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Synthetic Oligodeoxynucleotides Containing Multiple Telemeric TTAGGG Motifs Suppress Inflammasome Activity in Macrophages Subjected to Oxygen and Glucose Deprivation and Reduce Ischemic Brain Injury in Stroke-Prone Spontaneously Hypertensive Rats.

Zhao J, Mou Y, Bernstock JD, Klimanis D, Wang S, Spatz M, Maric D, Johnson K, Klinman DM, Li X, Li X, Hallenbeck JM - PLoS ONE (2015)

Bottom Line: Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells.In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion.Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Jinan Central Hospital affiliated with Shandong University, 105 Jiefang Road, Jinan, Shandong, 250013, P. R. China; Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
The immune system plays a fundamental role in both the development and pathobiology of stroke. Inflammasomes are multiprotein complexes that have come to be recognized as critical players in the inflammation that ultimately contributes to stroke severity. Inflammasomes recognize microbial and host-derived danger signals and activate caspase-1, which in turn controls the production of the pro-inflammatory cytokine IL-1β. We have shown that A151, a synthetic oligodeoxynucleotide containing multiple telemeric TTAGGG motifs, reduces IL-1β production by activated bone marrow derived macrophages that have been subjected to oxygen-glucose deprivation and LPS stimulation. Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells. In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion. These findings clearly suggest that the modulation of inflammasome activity via A151 may contribute to a reduction in pro-inflammatory cytokine production by macrophages subjected to conditions that model brain ischemia and modulate ischemic brain damage in an animal model of stroke. Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus

A151 reduced brain ischemic injury in SHR-SP rats 48 hours after pMCAO.The rats in saline groups were combined for analysis, as they were not statistically different. (A) Representative coronal brain sections stained with cresyl violet. (B) A151 reduced infarct volumes in male rats. (C) A151 reduced infarct volumes in female rats. (D) A151 improved performance in forepaw test in female rats. (E) A151 reduced brain NLRP3 mRNA 48 hours after pMCAO, the error bars represent the 95th upper and lower confidence intervals of gene expression. (n = 7–17 per group; *, p < 0.05 compared with saline control; **, p < 0.05 compared with saline control or C151).
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pone.0140772.g004: A151 reduced brain ischemic injury in SHR-SP rats 48 hours after pMCAO.The rats in saline groups were combined for analysis, as they were not statistically different. (A) Representative coronal brain sections stained with cresyl violet. (B) A151 reduced infarct volumes in male rats. (C) A151 reduced infarct volumes in female rats. (D) A151 improved performance in forepaw test in female rats. (E) A151 reduced brain NLRP3 mRNA 48 hours after pMCAO, the error bars represent the 95th upper and lower confidence intervals of gene expression. (n = 7–17 per group; *, p < 0.05 compared with saline control; **, p < 0.05 compared with saline control or C151).

Mentions: The ability of A151 to prevent and/or treat ischemic injury was evaluated in SHR-SP rats using the permanent middle cerebral artery occlusion (pMCAO) model. A single dose of 3 mg A151 was administered via i.p. injection 3 days prior to (-3d), 1 day prior to (-1d), or 3 hours post (+3h) pMCAO. Of note, we also tested 1 mg A151 administered 1 day prior to pMCAO in an effort demonstrate a threshold for effective dosing. Each of these treatment regimens significantly reduced infarct volumes (p<0.05, Fig 4). In male rats (Fig 4B), at 48 hours after MCAO, the infarct volumes (corrected for edema) of the saline treated (145.7 ± 6.6 mm3), 3 mg C151 -1d treated (141.3± 7.6 mm3) and +3h treated (151.2± 10.4 mm3) animals were similar; the infarct volumes in 3 mg A151 -3d treated animals (119.5 ± 5.8 mm3) averaged 15.4% smaller than in C151 -1d treated rats; infarct volume was decreased by 26.9% and 23.9%, respectively, in 3 mg A151 -1d group (103.2 ± 9.3 mm3) and +3h group (107.5 ± 11.7mm3); 1 mg A151 -1d reduced infarct volume (101.5 ± 14.0 mm3) by 28.1%. In female rats (Fig 4C), compared with the saline group (116.8 ± 7.1 mm3), infarct volume was decreased in 3 mg A151 -1d group (94.3 ± 3.9 mm3) and 3 mg A151 +3h group (89.2± 4.7mm3); 3 mg C151 +3h did not affect infarct volume (118.8 ± 10.3 mm3).


Synthetic Oligodeoxynucleotides Containing Multiple Telemeric TTAGGG Motifs Suppress Inflammasome Activity in Macrophages Subjected to Oxygen and Glucose Deprivation and Reduce Ischemic Brain Injury in Stroke-Prone Spontaneously Hypertensive Rats.

Zhao J, Mou Y, Bernstock JD, Klimanis D, Wang S, Spatz M, Maric D, Johnson K, Klinman DM, Li X, Li X, Hallenbeck JM - PLoS ONE (2015)

A151 reduced brain ischemic injury in SHR-SP rats 48 hours after pMCAO.The rats in saline groups were combined for analysis, as they were not statistically different. (A) Representative coronal brain sections stained with cresyl violet. (B) A151 reduced infarct volumes in male rats. (C) A151 reduced infarct volumes in female rats. (D) A151 improved performance in forepaw test in female rats. (E) A151 reduced brain NLRP3 mRNA 48 hours after pMCAO, the error bars represent the 95th upper and lower confidence intervals of gene expression. (n = 7–17 per group; *, p < 0.05 compared with saline control; **, p < 0.05 compared with saline control or C151).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608557&req=5

pone.0140772.g004: A151 reduced brain ischemic injury in SHR-SP rats 48 hours after pMCAO.The rats in saline groups were combined for analysis, as they were not statistically different. (A) Representative coronal brain sections stained with cresyl violet. (B) A151 reduced infarct volumes in male rats. (C) A151 reduced infarct volumes in female rats. (D) A151 improved performance in forepaw test in female rats. (E) A151 reduced brain NLRP3 mRNA 48 hours after pMCAO, the error bars represent the 95th upper and lower confidence intervals of gene expression. (n = 7–17 per group; *, p < 0.05 compared with saline control; **, p < 0.05 compared with saline control or C151).
Mentions: The ability of A151 to prevent and/or treat ischemic injury was evaluated in SHR-SP rats using the permanent middle cerebral artery occlusion (pMCAO) model. A single dose of 3 mg A151 was administered via i.p. injection 3 days prior to (-3d), 1 day prior to (-1d), or 3 hours post (+3h) pMCAO. Of note, we also tested 1 mg A151 administered 1 day prior to pMCAO in an effort demonstrate a threshold for effective dosing. Each of these treatment regimens significantly reduced infarct volumes (p<0.05, Fig 4). In male rats (Fig 4B), at 48 hours after MCAO, the infarct volumes (corrected for edema) of the saline treated (145.7 ± 6.6 mm3), 3 mg C151 -1d treated (141.3± 7.6 mm3) and +3h treated (151.2± 10.4 mm3) animals were similar; the infarct volumes in 3 mg A151 -3d treated animals (119.5 ± 5.8 mm3) averaged 15.4% smaller than in C151 -1d treated rats; infarct volume was decreased by 26.9% and 23.9%, respectively, in 3 mg A151 -1d group (103.2 ± 9.3 mm3) and +3h group (107.5 ± 11.7mm3); 1 mg A151 -1d reduced infarct volume (101.5 ± 14.0 mm3) by 28.1%. In female rats (Fig 4C), compared with the saline group (116.8 ± 7.1 mm3), infarct volume was decreased in 3 mg A151 -1d group (94.3 ± 3.9 mm3) and 3 mg A151 +3h group (89.2± 4.7mm3); 3 mg C151 +3h did not affect infarct volume (118.8 ± 10.3 mm3).

Bottom Line: Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells.In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion.Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Jinan Central Hospital affiliated with Shandong University, 105 Jiefang Road, Jinan, Shandong, 250013, P. R. China; Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
The immune system plays a fundamental role in both the development and pathobiology of stroke. Inflammasomes are multiprotein complexes that have come to be recognized as critical players in the inflammation that ultimately contributes to stroke severity. Inflammasomes recognize microbial and host-derived danger signals and activate caspase-1, which in turn controls the production of the pro-inflammatory cytokine IL-1β. We have shown that A151, a synthetic oligodeoxynucleotide containing multiple telemeric TTAGGG motifs, reduces IL-1β production by activated bone marrow derived macrophages that have been subjected to oxygen-glucose deprivation and LPS stimulation. Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells. In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion. These findings clearly suggest that the modulation of inflammasome activity via A151 may contribute to a reduction in pro-inflammatory cytokine production by macrophages subjected to conditions that model brain ischemia and modulate ischemic brain damage in an animal model of stroke. Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus