C1-inhibitor attenuates neurobehavioral deficits and reduces contusion volume after controlled cortical impact brain injury in mice*

Longhi, Luca; Perego, Carlo; Ortolano, Fabrizio; Zanier, Elisa R.; Bianchi, Paolo; Stocchetti, Nino; McIntosh, Tracy K.; Simoni, Maria Grazia De

doi:10.1097/ccm.0b013e318195998a

Cited by 84 publications

(83 citation statements)

References 53 publications

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“…A negative role for complement has been proposed in traumatic brain injury, since systemic depletion of complement by infusion of the cobra venom factor improved blood flow and neurological function and reduced cerebral edema during experimental intracerebral hemorrhage (88,89). Moreover, C1 deficiency (90) and complement inhibition by infusion of the C1 inhibitor revealed some neuroprotective effects (91,92). In contradiction to these results for traumatic/ischemic injuries, C1q has a strong neuroprotective effect in neurodegenerative diseases (93).…”

Section: Traumatic Brain Injurymentioning

confidence: 64%

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

Ehrnthaller

Ignatius

Gebhard

et al. 2010

Mol Med

188

154

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The complement system was discovered a century ago as a potent defense cascade of innate immunity. After its first description, continuous experimental and clinical research was performed, and three canonical pathways of activation were established. Upon activation by traumatic or surgical tissue damage, complement reveals beneficial functions of pathogen and danger defense by sensing and clearing injured cells. However, the latest research efforts have provided a more distinct insight into the complement system and its clinical subsequences. Complement has been shown to play a significant role in the pathogenesis of various inflammatory processes such as sepsis, multiorgan dysfunction, ischemia/reperfusion, cardiovascular diseases and many others. The three well-known activation pathways of the complement system have been challenged by newer findings that demonstrate direct production of central complement effectors (for example, C5a) by serine proteases of the coagulation cascade. In particular, thrombin is capable of producing C5a, which not only plays a decisive role on pathogens and infected/damaged tissues, but also acts systemically. In the case of uncontrolled complement activation, "friendly fire" is generated, resulting in the destruction of healthy host tissue. Therefore, the traditional research that focuses on a mainly positive-acting cascade has now shifted to the negative effects and how tissue damage originated by the activation of the complement can be contained. In a translational approach including structure-function relations of this ancient defense system, this review provides new insights of complement-mediated clinical relevant diseases and the development of complement modulation strategies and current research aspects.

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Section: Traumatic Brain Injurymentioning

confidence: 64%

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

Ehrnthaller

Ignatius

Gebhard

et al. 2010

Mol Med

188

154

View full text Add to dashboard Cite

show abstract

“…Early evidence, showing improved outcome after controlled cortical impact in mice treated with the C1 esterase inhibitor, point to the involvement of the classical and/or the lectin pathway (40), whereas the alternative pathway drives pathology (7,12). It is possible that mechanical shearing forces, caused by TBI, expose axonal epitopes and/or flipped membranes that are recognized as "danger" signals by C1q, resulting in activation of the classical pathway and MAC formation via an Ab-independent manner (41).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Membrane Attack Complex of the Complement System Reduces Secondary Neuroaxonal Loss and Promotes Neurologic Recovery after Traumatic Brain Injury in Mice

Fluiter

Opperhuizen

Morgan

et al. 2014

The Journal of Immunology

121

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Traumatic brain injury (TBI) is the leading cause of disability and death in young adults. The secondary neuroinflammation and neuronal damage that follows the primary mechanical injury is an important cause of disability in affected people. The membrane attack complex (MAC) of the complement system is detected in the traumatized brain early after TBI; however, its role in the pathology and neurologic outcome of TBI has not yet been investigated. We generated a C6 antisense oligonucleotide that blocks MAC formation by inhibiting C6, and we compared its therapeutic effect to that of Ornithodoros moubata complement inhibitor (OmCI), a known inhibitor of C5 activation that blocks generation of the anaphylatoxin C5a and C5b, an essential component of MAC. Severe closed head injury in mice induced abundant MAC deposition in the brain. Treatment with C6 antisense reduced C6 synthesis (85%) and serum levels (90%), and inhibited MAC deposition in the injured brain (91–96%). Treatment also reduced accumulation of microglia/macrophages (50–88%), neuronal apoptosis, axonal loss and weight loss (54–93%), and enhanced neurologic performance (84–92%) compared with placebo-treated controls after injury. These data provide the first evidence, to our knowledge, that inhibition of MAC formation in otherwise complement-sufficient animals reduces neuropathology and promotes neurologic recovery after TBI. Given the importance of maintaining a functional complement opsonization system to fight infections, a critical complication in TBI patients, inhibition of the MAC should be considered to reduce posttraumatic neurologic damage. This work identifies a novel therapeutic target for TBI and will guide the development of new therapy for patients.

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“…19,20 In rats, C1-inhibitor was intravenously injected 90 minutes after the induction of tMCAO at a dose of 20 U/kg body weight. Control animals received equal volumes of isotonic saline (vehicle).…”

Section: C1-inhibitor Treatmentmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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C1-inhibitor attenuates neurobehavioral deficits and reduces contusion volume after controlled cortical impact brain injury in mice*

Abstract: Our results show that post-traumatic administration of C1-INH attenuates neuro-behavioral deficits and histological damage associated with traumatic brain injury.

Cited by 84 publications

References 53 publications

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

New Insights of an Old Defense System: Structure, Function, and Clinical Relevance of the Complement System

Inhibition of the Membrane Attack Complex of the Complement System Reduces Secondary Neuroaxonal Loss and Promotes Neurologic Recovery after Traumatic Brain Injury in Mice

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

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