Recombinant C1 inhibitor in brain ischemic injury

Gesuete, Raffaella; Storini, Claudio; Fantin, Alessandro; Stravalaci, Matteo; Zanier, Elisa R.; Orsini, Franca; Vietsch, H.; Mannesse, Maurice; Ziere, Bertjan; Gobbi, Marco; Simoni, Maria Grazia De

doi:10.1002/ana.21740

Cited by 110 publications

(127 citation statements)

References 32 publications

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“…Several immunomodulatory agents for ischemic stroke treatment have the potential to provide a more expanded time window than provided by tPA to start intervention (7,36). However, some potential targets in the immune system have not been fully characterized (37).…”

Section: Discussionmentioning

confidence: 99%

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Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

130

128

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Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of αB-crystallin (Cryab), an endogenous immunomodulatory neuroprotectant. In Cryab −/− mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma Cryab was detected after experimental stroke in mice and after stroke in human patients. Administration of Cryab even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. Cryab is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke.

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Section: Discussionmentioning

confidence: 99%

“…However, some potential targets in the immune system have not been fully characterized (37). Many defined targets have been described that show promise (7,(36)(37)(38)(39)(40)(41)(42). Cryab is notable because it is endogenously produced after stroke, and has known antiinflammatory effects on inflammatory immune responses (11).…”

Section: Discussionmentioning

confidence: 99%

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

130

128

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“…32 The C1-inhibitor profoundly reduced intracerebral fibrin formation and kept inflammatory cells from entering the ischemic brain after tMCAO. Whereas the anti-inflammatory properties of C1-inhibitor are well-established in models of ischemia-reperfusion injury of different organ systems, including the central nervous system, 15,16,19,20,37,38 the present description of C1-inhibitor as powerful antithrombotic and antiedematous compound is novel and further adds to our understanding of this multifaceted molecule. Interestingly, C1-inhibitor could improve stroke outcome only after tMCAO but not permanent MCAO.…”

Section: Heydenreich Et Al C1-inh In Stroke 2465mentioning

confidence: 91%

C1-Inhibitor Protects From Brain Ischemia-Reperfusion Injury by Combined Antiinflammatory and Antithrombotic Mechanisms

Heydenreich

Nolte

Göb

et al. 2012

Stroke

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Background and Purpose-Inflammation and thrombosis are pathophysiological hallmarks of ischemic stroke still unamenable to therapeutic interventions. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is involved in stroke development. C1-inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-inhibitor in models of ischemic stroke. Methods-Male and female C57Bl/6 mice and rats of different ages were subjected to middle cerebral artery occlusion and treated with C1-inhibitor after 1 hour or 6 hours. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood-brain barrier damage, thrombus formation, and the local inflammatory response were determined poststroke. Results-Treatment with 15.0 U C1-inhibitor, but not 7.5 U, 1 hour after stroke reduced infarct volumes by Ϸ60% and improved clinical scores in mice of either sex on day 1. This protective effect was preserved at later stages of infarction as well as in elderly mice and in another species, ie, rats. Delayed C1-inhibitor treatment still improved clinical outcome. Blood-brain barrier damage, edema formation, and inflammation were significantly lower compared with controls. Moreover, C1-inhibitor showed strong antithrombotic effects. Conclusions-C1-inhibitor is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings. (Stroke. 2012;43:2457-2467.)Key Words: blood-brain barrier Ⅲ C1-inhibitor Ⅲ inflammation Ⅲ kallikrein-kinin system Ⅲ middle cerebral artery occlusion Ⅲ thrombosis T he pathology of brain ischemia-reperfusion injury is complex and involves a myriad of distinct molecular and cellular pathways. Among these inflammation is one of the most relevant processes. 1,2 Activation of the cerebral endothelium early after the ischemic event triggers upregulation of cellular adhesion molecules and successive trafficking of inflammatory cells (neutrophils, macrophages, T cells) from the circulation into the brain parenchyma. Those cells recruited from the periphery in concert with locally activated cell populations (endothelial cells, microglia, astrocytes) produce an array of highly active mediators such as cytokines and chemokines that perpetuate the inflammatory circuits, thereby causing direct or indirect tissue damage. Another characteristic of persisting ischemia is structural disintegration of the blood-brain barrier, which in consequence leads to the formation of brain edema. 3,4 Excessive edema can harm otherwise healthy brain regions by mechanical compression and is a frequent cause of worsening of neurological symptoms in stroke patients. Until now, convincing pharmacological strategies to combat inflammation or edema formation in acute ischemic stroke are lacking. 5 Current pathophysiological concepts also emphasize the importance of progressive thrombus formation...

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“…Similar to several previous studies including 2 in experimental stroke using 2-photon imaging and immunohistochemistry, we distinguished microglial cells from infiltrating leukocytes based on their lower CD45 expression. [27][28][29][30][31][32]39,40 A limitation of this approach is that CD45 can be upregulated on microglia as demonstrated by conversion toward the CD45 high phenotype in experimental autoimmune encephalitis. 41 We found a peak of all infiltrating leukocyte subsets 5 days after blood injection.…”

Section: Strokementioning

confidence: 99%

Leukocyte Invasion of the Brain After Experimental Intracerebral Hemorrhage in Mice

Mracskó

Javidi

et al. 2014

Stroke

131

115

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Background and Purpose-Neuroinflammatory processes contribute to secondary neuronal damage after intracerebral hemorrhage. We aimed to characterize the time course of brain immigration of different leukocyte subsets after striatal injection of either autologous blood or collagenase in mice. Methods-Intracerebral hemorrhage was induced by injection of either autologous blood (20 μL) or collagenase (0.03 U) in C57Bl/6J mice. Hematoma volumetry was performed on cryosections. Blood volume was measured by hemoglobin spectrophotometry. Leukocytes were isolated from hemorrhagic hemisphere 1, 3, 5, and 14 days after intracerebral hemorrhage, stained for leukocyte markers, and measured by flow cytometry. Heterologous blood injection from CD45.1 mice was used to investigate the origin of brain-invading leukocytes. Results-Collagenase injection induced a larger hematoma volume but a similar blood content compared with blood injection. Cerebral leukocyte infiltration in the hemorrhagic hemisphere was similar in both models. The majority of leukocytes isolated from the brain originated from the circulation. CD4 + T lymphocytes were the predominant brain leukocyte population in both models. However, cerebral granulocyte counts were higher after collagenase compared with blood injection. Conclusions-Brain infiltration of systemic immune cells is similar in both murine intracerebral hemorrhage models. The pathophysiological impact of invading leukocytes and, in particular, of T cells requires further investigation.

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Recombinant C1 inhibitor in brain ischemic injury

Abstract: rhC1-INH showed a surprisingly wider time window of efficacy compared with the corresponding plasmatic protein. We propose that the superiority of rhC1-INH is due to its selective binding to MBL, which emerged as a novel target for stroke treatment.

Cited by 110 publications

References 32 publications

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

C1-Inhibitor Protects From Brain Ischemia-Reperfusion Injury by Combined Antiinflammatory and Antithrombotic Mechanisms

Leukocyte Invasion of the Brain After Experimental Intracerebral Hemorrhage in Mice

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