Preischemic But Not Postischemic Zinc Protoporphyrin Treatment Reduces Infarct Size and Edema Accumulation After Temporary Focal Cerebral Ischemia in Rats

Kadoya, Chitoshi; Domino, Edward F.; Yang, Guo‐Yuan; Stern, Jeffrey J.; Betz, A. Lorris

doi:10.1161/01.str.26.6.1035

Cited by 99 publications

(53 citation statements)

References 11 publications

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“…61 This reduction in infarct size is accompanied by a decreased number of leukocytes in the ischemic hemisphere and improved neurological function. 62 Similar results have been achieved by means of the topical application of anti-IL-1␤ neutralizing antibody, 53 zinc protoporphyrin, 53,60,63 and fragments of lipocortin-1, 58 all of which act as IL-1 inhibitors. TGF-␤ administration has led to less severe histological damage in a rabbit model of embolic stroke 100 as well as in rats subjected to permanent MCA occlusion, 101 transient global ischemia, 104 and hypoxia-ischemia cerebral insult.…”

Section: Experimental Anti-leukocyte Interventionsmentioning

confidence: 66%

Cytokines and Cell Adhesion Molecules in Cerebral Ischemia

Pantoni

Sarti

Inzitari

1998

ATVB

125

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Abstract-The possibility of reopening an occluded cerebral artery by means of thrombolysis has renewed interest in a number of the several mechanisms that are active during acute cerebral ischemia. Over recent years, it has become apparent that leukocytes play a central role not only during the healing stage of brain infarction but also during the early phases of cerebral ischemia, when it is postulated that these cells produce harmful effects, particularly in the presence of reperfusion. This review is based on the critical analysis of more than 150 publications dealing with the role of leukocytes and some inflammatory mediators (cytokines, chemokines, and adhesion molecules) in cerebral ischemia. Animal studies indicate that leukocyte involvement is promoted by a variety of inflammatory molecules produced immediately after the onset of cerebral ischemia. Considerable experimental evidence suggests that these mediators play a key role in the progression from ischemia to irreversible injury (ie, cellular death and necrosis). However, the precise role of each molecule alone remains to be further elucidated as well as in relation to the complex network existing among different mediators. Progress in our understanding of the inflammatory mechanisms operating in cerebral ischemia has enabled the testing of new compounds with promising results in animals; in contrast, one recent controlled trial of an anti-leukocyte molecule in acute stroke patients showed negative results. This discrepancy may derive in part from our incomplete understanding of the complexity of the inflammatory mechanisms involved in cerebral ischemia. Our analysis suggests that until sufficient knowledge of the underlying disease mechanisms is acquired, more care should be taken when testing new and potentially efficacious drugs in stroke patients.

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Section: Experimental Anti-leukocyte Interventionsmentioning

confidence: 66%

Cytokines and Cell Adhesion Molecules in Cerebral Ischemia

Pantoni

Sarti

Inzitari

1998

ATVB

125

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“…The administration of HO inhibitors such as tin-protoporphyrin (SnPP), for example, has been shown to reduce the formation of brain edema and to reduce injury from ischemic, hemorrhagic, and even traumatic injury to CA3 hippocampal slices (Kadoya et al, 1995;Panizzon et al, 1996;Huang et al, 2002). It should be noted, however, that SnPP and other metalloporphyrins are nonspecific inhibitors of heme-binding proteins.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-2 Protects against Lipid Peroxidation-Mediated Cell Loss and Impaired Motor Recovery after Traumatic Brain Injury

et al. 2003

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After traumatic brain injury (TBI), substantial extracellular heme is released from hemoproteins during hemorrhage and cell injury. Heme oxygenase (HO) isozymes are thought to detoxify the pro-oxidant heme to the potent antioxidant, bilirubin. HO-1, the inducible isozyme, is expressed in glial populations after injury and may play a protective role. However, the role of HO-2, the predominant and constitutively expressed isozyme in the brain, remains unclear after TBI. We used a controlled cortical impact injury model to determine the extent and mechanism of damage between HO-2 knock-out (KO) (Ϫ/Ϫ) and wild-type (WT) (ϩ/ϩ) mice. The specific cellular and temporal expressions of HO-2 and HO-1 were characterized by immunocytochemistry and Western blots. HO-2 was immunolocalized in neurons both before and after TBI, whereas HO-1 was highly upregulated in glia only after TBI. HO activity determined by gas chromatography using brain sonicates from injured HO-2 KO mice was significantly less than that of HO-2 wild types, despite the induction of HO-1 expression after TBI. Cell loss was significantly greater in KO mice in areas including the cortex, the CA3 region of hippocampus, and the lateral dorsal thalamus. Furthermore, motor recovery after injury, as measured by the rotarod assay and an inclined beam-walking task, was compromised in the KO mice. Finally, brain tissue from injured HO-2 KO mice exhibited decreased ability to reduce oxidative stress, as measured with an Fe 2ϩ /ascorbic acid-mediated carbon monoxide generation assay for lipid peroxidation susceptibility. These findings demonstrate that HO-2 expression protects neurons against TBI by reducing lipid peroxidation via the catabolism of free heme.

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“…A central concern is that heme degradation may generate toxic levels of free iron (Huang et al, 2002;Kadoya et al, 1995;Panizzon et al, 1996). Cell injury is speculated to be mediated through the generation of free Fe 2 þ during heme degradation, which may potentiate free radical-induced damage via the Fenton reaction.…”

Section: Heme Oxygenase As Modulator Of Neural Injurymentioning

confidence: 99%

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

Chang

Claus

Vreman

et al. 2005

J Cereb Blood Flow Metab

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Intracranial bleeding is one of the most prominent aspects in the clinical diagnosis and prognosis of traumatic brain injury (TBI). Substantial amounts of blood products, such as heme, are released because of traumatic subarachnoid hemorrhages, intraparenchymal contusions, and hematomas. Despite this, surprisingly few studies have directly addressed the role of blood products, in particular heme, in the setting of TBI. Heme is degraded by heme oxygenase (HO) into three highly bioactive products: iron, bilirubin, and carbon monoxide. The HO isozymes, in particular HO-1 and HO-2, exhibit significantly different expression patterns and appear to have specific roles after injury. Developmentally, differences between the adult and immature brain have implications for endogenous protection from oxidative stress. The aim of this paper is to review recent advances in the understanding of heme regulation and metabolism after brain injury and its specific relevance to the developing brain. These findings suggest novel clinical therapeutic options for further translational study.

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Preischemic But Not Postischemic Zinc Protoporphyrin Treatment Reduces Infarct Size and Edema Accumulation After Temporary Focal Cerebral Ischemia in Rats

Abstract: ZnPP treatment protected the brain when administered early in the temporary ischemia model.

Cited by 99 publications

References 11 publications

Cytokines and Cell Adhesion Molecules in Cerebral Ischemia

Cytokines and Cell Adhesion Molecules in Cerebral Ischemia

Heme Oxygenase-2 Protects against Lipid Peroxidation-Mediated Cell Loss and Impaired Motor Recovery after Traumatic Brain Injury

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

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