Potential molecular targets of peroxynitrite in mediating blood–brain barrier damage and haemorrhagic transformation in acute ischaemic stroke with delayed tissue plasminogen activator treatment

Chen, Hansen; Chen, Xi; Luo, Yun; Shen, Jiangang

doi:10.1080/10715762.2018.1521519

Cited by 30 publications

(14 citation statements)

References 325 publications

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“…It is well known that cerebral ischemia–reperfusion could produce a large amount of ROS/RNS to induce oxidative/nitrative stress and MMP activations, leading to BBB disruption (Chen et al, 2013; Chen et al, 2018). Our previous studies demonstrated that RNS, especially peroxynitrite, plays crucial roles in activating MMPs, destroying the BBB and inducing neurological deficits in cerebral ischemia–reperfusion injury (Chen et al, 2013;Chen et al, 2015; Feng et al, 2018a).…”

Section: Discussionmentioning

confidence: 99%

“…During cerebral ischemia–reperfusion injury, large quantities of free radicals are produced in the ischemic brains, including reactive oxygen species (ROS) and reactive nitrogen species (RNS). Free radicals could mediate leukocyte adhesion, MMP activations, and BBB disruption (Chen et al, 2013; Chen et al, 2018). Superoxide (O 2 − ) and nitric oxide (NO) can rapidly react with each other to form peroxynitrite (ONOO − ) with diffusion limit ( k 2 = 4.7 × 10 9 M −1 s −1 ).…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Effects and Hepatorenal Toxicity of Angong Niuhuang Wan Against Ischemia–Reperfusion Brain Injury in Rats

et al. 2019

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Angong Niuhuang Wan (AGNHW) is a classic prescription in traditional Chinese medicine (TCM) used for stroke treatment, but its efficacies remain to be confirmed. With its arsenic- and mercury-containing materials, the application of AGNHW raises great safety concerns. Herein, we aim to explore the neuropharmacological effects against cerebral ischemia–reperfusion injury and evaluate the toxicological effects of AGNHW for better use. Male SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) and following 22 h of reperfusion. AGNHW (257 mg/kg, 1× AGNHW) were orally administered for pharmacological effects and 257, 514, and 1,028 mg/kg (equivalent to 1×, 2×, 4× AGNHW) were used for the toxicological study. The results revealed that AGNHW treatment reduced the infarct size and protected the blood–brain barrier (BBB) integrity in the MCAO rat ischemic stroke model. AGNHW treatment up-regulated bcl-2 expression and down-regulated the expressions of Bax, p47 phox , inducible nitric oxide synthase (iNOS), and 3-nitrotyrosine (3-NT), and inhibited the expressions and activities of matrix metalloproteinase-2 (MMP-2), MMP-9, and reserved tight junction protein zonula occludens-1 (ZO-1) and claudin-5 in the ischemic brains. These results indicated that the neuroprotective mechanisms of AGNHW could be associated with its antioxidant properties by inhibiting oxidative/nitrative stress-mediated MMP activation and protecting tight junction proteins in the ischemic brains. Administration of 1× AGNHW for 7 days would not induce the accumulation of mercury in blood, liver, and kidney at day 14. Administration of 2× AGNHW and 4× AGNHW for 7 days increased the level of mercury in the kidney. For arsenic level, administration of 1× AGNHW for 7 days would increase the level of arsenic in the liver and blood without increase of arsenic in the kidney at day 14. Administration of 2× AGNHW and 4× AGNHW for 7 days would further increase the level of arsenic in the liver and blood. There is no influence on body weight, organ index, histological structures, and renal and liver functions. These results suggest that short-term treatment of AGNHW within 1 week should be safe and has neuroprotective effects against cerebral ischemia–reperfusion injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effects and Hepatorenal Toxicity of Angong Niuhuang Wan Against Ischemia–Reperfusion Brain Injury in Rats

et al. 2019

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“…Other signaling pathways that can be targeted by peroxynitrite and promote BBB dysfunction include high mobility group box 1 (HMGB1), TLR-2 and 4, poly(ADP ribose) polymerase, Src, Rho-associated protein kinase (ROCK), and glycogen synthase kinase (GSK)3β. 75 Of these pathways, the link between Src signaling and BBB opening is particularly intriguing. This connection is supported by a previous study where imatinib, a drug commonly used to treat chronic myeloid leukemia, decreased CNS expression of phosphorylated Src, reduced MMP-9 activity, and reduced Evan’s blue-albumin extravasation in a rodent model of subarachnoid hemorrhage (SAH).…”

Section: Microglial Activation: M1 Pro-inflammatory Phenotype and Bbbmentioning

confidence: 99%

Regulation of blood–brain barrier integrity by microglia in health and disease: A therapeutic opportunity

Ronaldson

Davis

2020

J Cereb Blood Flow Metab

267

180

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The blood–brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes, transporters) that are necessary for the BBB to perform this physiological role. Microvascular endothelial cells require support from astrocytes, pericytes, microglia, neurons, and constituents of the extracellular matrix. This intricate relationship implies the existence of a neurovascular unit (NVU). NVU cellular components can be activated in disease and contribute to dynamic remodeling of the BBB. This is especially true of microglia, the resident immune cells of the brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate that M1 pro-inflammatory microglia contribute to BBB dysfunction and vascular “leak”, while M2 anti-inflammatory microglia play a protective role at the BBB. Understanding biological mechanisms involved in microglia activation provides a unique opportunity to develop novel treatment approaches for neurological diseases. In this review, we highlight characteristics of M1 proinflammatory and M2 anti-inflammatory microglia and describe how these distinct phenotypes modulate BBB physiology. Additionally, we outline the role of other NVU cell types in regulating microglial activation and highlight how microglia can be targeted for treatment of disease with a focus on ischemic stroke and Alzheimer’s disease.

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“…Given that there is a wide range for prognosis after reperfusion, literature has supported the development of a more standardized system of image-based criteria for patient selection undergoing revascularization in acute and extended time-windows. 14 , 21–23 Rationale for altering recanalization guidelines in stroke patients is supported by the observed benefits from delayed recanalization (outside 6 h) in patients with a small completed infarct and a large area of perfusion mismatch– resulting in minimal intracerebral hemorrhage compared to patients that undergo recanalization of mostly infarcted tissue. 21 Leonard et al.…”

Section: Reperfusion Rationalementioning

confidence: 99%

Evolution of the stroke paradigm: A review of delayed recanalization

Camara

Matei

Zhang

2020

J Cereb Blood Flow Metab

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While the time window for reperfusion after ischemic stroke continues to increase, many patients are not candidates for reperfusion under current guidelines that allow for reperfusion within 24 h after last known well time; however, many case studies report favorable outcomes beyond 24 h after symptom onset for both spontaneous and medically induced recanalization. Furthermore, modern imaging allows for identification of penumbra at extended time points, and reperfusion risk factors and complications are becoming better understood. Taken together, continued urgency exists to better understand the pathophysiologic mechanisms and ideal setting of delayed recanalization beyond 24 h after onset of ischemia.

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Potential molecular targets of peroxynitrite in mediating blood–brain barrier damage and haemorrhagic transformation in acute ischaemic stroke with delayed tissue plasminogen activator treatment

Cited by 30 publications

References 325 publications

Neuroprotective Effects and Hepatorenal Toxicity of Angong Niuhuang Wan Against Ischemia–Reperfusion Brain Injury in Rats

Neuroprotective Effects and Hepatorenal Toxicity of Angong Niuhuang Wan Against Ischemia–Reperfusion Brain Injury in Rats

Regulation of blood–brain barrier integrity by microglia in health and disease: A therapeutic opportunity

Evolution of the stroke paradigm: A review of delayed recanalization

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