Local neutrophil influx following lateral fluid-percussion brain injury in rats is associated with accumulation of complement activation fragments of the third component (C3) of the complement system

Keeling, Kristen L.; Hicks, R.R; Mahesh, J; Billings, Brooke; Kotwal, Girish J.

doi:10.1016/s0165-5728(00)00183-1

Cited by 63 publications

(49 citation statements)

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“…2,6,7,30 In our study, deposition of C1q and C3 was found only in the injured cerebral tissue. Our data do not indicate the source (systemic or local) of these deposited C components in injured brain.…”

Section: Discussionsupporting

confidence: 45%

“…Neutrophil influx and degranulation in the injured brain after lateral fluid percussion head injury in rats was accompanied by accumulation of C3. 30 Neutrophil accumulation in brain after injury is thought to be a contributing factor to ischemic damage. 31 Our data suggest an important causal link between inflammatory cell recruitment and C1q-mediated exacerbation of HI-induced brain injury.…”

Section: Discussionmentioning

confidence: 99%

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C1q-Deficiency Is Neuroprotective Against Hypoxic-Ischemic Brain Injury in Neonatal Mice

Ten

Sosunov

Mazer

et al. 2005

Stroke

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Background and Purpose-This study was undertaken to determine whether the initial component of the classical complement (C) activation pathway contributes to hypoxic-ischemic brain injury in neonatal mice. Methods-Hypoxia-ischemia (HI) was produced in C1qϪ/Ϫ and wild-type (WT) neonatal mice. At 24 hours after HI, neonatal mouse reflex performance and cerebral infarct volume were assessed. Long-term outcomes were measured by water-maze performance and degree of cerebral atrophy at 7 to 8 weeks after HI. Activation of circulating neutrophils, and C1q, C3, and neutrophil deposition in brains were examined. Results-C1qϪ/Ϫ mice were significantly protected against HI (meanϮSE infarct volume in C1q Ϫ/Ϫ miceϭ17.3Ϯ5.5% versus 53.6Ϯ6.8% in WT mice; PϽ0.0001) and exhibited significantly less neurofunctional deficit compared with WT mice. Immunostaining revealed significantly greater deposition of C3 (and C1q) as well as granulocytes in the infarcted brains in WT mice compared with C1q Ϫ/Ϫ animals. Activation of circulating leukocytes was significantly decreased in C1q Ϫ/Ϫ mice compared with WT mice, which correlated strongly (rϭ0.7) with cerebral infarct volumes. Conclusions-Cerebral deposition of C1q and C3 after hypoxic-ischemic insult is associated with significantly greater neurologic damage in WT mice compared with C1q Ϫ/Ϫ mice, providing strong evidence that the classical C pathway contributes to the hypoxic-ischemic brain injury. Significantly decreased activation of circulating neutrophils associated with diminished local accumulation and attenuation of brain injury in C1q Ϫ/Ϫ mice suggests a potential cellular mechanism by which C1q mediates neurodegeneration in HI.

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Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 99%

C1q-Deficiency Is Neuroprotective Against Hypoxic-Ischemic Brain Injury in Neonatal Mice

Ten

Sosunov

Mazer

et al. 2005

Stroke

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“…These pro-inflammatory cytokines stimulate inflammatory cells to release damaging reactive oxygen and nitrogen species, raise glutamate levels to excitotoxic levels, impair the ability of glia cells to buffer extracellular potassium, compromise the blood-brain barrier, and attract more inflammatory cells into the brain (Tanaka et al, 1994, Meda et al, 1995, Soares et al, 1995, Hu et al, 1997, Keeling et al, 2000. Once initiated, the inflammatory cascade becomes a toxic positivefeedback loop, further exacerbating brain pathology.…”

Section: Nih Public Accessmentioning

confidence: 99%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

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Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipramtreated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI. Keywordscamp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI Traumatic brain injury (TBI) is a prevalent, debilitating health problem, occurring in 1.4 million people each year and disabling 5 million people in the United States (Langlois et al., 2004). The subsequent progressive injury after brain trauma develops from hours to days after the initiating insult, providing an accessible time window for pharmacological therapies. Despite Address correspondence to: W. Dalton Dietrich, Scientific Director, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, P.O. Box 016960, (R-48), Miami, FL 33101, E-mail: ddietrich@miami.edu, Phone: 305-243-2297, Fax: 305-243-3207. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brain trauma results in contusion formation, neuronal apoptosis, and axonal tract damage. These pathologies are worsened by the inflammatory cascade set into motion by the initial injury (Morganti-Kossmann et al., 2002. Two pro-i...

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“…Activation of complement amplifies local inflammation and exacerbates tissue damage and organ dysfunction after systemic and central nervous system ischemia-reperfusion injury (Chan et al, 2003;del Zoppo, 1999;Zhou et al, 2000), and studies in humans and in experimental animal models provide convincing evidence that complement is activated in brain after traumatic brain injury (TBI) (Schmidt et al, 2005;van Beek et al, 2003). Activated complement components, including the terminal membrane attack complex and proinflammatory anaphylatoxins, are detectable in cerebrospinal fluid and on brain parenchymal cells in patients with severe TBI (Bellander et al, 2001;Kossmann et al, 1997;Stahel et al, 2001), and experimental TBI induces intrathecal synthesis of complement proteins and their receptors on neurons, microglia, and astrocytes (Keeling et al, 2000;Stahel et al, 2000). Complement signaling in injured brain parenchyma may also be contributed by serum components that enter the brain through a compromised blood-brain barrier.…”

Section: Introductionmentioning

confidence: 99%

Reduced Tissue Damage and Improved Recovery of Motor Function after Traumatic Brain Injury in Mice Deficient in Complement Component C4

You

Yang

Takahashi

et al. 2007

J Cereb Blood Flow Metab

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Complement component C4 mediates C3-dependent tissue damage after systemic ischemiareperfusion injury. Activation of C3 also contributes to the pathogenesis of experimental and human traumatic brain injury (TBI); however, few data exist regarding the specific pathways (classic, alternative, and lectin) involved. Using complement knockout mice and a controlled cortical impact (CCI) model, we tested the hypothesis that the classic pathway mediates secondary damage after TBI. After CCI, C4c and C3d immunostaining were detected in cortical vascular endothelial cells in wild-type (WT) mice; however, C4c and C3d immunostaining were also detected in C1q À/À mice, and C3d immunostaining was detected in C4 À/À mice. After CCI, WT and C1q À/À mice had similar motor deficits, Morris water maze performance, and brain lesion size. Naive C4 À/À and WT mice did not differ in baseline motor performance, but C4 À/À mice had reduced postinjury motor deficits (days 1 to 7, P < 0.05) and decreased brain tissue damage (days 14 and 35, P < 0.05) versus WT. Reconstitution of C4 À/À mice with human C4 (hC4) reversed their protection against postinjury motor deficits (P < 0.05 versus vehicle), but administration of hC4 did not impair postinjury motor performance (versus vehicle) in WT mice. The protective effects of C4 À/À were functionally distinct from the classic pathway and terminal complement, as C1q À/À and C3 À/À mice had postinjury tissue damage and motor dysfunction similar to WT. Thus, C4 contributes to motor deficits and brain tissue damage after CCI by mechanism(s) fundamentally different from those involved in experimental systemic ischemia-reperfusion injury.Journal of Cerebral Blood Flow & Metabolism (2007) 27, 1954-1964 doi:10.1038/sj.jcbfm.9600497; published online 25 April 2007 Keywords: complement; mice; behavior; traumatic brain injury; inflammation; genetics Introduction Traumatic brain injury induces an acute inflammatory response that contributes to posttraumatic cell death and functional neurologic deficits (Schmidt et al, 2005). Activation of complement amplifies local inflammation and exacerbates tissue damage and organ dysfunction after systemic and central nervous system ischemia-reperfusion injury (Chan et al, 2003;del Zoppo, 1999;Zhou et al, 2000), and studies in humans and in experimental animal models provide convincing evidence that Stahel et al, 2000). Complement signaling in injured brain parenchyma may also be contributed by serum components that enter the brain through a compromised blood-brain barrier.To date, only four published studies have examined a role for complement in traumatic cerebral contusion models. The investigators showed beneficial effects on histopathologic or functional outcome of pharmacologic C3 convertase inhibitors (Kaczorowski et al, 1995;Leinhase et al, 2006b), genetic inhibition of factor B (a component of the alternative pathway) (Leinhase et al, 2006a), or of astrocyte-specific overexpression of an endogenous C3 convertase inhibitor (Rancan et al, 2003). These studies...

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Local neutrophil influx following lateral fluid-percussion brain injury in rats is associated with accumulation of complement activation fragments of the third component (C3) of the complement system

Cited by 63 publications

References 50 publications

C1q-Deficiency Is Neuroprotective Against Hypoxic-Ischemic Brain Injury in Neonatal Mice

C1q-Deficiency Is Neuroprotective Against Hypoxic-Ischemic Brain Injury in Neonatal Mice

Modulation of the cAMP signaling pathway after traumatic brain injury

Reduced Tissue Damage and Improved Recovery of Motor Function after Traumatic Brain Injury in Mice Deficient in Complement Component C4

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