42). Furthermore, recent studies suggest that certain PARP polymorphisms may affect the outcome of various forms of critical illness (43,44). In summary, the field of PARP has entered the clinical stage, which underlines the timeliness of additional translational studies in various areas including burns and various forms or critical illness.…”

Section: Discussionmentioning

confidence: 99%

Increased Poly(ADP-Ribosyl)ation in Skeletal Muscle Tissue of Pediatric Patients with Severe Burn Injury

Oláh¹,

Finnerty²,

Sbrana³

et al. 2011

Shock

View full text Add to dashboard Cite

Summary Activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) has been shown to promote cellular energetic collapse and cellular necrosis in various forms of critical illness. Most of the evidence implicating the PARP pathway in disease processes is derived from preclinical studies. With respect to PARP and burns, studies in rodent and large animal models of burn injury have demonstrated the activation of PARP in various tissues and the beneficial effect of its pharmacological inhibition. The aim of the current study was to measure the activation of PARP in human skeletal muscle biopsies at various stages of severe pediatric burn injury and to identify the cell types where this activation may occur. Another aim of the study was to test the effect of propranolol (an effective treatment of patients with burns), on the activation of PARP in skeletal muscle biopsies. PARP activation was measured by Western blotting for its product, poly(ADP-ribose) (PAR). The localization of PARP activation was determined by PAR immunohistochemistry. The results showed that PARP becomes activated in the skeletal muscle tissue after burns, with the peak of the activation occurring in the middle stage of the disease (13–18 days after burns). Even at the late stage of the disease (69–369 days post-burn) an elevated degree of PARP activation persisted in some of the patients. Immunohistochemical studies localized the staining of PAR primarily to vascular endothelial cells, and occasionally to resident mononuclear cells. There was a marked suppression of PARP activation in the skeletal muscle biopsies of patients who received propranolol treatment. We conclude that human burn injury is associated with the activation of PARP. We hypothesize that this response may contribute to the inflammatory responses and cell dysfunction in burns. Some of the clinical benefit of propranolol in burns may be related to its inhibitory effect on PARP activation.

show abstract

“…Clark and colleagues have investigated whether tagging single nucleotide polymorphisms (tSNPs) covering multiple regions of the PARP1 gene are related to outcome after TBI in humans (Sarnaik et al, 2010). DNA from 191 adult patients with severe TBI was assayed for four tSNPs corresponding to haplotype blocks spanning the PARP1 gene.…”

Section: Beyond Anticancer Therapy: Stroke Circulatory Shock Carmentioning

confidence: 99%

“…In multiple logistic regression analysis controlling for age, initial Glasgow Coma Scale score, and gender, the AA genotype of SNP rs3219119, which tags a haplotype block spanning the automodification and catalytic domains of the PARP 1 gene, was an independent predictor of favorable neurologic outcome. A second SNP (rs2271347), which tags a haplotype block spanning the automodification and catalytic domains of the PARP 1 gene, correlated with the amount of PARylated proteins in the cerebrospinal fluid, but did not correlate with the clinical outcome (Sarnaik et al, 2010). From these findings it can be concluded that after severe brain trauma in humans, a PARP1 polymorphism within the automodification-catalytic domain is associated with neurological outcome, while a polymorphism within the promoter region is associated with poly(ADP-ribose)-modified protein level.…”

Section: Beyond Anticancer Therapy: Stroke Circulatory Shock Carmentioning

confidence: 99%

Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

Curtin

Szabó

2013

Molecular Aspects of Medicine

Self Cite

327

286

View full text Add to dashboard Cite

The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination (HRR) repair is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.

show abstract

Influence of PARP-1 Polymorphisms in Patients after Traumatic Brain Injury

Cited by 38 publications

References 31 publications

Unmasking Sex-Based Disparity in Neuronal Metabolism

Unmasking Sex-Based Disparity in Neuronal Metabolism

Increased Poly(ADP-Ribosyl)ation in Skeletal Muscle Tissue of Pediatric Patients with Severe Burn Injury

Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

Contact Info

Product

Resources

About