Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury

Chen, Xingmiao; Chen, Hansen; Xu, Mingjing; Shen, Jiangang

doi:10.1038/aps.2012.82

Cited by 109 publications

(72 citation statements)

References 151 publications

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“…Polymorphonuclear cells have long been implicated in the brain damage induced by post-ischemic inflammation, through a wide variety of mechanisms (39–42). Our data suggest that iNOS-derived NO, which promotes lipid peroxidation, protein nitration, DNA damage and BBB breakdown (43), is a major neurotoxic molecule produced by neutrophils (44, 45). To provide further evidences that expression of iNOS in infiltrating leukocytes exacerbates ischemic injury, we adoptively transferred neutrophils into iNOS −/− mice.…”

Section: Discussionmentioning

confidence: 85%

Inducible Nitric Oxide Synthase in Neutrophils and Endothelium Contributes to Ischemic Brain Injury in Mice

García-Bonilla

Moore

Racchumi

et al. 2014

The Journal of Immunology

115

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Nitric oxide produced by inducible nitric oxide synthase (iNOS) contributes to ischemic brain injury, but the cell types expressing iNOS and mediating tissue damage have not been elucidated. To examine the relative contribution of iNOS in resident brain cells and peripheral leukocytes infiltrating the ischemic brain, we used bone marrow (BM) chimeric mice in which the middle cerebral artery was occluded and infarct volume was determined 3 days later. iNOS−/− mice engrafted with iNOS+/+ BM exhibited larger infarcts (44±2 mm3; n=13; Mean±SE) compared to autologous transplanted iNOS−/− mice (24±3 mm3; n=10; p<0.01), implicating blood-borne leukocytes in the damage. Furthermore, iNOS+/+ mice transplanted with iNOS−/− BM had large infarcts (39±6 mm3; n=13), similar to those of autologous transplanted iNOS+/+ mice (39±4 mm3; n=14), indicating the resident brain cells also play a role. Flow cytometry and cell sorting revealed that iNOS is highly expressed in neutrophils and endothelium, but not microglia. Surprisingly, post-ischemic iNOS expression was enhanced in the endothelium of iNOS+/+ mice transplanted with iNOS−/− BM, and in leukocytes of iNOS−/− mice with iNOS+/+ BM, suggesting that endothelial iNOS suppresses iNOS expression in leukocytes and vice-versa. To provide independent evidence that neutrophils mediate brain injury, neutrophils were isolated and transferred to mice 24 hours after stroke. Consistent with the result in chimeric mice, transfer of iNOS+/+, but not iNOS−/−, neutrophils into iNOS−/−mice increased infarct volume. The findings establish that iNOS both in neutrophils and endothelium mediates tissue damage and identify these cell types as putative therapeutic targets for stroke injury.

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Section: Discussionmentioning

confidence: 85%

Inducible Nitric Oxide Synthase in Neutrophils and Endothelium Contributes to Ischemic Brain Injury in Mice

García-Bonilla

Moore

Racchumi

et al. 2014

The Journal of Immunology

115

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“…Similar to ROS, reactive nitrogen species (RNS) are harmful to cellular components and can induce neuronal death (26). NO can react rapidly with superoxide to generate the strong oxidant peroxynitrite, which is extremely cytotoxic (27). NOS activity and NO production are increased in the ischemic brain, leading to increased peroxynitrite production and ensuing cellular damage.…”

Section: Oxidative and Nitrosative Stressmentioning

confidence: 99%

“…NOS activity and NO production are increased in the ischemic brain, leading to increased peroxynitrite production and ensuing cellular damage. RNS are known to contribute to breakdown of the blood brain barrier (BBB) via activation of matrix metalloproteinases (MMPs) (27,28). Taken together, ROS and RNS are damaging neurotoxic agents that intensify ischemic damage after reperfusion.…”

Section: Oxidative and Nitrosative Stressmentioning

confidence: 99%

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Ischemic Stroke Mechanisms, Prevention, and Treatment: The Anesthesiologist’s Perspective

McCrary¹,

Wang²,

Wei³

2017

J Anesth Perioper Med

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“…Ischemic brains produce a large amount of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [25]. Superoxide (O 2 - ) and nitric oxide (NO) are representative free radicals in cerebral ischemia-reperfusion injury.…”

Section: Mechanisms Of T-pa-induced Htmentioning

confidence: 99%

Targeting ONOO<sup>-</sup>/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment

Chen¹,

Guan²,

Shen³

2016

Integr Med Int

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Stroke is the leading cause of death and disability worldwide, and ischemic stroke accounts for more than 85% of the stroke incidence. Tissue plasminogen activator (t-PA) is the only FDA-approved drug for ischemic stroke treatment with a narrow treatment time window of 4.5 h. Hemorrhagic transformation (HT) is a severe complication of delayed t-PA treatment in ischemic stroke. Thus, it is critically important to develop combination therapies to reduce HT and extend the therapeutic time window of t-PA. Current progress suggests that peroxynitrite (ONOO^-)/high-mobility group box 1 protein (HMGB1)/matrix metalloproteinase-9 (MMP-9) signaling cascades could be important for attenuating HT during thrombolytic treatment for acute ischemic stroke. Recently, important progress has been made in seeking for natural compounds from Chinese medicine for reducing ischemic stroke injury, with some of them targeting ONOO^-/HMGB1/MMP-9 signaling cascades. Herein, we analyze the roles and interactions of these three targets in mediating HT; subsequently, we summarize the potential compounds from Chinese herbal medicine for attenuating HT and analyze the related targets. Finally, we raise the potential issues to be addressed in further development of these compounds as combination therapy.

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Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury

Cited by 109 publications

References 151 publications

Inducible Nitric Oxide Synthase in Neutrophils and Endothelium Contributes to Ischemic Brain Injury in Mice

Inducible Nitric Oxide Synthase in Neutrophils and Endothelium Contributes to Ischemic Brain Injury in Mice

Ischemic Stroke Mechanisms, Prevention, and Treatment: The Anesthesiologist’s Perspective

Targeting ONOO<sup>-</sup>/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment

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