Lazaroids and deferoxamine attenuate the intracellular effects of oxyhaemoglobin in vascular smooth muscle

Vollrath, Bozena; Chan, Patrick Y.; Findlay, Megan; Cook, David A.

doi:10.1016/s0008-6363(95)00137-9

Cited by 22 publications

(13 citation statements)

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“…This lazaroid compound is a potent antioxidant that inhibits lipid peroxidation in many models of oxidative stress. [33][34][35][36][37] Our data showed that U83836E significantly reduced hemoglobin neurotoxicity in a dose-dependent manner. Combination therapy using both U83836E and the broad-spectrum caspase inhibitor zVADfmk did not yield any additional protection.…”

Section: Discussionmentioning

confidence: 53%

Hemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons

Wang

Mori

Sumii

et al. 2002

Stroke

184

141

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Background and Purpose-Apoptotic-like pathways may contribute to brain cell death after intracerebral hemorrhage. In this study, we used a simplified in vitro model of hemoglobin neurotoxicity to map the caspase cascades involved and to document the role of oxidative stress. Methods-Primary neuronal cultures were obtained from rat cerebral cortex and exposed to hemoglobin to induce cell death. Cytotoxicity was assessed via measurements of mitochondrial viability (MTT assay) and lactate dehydrogenase (LDH assay). Activation of caspase-3, -8, and -9 was measured by Western blot and enzyme activity assays. Various caspase inhibitors (zVADfmk, zDEVDfmk, zIETDfmk, and zLEHDfmk) were tested for neuroprotective efficacy. The role of oxidative stress was assessed with the use of U83836E as a potent scavenger of free radicals. Results-Exposure of primary cortical neurons to hemoglobin induced a dose-and time-dependent cytotoxicity. Western blots showed upregulation of cleaved caspase-3. Enzyme assays showed an increase in caspase-9 -like and caspase-3-like activity. However, caspase inhibition did not result in neuroprotection. In contrast, the free radical scavenger U83836E significantly reduced hemoglobin-induced neuronal death. Combination treatment with both U83836E and the broad spectrum caspase inhibitor zVADfmk did not yield additional protection. Conclusions-Upstream and downstream caspases were upregulated after hemoglobin-induced neurotoxicity in vitro, but only an antioxidant approach with a potent free radical scavenger significantly improved neuronal survival. These data suggest that in addition to the activation of caspase cascades, parallel pathways of oxidative stress may predominate in this model of hemoglobin neurotoxicity.

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Section: Discussionmentioning

confidence: 53%

Hemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons

Wang

Mori

Sumii

et al. 2002

Stroke

184

141

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“…Catalase or dimethyl sulfoxide (hydroxyl radical scavenger) afforded protection, but SOD only partially, and OH radicals reproduced these effects (67). Work with SMC cultures similarly revealed that contraction and intracellular Ca 2+ increase by oxyHb were attributable to the action of OH radicals (68,69).…”

Section: Hb and Free Radicalsmentioning

confidence: 99%

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Sercombe

Dinh

Gomis

2002

Japanese Journal of Pharmacology

184

140

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ABSTRACT-Aneurysmal subarachnoid hemorrhage frequently results in complications including intracranial hypertension, rebleeding and vasospasm. The extravasated blood is responsible for a cascade of reactions involving release of various vasoactive and pro-inflammatory factors (several of which are purported to induce vasospasm) from blood and vascular components in the subarachnoid space. The authors review the available evidence linking these factors to the development of inflammatory lesions of the cerebral vasculature, emphasizing: 1) neurogenic inflammation due to massive release of sensory nerve neuropeptides; 2) hemoglobin from lysed erythrocytes, which creates functional lesions of endothelial and smooth muscle cells; 3) activity, expression and metabolites of lipoxygenases cyclooxygenases and nitric oxide synthases; 4) the possible role of endothelin-1 as a pro-inflammatory agent; 5) serotonin, histamine and bradykinin which are especially involved in blood-brain barrier disruption; 6) the prothrombotic and pro-inflammatory action of complement and thrombin towards endothelium; 7) the multiple actions of activated platelets, including platelet-derived growth factor production; 8) the presence of perivascular and intramural macrophages and granulocytes and their interaction with adhesion molecules; 9) the evolution, origins, and effects of pro-inflammatory cytokines, especially IL-1, TNF-a and IL-6. Human and animal studies on the use of anti-inflammatory agents in subarachnoid hemorrhage include superoxide and other radical scavengers, lipid peroxidation inhibitors, iron chelators, NSAIDs, glucocorticoids, and serine protease inhibitors. Many animal studies claim reduced vasospasm, but these effects are not always confirmed in human trials, where symptomatic vasospasm and outcome are the major endpoints. Despite recent work on penetrating vessel constriction, there is a paucity of studies on inflammatory markers in the microcirculation.

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“…This value was chosen on the basis of prior experiments to set a tissue length in the optimal range for maximal force generation (Lo). 21 Viability was determined by maximal force response to high KCl (60 mmol/L).…”

Section: Tissue Preparationmentioning

confidence: 99%

“…21,22 Briefly, basilar arteries were isolated under sterile conditions and placed in a Petri dish containing Dulbecco's modified Eagle medium (DMEM). The vessels were cut into segments and the endothelium was removed mechanically.…”

Section: Cerebrovascular Smooth Muscle Cell Culturementioning

confidence: 99%

Functional Roles of the Rho/Rho Kinase Pathway and Protein Kinase C in the Regulation of Cerebrovascular Constriction Mediated by Hemoglobin

Wickman

Lan

Vollrath

2003

Circulation Research

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Abstract-Although there is evidence that the Rho/Rho kinase pathway and protein kinase C (PKC) are involved in the development of cerebral vasospasm, the mechanism by which subarachnoid hemorrhage (SAH) activates these pathways is unclear. A large body of evidence points to oxyhemoglobin (OxyHb) as a major causative component of blood clot responsible for vasospasm. Therefore, the present studies were conducted to explore whether the Rho/Rho kinase and PKC may be involved in a sustained vasoconstriction induced by OxyHb in cerebral arteries.

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Lazaroids and deferoxamine attenuate the intracellular effects of oxyhaemoglobin in vascular smooth muscle

Cited by 22 publications

References 0 publications

Hemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons

Hemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Functional Roles of the Rho/Rho Kinase Pathway and Protein Kinase C in the Regulation of Cerebrovascular Constriction Mediated by Hemoglobin

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