Effect of Iron Chelators on Methemoglobin and Thrombin Preconditioning

Chen-Roetling, Jing; Sinanan, Jesse K.; Regan, Raymond F.

doi:10.1007/s12975-012-0195-4

Cited by 15 publications

(8 citation statements)

References 33 publications

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“…Vascular injury is associated with activation of the coagulation cascade and release of thrombin, which activates cytokine/chemokine production (Szaba and Smiley, 2002; Chen-Roetling et al, 2012). Monocyte-endothelial interactions are key initiating events for vascular inflammation (Bolick et al, 2005; Hammond et al, 2012), and increase endothelial permeability (Mehta and Malik, 2006).…”

Section: Discussionmentioning

confidence: 99%

Isoflurane on brain inflammation

Altay

Suzuki

Hasegawa

et al. 2014

Neurobiology of Disease

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Brain inflammation may play an important role in the pathophysiology of early brain injury after subarachnoid hemorrhage (SAH). Our aim was to demonstrate brain inflammation development and to determine whether isoflurane, a clinically available volatile anesthetic agent, prevents brain inflammation after SAH. This study used 162 8-week-old male CD-1 mice. We induced SAH with endovascular perforation in mice and randomly assigned animals to sham-operated (n=21), SAH+vehicle-air (n=35) and SAH+2% isoflurane (n=31). In addition to evaluation of brain injury (neurological scores, brain edema and Evans blue dye extravasation), brain inflammation was evaluated by means of expression changes in markers of inflammatory cells (ionized calcium binding adaptor molecule-1, myeloperoxidase), cytokines (tumor necrosis factor [TNF]-α, interleukin-1β), adhesion molecules (intercellular adhesion molecule [ICAM]-1, P-selectin), inducers of inflammation (cyclooxygenase-2, phosphorylated c-Jun N-terminal kinase [p-JNK]) and endothelial cell activation (von Willebrand factor) at 24 hours post-SAH. Sphingosine kinase inhibitor (N, N-dimethylsphingosine [DMS]) and sphingosine-1-phosphate receptor-1/3 antagonist (VPC23019) were used to block isoflurane’s effects (n=22, each). SAH caused early brain injury, which was associated with inflammation so that all evaluated markers of inflammation were increased. Isoflurane significantly inhibited both brain injury (P<0.001, respectively) and inflammation (myeloperoxidase, P=0.022; interleukin-1β, P=0.002; TNF-α, P=0.015; P-selectin, P=0.010; ICAM-1, P=0.016; p-JNK, P<0.001; cyclooxygenase-2, P=0.003, respectively). This beneficial effect of isoflurane was abolished with DMS and VPC23019. Isoflurane may suppress post-SAH brain inflammation possibly via the sphingosine-related pathway.

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Section: Discussionmentioning

confidence: 99%

Isoflurane on brain inflammation

Altay

Suzuki

Hasegawa

et al. 2014

Neurobiology of Disease

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“…Both methods have been described in detail in prior publications (Chen-Roetling et al, 2013; Chen-Roetling et al, 2012). …”

Section: Methodsmentioning

confidence: 99%

Systemic hemin therapy attenuates blood–brain barrier disruption after intracerebral hemorrhage

Chen-Roetling

Regan

2014

Neurobiology of Disease

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Injury to the blood-brain barrier (BBB) is a key feature of intracerebral hemorrhage (ICH) and may contribute to perihematomal cell injury. Pretreatment with the heme oxygenase (HO)-1 inducer hemin improves barrier function and neurological outcome in experimental models of traumatic and ischemic CNS injury. Since hemin is already in clinical use to treat acute porphyrias, this translational study was designed to test its effect on BBB function when initiated after ICH in two mouse models. At a dose similar to those used in most preconditioning studies (26 mg/kg i.p.), post-hemorrhage treatment with hemin reduced parenchymal extravasation of Evans blue by about three-quarters in both the blood injection and collagenase ICH models. Similar efficacy was observed when treatment was begun at one or three hours. At the lower dose that is currently in clinical use (4 mg/kg beginning at 3 hours), hemin also improved barrier function in both models, as assessed by both Evans blue and FITC-dextran leakage; however, it was somewhat less potent, reducing Evans blue leakage by about half. This dose was nevertheless sufficient to attenuate striatal cell loss and accelerate neurological recovery. Consistent with prior observations, striatal HO-1 expression was increased by hemin, and was localized to perivascular cells. These results suggest that hemin may be an effective therapy for ICH with a clinically relevant time window. Further study of the repurposing of this old drug seems warranted.

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“…This effect could be prevented by blocking synthesis of both HO-1 and ferritin, and was reduced by protoporphyrin HO activity inhibitors. It is also noteworthy that the iron chelator deferoxamine, which is currently in clinical trials for ICH, also blocked the protective effect of heme preconditioning [85]. While having no effect on HO-1 expression, deferoxamine prevented ferritin upregulation.…”

Section: Pathophysiologymentioning

confidence: 99%

Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage

Chen-Roetling

Regan

2017

CPD

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Background Injury to cells adjacent to an intracerebral hemorrhage (ICH) is likely mediated at least in part by toxins released from the hematoma that initiate complex and interacting injury cascades. Pharmacotherapies targeting a single toxin or pathway, even if consistently effective in controlled experimental models, have a high likelihood of failure in a variable clinical setting. Nuclear factor erythroid-2 related factor 2 (Nrf2) regulates the expression of heme oxygenase-1 (HO-1) and multiple other proteins with antioxidant and anti-inflammatory effects, and may be a target of interest after ICH. Methods Studies that tested the effect of HO and Nrf2 in models relevant to ICH are summarized, with an effort to reconcile conflicting data by consideration of methodological limitations. Results In vitro studies demonstrated that Nrf2 activators rapidly increased HO-1 expression in astrocytes, and reduced their vulnerability to hemoglobin or hemin. Modulating HO-1 expression via genetic approaches yielded similar results. Systemic treatment with small molecule Nrf2 activators increased HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators were consistently protective, improving barrier function and attenuating edema, inflammation, neuronal loss and neurological deficits. These effects were mimicked by selective astrocyte HO-1 overexpression in transgenic mice. Conclusion Systemic treatment with Nrf2 activators after ICH is protective in rodents. Two compounds, dimethyl fumarate and hemin, are currently approved for treatment of multiple sclerosis and acute porphyria, respectively, and have acceptable safety profiles over years of clinical use. Further development of these drugs as ICH therapeutics seems warranted.

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Effect of Iron Chelators on Methemoglobin and Thrombin Preconditioning

Cited by 15 publications

References 33 publications

Isoflurane on brain inflammation

Isoflurane on brain inflammation

Systemic hemin therapy attenuates blood–brain barrier disruption after intracerebral hemorrhage

Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage

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