scholarly journals Inhibition of Poly(ADP-Ribose) Polymerase Suppresses Inflammation and Promotes Recovery after Ischemic Injury

2009 ◽  
Vol 29 (4) ◽  
pp. 820-829 ◽  
Author(s):  
Tiina M Kauppinen ◽  
Sang Won Suh ◽  
Ari E Berman ◽  
Aaron M Hamby ◽  
Raymond A Swanson
Keyword(s):  
Inflammatory Responses ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Bilateral Carotid Occlusion ◽  
Hippocampal Ca1 ◽  
Bilateral Carotid ◽  
Ca1 Area ◽  
The Brain ◽  
Parp 1

The brain inflammatory response induced by stroke contributes to cell death and impairs neurogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1) is a coactivator of the transcription factor NF-κB and required for NF-κB-mediated inflammatory responses. Here we evaluated PARP inhibition as a means of suppressing post-stroke inflammation and improving outcome after stroke. Rats were subjected to bilateral carotid occlusion-reperfusion, and treatment with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)- N,N-dimethylacetamide (PJ34) was begun 48 h later. PJ34 was found to rapidly suppress the ischemia-induced microglial activation and astrogliosis. Behavioral tests performed 6 to 8 weeks after ischemia showed deficits in spatial memory and learning that were lessened by the PJ34 treatment. Immunohistochemical evaluation of hippocampus at 8 weeks after ischemia showed increased neuronal density in CA1 layer of PJ34-treated animals relative to vehicle-treated animals. Bromodeoxyuridine labeling showed formation of new neurons in hippocampal CA1 area in PJ34-treated animals, but not in vehicle-treated animals. Together, these results suggest that treatment with a PARP inhibitor for several days after ischemia enhances long-term neuronal survival and neurogenesis by reducing inflammation.

Differential Effects of Anesthetic Agents on Outcome from Near-complete but Not Incomplete Global Ischemia in the Rat 

1998 ◽  
Vol 89 (2) ◽  
pp. 391-400 ◽  
Author(s):  
Yoshihide Miura ◽  
Hilary P. Grocott ◽  
Robert D. Bart ◽  
Robert D. Pearlstein ◽  
Franklin Dexter ◽  
...  
Keyword(s):  
Carotid Occlusion ◽  
Ca1 Neurons ◽  
Differential Effects ◽  
Anesthetic Agents ◽  
Bilateral Carotid Occlusion ◽  
Hippocampal Ca1 ◽  
Bilateral Carotid ◽  
Cerebral Ischemic ◽  
The Brain ◽  
Incomplete Ischemia

Background It has been postulated that anesthetic agents that reduce cerebral metabolic rate will protect the brain against ischemia when electroencephalographic (EEG) activity is persistent, but will provide no protection when ischemia is severe enough to cause EEG isoelectricity. No outcome studies have addressed this issue. The authors studied anesthetic agents to determine if they provide differential effects on outcome from global cerebral ischemic insults that cause either an attenuated or isoelectric EEG. Methods Fasted rats were subjected to either (1) incomplete ischemia (attenuated EEG; 20 min of mean arterial pressure [MAP] = 50 mmHg and bilateral carotid occlusion) or (2) near-complete ischemia (isoelectric EEG; 10 min of MAP = 30 mmHg and bilateral carotid occlusion) while anesthetized with 1.4% isoflurane, 1 mg x kg(-1) x min(-1) ketamine, or 25 microg x kg(-1) x h(-1) 70% nitrous oxide and fentanyl. The brain was maintained at normothermia during ischemia and for 22 h after ischemia. Five days later, hippocampal CA1 and cortical injury were measured. Results There was no difference among anesthetic agents during incomplete ischemia for mean +/- SD percentage dead CA1 neurons (fentanyl, 38%+/-20%; isoflurane, 31%+/-10%; ketamine, 40%+/-19%; P = 0.38). During near-complete ischemia, there was a difference among anesthetic agents (fentanyl, 88%+/-9%; isoflurane, 37%+/-20%; ketamine, 70%+/-28%; P = 0.00008). Isoflurane was protective compared with fentanyl (P = 0.00007) and ketamine (P = 0.0061). There was no difference between fentanyl and ketamine (P = 0.143). Similar observations were made in the cortex. Neurologic function correlated with histologic damage. Conclusions Outcome from near-complete but not incomplete cerebral ischemia depended on the anesthetic agent administered during the ischemic insult.

scholarly journals Long-Term Glucose Starvation Induces Inflammatory Responses and Phenotype Switch in Primary Cortical Rat Astrocytes

2021 ◽  
Author(s):  
Vanessa Kogel ◽  
Stefanie Trinh ◽  
Natalie Gasterich ◽  
Cordian Beyer ◽  
Jochen Seitz
Keyword(s):  
Cerebral Cortex ◽  
Synapse Formation ◽  
Inflammatory Responses ◽  
Glucose Starvation ◽  
Unfolded Protein ◽  
Genes Encoding ◽  
Phenotype Switch ◽  
The Unfolded Protein Response ◽  
The Brain

AbstractAstrocytes are the most abundant cell type in the brain and crucial to ensure the metabolic supply of neurons and their synapse formation. Overnutrition as present in patients suffering from obesity causes astrogliosis in the hypothalamus. Other diseases accompanied by malnutrition appear to have an impact on the brain and astrocyte function. In the eating disorder anorexia nervosa (AN), patients suffer from undernutrition and develop volume reductions of the cerebral cortex, associated with reduced astrocyte proliferation and cell count. Although an effect on astrocytes and their function has already been shown for overnutrition, their role in long-term undernutrition remains unclear. The present study used primary rat cerebral cortex astrocytes to investigate their response to chronic glucose starvation. Cells were grown with a medium containing a reduced glucose concentration (2 mM) for 15 days. Long-term glucose starvation increased the expression of a subset of pro-inflammatory genes and shifted the primary astrocyte population to the pro-inflammatory A1-like phenotype. Moreover, genes encoding for proteins involved in the unfolded protein response were elevated. Our findings demonstrate that astrocytes under chronic glucose starvation respond with an inflammatory reaction. With respect to the multiple functions of astrocytes, an association between elevated inflammatory responses due to chronic starvation and alterations found in the brain of patients suffering from undernutrition seems possible.

scholarly journals Physiological Sympathetic Activation Reduces Systemic Inflammation: Role of Baroreflex and Chemoreflex

2021 ◽  
Vol 12 ◽  
Author(s):  
Fernanda Brognara ◽  
Jaci Airton Castania ◽  
Alexandre Kanashiro ◽  
Daniel Penteado Martins Dias ◽  
Helio Cesar Salgado
Keyword(s):  
Nervous System ◽  
Arterial Pressure ◽  
Systemic Inflammation ◽  
Inflammatory Responses ◽  
Low Frequency ◽  
Systolic Arterial Pressure ◽  
Sympathetic Activation ◽  
Bilateral Carotid Occlusion ◽  
Bilateral Carotid ◽  
Reflex Activation

Baroreflex and chemoreflex act through the autonomic nervous system, which is involved with the neural regulation of inflammation. The present study reports the effects of reflex physiological sympathetic activation in endotoxemic rats using bilateral carotid occlusion (BCO), a physiological approach involving the baroreflex and chemoreflex mechanisms and the influence of the baroreceptors and peripheral chemoreceptors in the cardiovascular and systemic inflammatory responses. After lipopolysaccharide (LPS) administration, the arterial pressure was recorded during 360 min in unanesthetized rats, and serial blood samples were collected to analyze the plasma cytokine levels. BCO elicited the reflex activation of the sympathetic nervous system, providing the following outcomes: (I) increased the power of the low-frequency band in the spectrum of the systolic arterial pressure during the BCO period; (II) reduced the levels of pro-inflammatory cytokines in plasma, including the tumor necrosis factor (TNF) and the interleukin (IL)-1β; (III) increased the plasma levels of anti-inflammatory cytokine IL-10, 90 min after LPS administration. Moreover, selective baroreceptor or chemoreceptor denervation deactivated mechanosensitive and chemical sensors, respectively, and decreased the release of the LPS-induced cytokine but did not alter the BCO modulatory effects. These results show, for the first time, that physiological reflex activation of the sympathetic circuit decreases the inflammatory response in endotoxemic rats and suggest a novel function for the baroreceptors as immunosensors during the systemic inflammation.

scholarly journals Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1901 ◽  
Author(s):  
Rui Min ◽  
Weibin Wu ◽  
Mingzhong Wang ◽  
Lin Tang ◽  
Dawei Chen ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Anticancer Activities ◽  
Reference Drug ◽  
Structure Activity ◽  
Ic50 Values ◽  
Proliferation Assays ◽  
Parp 1

A series of benzimidazole carboxamide derivatives have been synthesized and characterized by 1H-NMR, 13C-NMR and HRMS. PARP inhibition assays and cellular proliferation assays have also been carried out. Compounds 5cj and 5cp exhibited potential anticancer activities with IC50 values of about 4 nM against both PARP-1 and PARP-2, similar to the reference drug veliparib. The two compounds also displayed slightly better in vitro cytotoxicities against MDA-MB-436 and CAPAN-1 cell lines than veliparib and olaparib, with values of 17.4 µM and 11.4 µM, 19.8 µM and 15.5 µM, respectively. The structure-activity relationship based on molecular docking was discussed as well.

Lipopolysaccharide inhibits induction of long-term potentiation and depression in the rat hippocampal CA1 area

2001 ◽  
Vol 422 (1-3) ◽  
pp. 69-76 ◽  
Author(s):  
Ji-Hoon Jo ◽  
Eun-Jin Park ◽  
Jae-Kwang Lee ◽  
Min-Whan Jung ◽  
Chang-Joong Lee
Keyword(s):  
Long Term Potentiation ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca1 Area ◽  
Ca1 Area

scholarly journals Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1722 ◽  
Author(s):  
Mark B. Plotnikov ◽  
Galina A. Chernysheva ◽  
Oleg I. Aliev ◽  
Vera I. Smol’iakova ◽  
Tatiana I. Fomina ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cerebral Ischemia ◽  
Endothelial Dysfunction ◽  
Neurological Deficit ◽  
Neuroprotective Effect ◽  
Global Cerebral Ischemia ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca1 Area ◽  
Ca1 Area ◽  
The Brain

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5′-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 μM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.

Effect of inhibition of poly-(ADP ribose) polymerase on gemcitabine and radiation-induced cytotoxicity of pancreatic cancer cells.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 203-203
Author(s):  
R. Tuli ◽  
A. Surmak ◽  
A. Blackford ◽  
A. Leubner ◽  
E. M. Jaffee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Dna Repair ◽  
Cancer Cells ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Pancreatic Cancer Cells ◽  
Synergistic Mechanism ◽  
Radiation Induced ◽  
Parp 1

203 Background: Poly-(ADP ribose) polymerases (PARPs) are DNA-binding proteins involved in DNA repair. PARP inhibition has resulted in excellent antitumor activity when used with other cytotoxic therapies. ABT-888 is a promising PARP inhibitor with excellent potency against the PARP-1/2 enzymes and good oral bioavailability. We attempt to determine whether PARP-1/2 inhibition alone, or in combination with gemcitabine, will enhance the effects of irradiation (RT) of pancreatic cancer cells. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were treated with ABT-888, gemcitabine, RT, or combinations thereof. RT was delivered with a 137-Cs Gammacell in a single fraction. Cells were pre-treated once with ABT-888 and/or gemcitabine 30 minutes prior to RT. Viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3/7 activity using a luminescent assay. PARP activity was determined using a chemiluminescent PAR elisa. Results: The half maximal inhibitory concentration (IC50) of RT was 5 Gy; IC10 for ABT-888 and gemcitabine were 10 uM and 5 nM, respectively. Treatment with ABT-888 (10 uM), gemcitabine (5 nM), or combinations of the two with RT led to increasingly higher rates of cell death 8 days after treatment (p<0.001). RT dose enhancement factors were 1.5, 1.82 and 2.36 for 1, 10 and 100 uM ABT-888, respectively. Minimal cytotoxicity was noted when cells were treated with ABT-888 alone up to 100 uM. Caspase activity was not significantly increased when treated with ABT-888 (10 uM) alone (1.28 fold, p=0.077), but became significant when RT (2 Gy) was added (2.03 fold, p=0.006). This difference was further enhanced by the addition of gemcitabine (2.95 fold, p=0.004). Conclusions: ABT-888 is a potent radiosensitizer of pancreatic cancer cells with minimal cytotoxicity when used alone. Cell death is further potentiated by cotreatment with gemcitabine. Radiation-induced apoptosis was significantly enhanced by ABT-888 and gemcitabine, suggesting a synergistic mechanism of interference with DNA repair. These data are currently being validated in an orthotopic pancreatic cancer mouse model. No significant financial relationships to disclose.

PARPi in PCa results in decreased availability of DNA repair factors.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 301-301
Author(s):  
Matthew Joseph Schiewer ◽  
Karen E. Knudsen
Keyword(s):  
Dna Repair ◽  
Enzymatic Activity ◽  
Disease Progression ◽  
Target Genes ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Clinical Trial Data ◽  
Parp Inhibition ◽  
Transcriptional Regulatory ◽  
Parp 1

301 Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions in cancer, including regulating NFkB and HIF function. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of AR function PCa, and assists in regulating AR-driven, PCa-associated phenotypes, including castrate-resistant AR function, tumor growth, and transition to CRPC. Additionally, recent clinical trial data of PARP inhibition as a single agent in advanced cancers has been promising. Given the preclinical and clinical data, pursuing a deeper understanding of the molecular underpinnings of PARP inhibitor action in PCa may yield markers of response and/or rationale for precision medicine. Methods: Hormone therapy-sensitive and CRPC models were transcriptionally profiled in response to PARP inhibition. Pathways were nominated for validation. Bioinformatics approaches were used to compare the PARP-1-sensitive transcritome with publicly available data sets. ChIP-qPCR was performed to examine the effect of PARPi on target genes of the nominated pathways. Patient specimen TMAs were utilized for PAR IHC. PARP inhibition reduced AR and E2F1 target gene expression, as well as significantly decreased expression of DNA repair genes. Both PARP enzymatic activity and the PARP-1-dependent transcriptional program are increased as a function of disease progression. Results: These data indicate that:(1) The PARPi-sensitive transcriptome holds major transcriptional regulatory events beyond AR signaling. (2) E2F1-regulated genes are sensitive to PARP-1 function. (3) The PARPi-sensitive E2F-regulated transcriptome is enriched for DNA repair factors. (4) PARP enzymatic and transcriptional functions are increased during disease progression. Conclusions: Taken together, this study demonstrates that the transcriptional roles of PARP-1 may contribute to the clinical response to PARP-1 inhibitors as single agents. This work was supported by a PCF YI award (to MJS).

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