Neuroprotection by Complement (C1) Inhibitor in Mouse Transient Brain Ischemia

Simoni, M.G. De; Storini, Claudio; Barba, M.; Catapano, L.; Arabia, Antonella; Rossi, Emanuela; Bergamaschini, Luigi

doi:10.1097/00004647-200302000-00010

Cited by 71 publications

(46 citation statements)

References 33 publications

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“…Genetic deficiency of C3 was associated with larger cerebral infarct after experimental permanent focal brain ischemia [7]. On the other hand, inhibition of complement activation or C3 deficiency reduced infarct volume and neurological impairments after transient cerebral ischemia in rodents [10,11,12,13,26]. Blocking of C3a binding to its receptor reduced infarct volume assessed 24 h after transient but not permanent cerebral ischemia in rodents [27].…”

Section: Discussionmentioning

confidence: 99%

“…Anaphylatoxic peptides C3a and C5a, generated in the process of complement activation, can be protective against excitotoxicity-induced neuronal death and can ultimately contribute to healing [8,9]. On the other hand, inhibition of complement activation reduced infarct volume and neurological impairments after transient cerebral ischemia in animal models [10,11,12,13]. In humans, the role of complement in ischemic stroke is less clear.…”

Section: Introductionmentioning

confidence: 99%

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Plasma C3 and C3a Levels in Cryptogenic and Large-Vessel Disease Stroke: Associations with Outcome

et al. 2011

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Background and Purpose: Inflammation seems to be a key player in the pathophysiology of stroke. In this study, we compared plasma C3 and C3a levels in cryptogenic and large-vessel disease (LVD) subtypes of ischemic stroke and control subjects and evaluated their association to outcome at 3 months and 2 years. Methods: C3 and C3a levels in plasma of 79 cryptogenic stroke and 73 LVD stroke patients, sampled within 10 days and at 3 months after stroke, and age- and sex-matched control subjects from the Sahlgrenska Academy Study on Ischemic Stroke were measured by ELISA. Functional outcome was assessed with the modified Rankin Scale. Results: Plasma C3 was increased in both stroke groups at both time points. Systemic elevation of C3a was limited to the acute phase in the cryptogenic stroke group, whereas plasma C3a levels in the LVD group were also elevated at the 3-month follow-up. In the LVD group, plasma C3 levels in the upper third at the 3-month follow-up were associated with an unfavorable outcome after 3 months independently of age and sex: odds ratio (OR) 5.56; 95% confidence interval (CI) 1.03–29.93; p = 0.045; as well as after 2 years: OR 4.75; 95% CI 1.11–20.30; p = 0.036. In the cryptogenic stroke group, high plasma C3a levels in the acute phase were associated with an unfavorable outcome after 3 months: OR 3.75; 95% CI 1.01–13.96; p = 0.049 in univariate analysis but not after adjustment for age and sex (p = 0.050). Conclusions: Plasma C3 and C3a levels are elevated in cryptogenic and LVD stroke and the predictive value of these markers may depend on stroke subtype. Further studies on the role of the complement system in ischemic stroke outcome based on larger patient populations and controlling for the effect of infections, are clearly warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plasma C3 and C3a Levels in Cryptogenic and Large-Vessel Disease Stroke: Associations with Outcome

et al. 2011

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“…Ischemia was achieved by intraluminal model of MCAO as previously described [9], [38], [39]. To confirm the adequacy of the vascular occlusion in each animal, blood flow was measured by laser Doppler flowmetry (Transonic BLF-21) using a flexible 0.5 mm fiberoptic probe (Transonic, Type M, 0.5 mm diameter) positioned on the brain surface in the MCA territory and secured with impression material on the skull at the following stereotaxic coordinates: AP = −1 mm; L = −3.5 mm.…”

Section: Methodsmentioning

confidence: 99%

“…During surgery mice were maintained at constant temperature (37+/−0.5°C) using a heathing pad equipped with a rectal probe (LSI-Letica Spain). Sham-operated mice were also prepared as previously described [9], [38], [39].…”

Section: Methodsmentioning

confidence: 99%

Neurosphere-Derived Cells Exert a Neuroprotective Action by Changing the Ischemic Microenvironment

et al. 2007

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BackgroundNeurosphere-derived cells (NC), containing neural stem cells, various progenitors and more differentiated cells, were obtained from newborn C57/BL6 mice and infused in a murine model of focal ischemia with reperfusion to investigate if: 1) they decreased ischemic injury and restored brain function; 2) they induced changes in the environment in which they are infused; 3) changes in brain environment consequent to transient ischemia were relevant for NC action.Methodology/Principal FindingsNC were infused intracerebroventricularly 4 h or 7 d after 30 min middle cerebral artery occlusion. In ischemic mice receiving cells at 4 h, impairment of open field performance was significantly improved and neuronal loss significantly reduced 7–14 d after ischemia compared to controls and to ischemic mice receiving cells at 7 d. Infusion of murine foetal fibroblast in the same experimental conditions was not effective. Assessment of infused cell distribution revealed that they migrated from the ventricle to the parenchyma, progressively decreased in number but they were observable up to 14 d. In mice receiving NC at 7 d and in sham-operated mice, few cells could be observed only at 24 h, indicating that the survival of these cells in brain tissue relates to the ischemic environment. The mRNA expression of trophic factors such as Insulin Growth Factor-1, Vascular Endothelial Growth Factor-A, Transforming Growth Factor-β1, Brain Derived Neurotrophic Factor and Stromal Derived Factor−1α, as well as microglia/macrophage activation, increased 24 h after NC infusion in ischemic mice treated at 4 h compared to sham-operated and to mice receiving cells at 7 d.Conclusions/SignificanceNC reduce functional impairment and neuronal damage after ischemia/reperfusion injury. Several lines of evidence indicate that the reciprocal interaction between NC and the ischemic environment is crucial for NC protective actions. Based on these results we propose that a bystander control of the ischemic environment may be the mechanism used by NC to rapidly restore acutely injured brain function.

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“…In particular, quantitative values of the parameters can be more precisely determined. To make the model agree better with the biological facts described in §1, it would be interesting to introduce in the model the complement cascade (De Simoni et al 2003), the endothelium (Dereski et al 1993) and anti-inflammatory neuroprotective trophic biomolecules (neurotrophins, glutamate transporters and antioxidants) released upon the inflammatory process in stroke (Lai & Todd 2008). The increase of both neutrophils and macrophages in the brain parenchyma occurs 24 h after permanent occlusion but these increases have different dynamics (Garcia et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Exploration of beneficial and deleterious effects of inflammation in stroke: dynamics of inflammation cells

Lelekov-Boissard

Chapuisat

Boissel

et al. 2009

Phil. Trans. R. Soc. A.

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The inflammatory process during stroke consists of activation of resident brain microglia and recruitment of leucocytes, namely neutrophils and monocytes/macrophages. During inflammation, microglial cells, neutrophils and macrophages secrete inflammatory cytokines and chemokines, and phagocytize dead cells. The recruitment of blood cells (neutrophils and macrophages) is mediated by the leucocyte-endothelium interactions and more specifically by cell adhesion molecules.A mathematical model is proposed to represent the dynamics of various brain cells and of immune cells (neutrophils and macrophages). This model is based on a set of six ordinary differential equations and explores the beneficial and deleterious effects of inflammation, respectively phagocytosis by immune cells and the release of pro-inflammatory mediators and nitric oxide (NO).The results of our simulations are qualitatively consistent with those observed in experiments in vivo and would suggest that the increase of phagocytosis could contribute to the increase of the percentage of living cells. The inhibition of the production of cytokines and NO and the blocking of neutrophil and macrophage infiltration into the brain parenchyma led also to the improvement of brain cell survival.This approach may help to explore the respective contributions of the beneficial and deleterious roles of the inflammatory process in stroke, and to study various therapeutic strategies in order to reduce stroke damage.

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Neuroprotection by Complement (C1) Inhibitor in Mouse Transient Brain Ischemia

Cited by 71 publications

References 33 publications

Plasma C3 and C3a Levels in Cryptogenic and Large-Vessel Disease Stroke: Associations with Outcome

Plasma C3 and C3a Levels in Cryptogenic and Large-Vessel Disease Stroke: Associations with Outcome

Neurosphere-Derived Cells Exert a Neuroprotective Action by Changing the Ischemic Microenvironment

Exploration of beneficial and deleterious effects of inflammation in stroke: dynamics of inflammation cells

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