C1-inhibitor protects against brain ischemia–reperfusion injury via inhibition of cell recruitment and inflammation

Storini, Claudio; Rossi, Emanuela; Marrella, Veronica; Distaso, Maria; Veerhuis, Robert; Vergani, Carlo; Bergamaschini, Luigi; Simoni, Maria Grazia De

doi:10.1016/j.nbd.2004.11.001

Cited by 88 publications

(56 citation statements)

References 41 publications

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“…Previous research has shown that C1INH reduces complement activation with significant protection of the myocardium and brain from ischemic damage. [27][28][29][30] Moreover, C1INH limited leukocyte adhesion and neutrophil infiltration in a model of ischemia-reperfusion in the liver. [31][32][33] We observed that rhC1INH was very effective in limiting complement activation in renal tissue, as showed by the dramatic reduction of C4d and C5b-9 deposition.…”

Section: Discussionmentioning

confidence: 91%

Therapeutic Targeting of Classical and Lectin Pathways of Complement Protects from Ischemia-Reperfusion-Induced Renal Damage

Castellano

Melchiorre

Loverre

et al. 2010

The American Journal of Pathology

133

121

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Ischemia-reperfusion injury is the major cause of delayed graft function in transplanted kidneys, an early event significantly affecting long-term graft function and survival. Several studies in rodents suggest that the alternative pathway of the complement system plays a pivotal role in renal ischemia-reperfusion injury. However, limited information is currently available from humans and larger animals. Here we demonstrated that 30 minutes of ischemia resulted in the induction of C4d/C1q, C4d/MLB, and MBL/MASP-2 deposits in a swine model of ischemia-reperfusion injury. The infusion of C1-inhibitor led to a significant reduction in peritubular capillary and glomerular C4d and C5b-9 deposition. Moreover, complement-inhibiting treatment significantly reduced the numbers of infiltrating CD163 ؉ , SWC3a ؉ , CD4a ؉ , and CD8a

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Section: Discussionmentioning

confidence: 91%

Therapeutic Targeting of Classical and Lectin Pathways of Complement Protects from Ischemia-Reperfusion-Induced Renal Damage

Castellano

Melchiorre

Loverre

et al. 2010

The American Journal of Pathology

133

121

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“…RNA Isolation, cDNA Synthesis, and Real-Time Polymerase Chain Reaction Twenty-four hours after TBI, mice were killed and ipsilateral cortices dissected for gene expression analysis as previously described (Storini et al, 2005;Troglio et al, 2004). Briefly, total RNA was obtained from tissue specimens using the Trizol reagent (Gibco BRL, Kidlington, MD, USA).…”

Section: Transferase-mediated Dutp Nick End Labeling Stainingmentioning

confidence: 99%

Long-lasting protection in brain trauma by endotoxin preconditioning

Longhi

Gesuete

Perego

et al. 2011

J Cereb Blood Flow Metab

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We investigated the occurrence of endotoxin (lipopolysaccharide, LPS) preconditioning in traumatic brain injury (TBI), evaluating the time window of LPS-induced protection, its persistence, and the associated molecular mechanisms. Mice received 0.1 mg/kg LPS or saline intraperitoneally and subsequently TBI (by controlled cortical impact brain injury) at various time intervals. Mice receiving LPS 3, 5, or 7 days before TBI showed attenuated motor deficits at 1 week after injury compared with mice receiving saline. Those receiving LPS 5 days before injury had also a reduced contusion volume (7.9±1.3 versus 12±2.3 mm 3 ) and decreased cell death. One month after injury, the protective effect of LPS on contusion volume (14.5 ± 1.2 versus 18.2 ± 1.2 mm 3 ) and neurologic function was still present. Traumatic brain injury increased glial fibrillary acidic protein, CD11b, CD68, tumor necrosis factor-a, interleukin (IL)-10, and IL-6 mRNA expression 24 hours after injury. Lipopolysaccharide administered 5 (but not 9) days before injury increased the expression of CD11b (233%) and of interferon b (500%) in uninjured mice, while it reduced the expression of CD68 (by 46%) and increased that of IL-6 (by 52%) in injured mice. Lipopolysaccharide preconditioning conferred a long-lasting neuroprotection after TBI, which was associated with a modulation of microglia/macrophages activity and cytokine production.

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“…With the ischemic protocol used, this brain area typically includes a portion of the lesion, as well as the penumbra, where the tissue is functionally impaired but potentially salvageable and is well suited for studying ischemic gene expression (Storini et al, 2005). The mRNA expression of the inflammatory cytokines TNF-a and IL-1b are significantly upregulated by ischemia compared to sham-operated mice both at 24 and 48 h. ST1942 treatment significantly prevents the upregulation of these cytokines at both time points (Figure 4).…”

Section: Gene Expression Datamentioning

confidence: 99%

“…Soon after ischemia, several inflammatory cascades are initiated. Vascular endothelial cells become rapidly activated, leading to rapid upregulation of adhesion molecules (Connolly et al, 1996;Frijns and Kappelle, 2002;Pantoni et al, 1998;Storini et al, 2005). Resident cellular populations, namely astrocytes and microglia, and recruited inflammatory cells, such as neutrophils and macrophages, are triggered to produce an array of inflammatory molecules, including pro-inflammatory cytokines that profoundly affect the pathogenesis of brain injury (Frijns and Kappelle, 2002;Touzani et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

2-Aminotetraline Derivative Protects from Ischemia/Reperfusion Brain Injury with a Broad Therapeutic Window

Capone

Fabrizi

Piovesan

et al. 2006

Neuropsychopharmacol

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The effect of ST1942, a 2-aminotetraline derivative with anti-inflammatory properties, was evaluated in ischemia/reperfusion injury in CD1 and C57BL/6 mice. ST1942 or saline were injected intraperitoneally 30 min and 6, 24, 36 h after ischemia. Forty-eight hours after ischemia, ST1942 (25 mg/kg) reduced the infarct volume by 50% in CD1 and 61% in C57BL/6 mice. All subsequent data were obtained from the latter strain. The ischemic lesion was significantly reduced by 30% when the first injection was administered 6 h after ischemia, revealing a broad effective window. Degenerating neurons in striatum, cortex and hippocampus of ischemic mice were markedly decreased by ST1942. Also examined was the effect of ST1942 on general and focal neurological deficits for 4 days after ischemia. Mice receiving the drug twice daily showed constantly reduced deficits. We then investigated the cortical mRNA expression of some inflammatory and apoptotic genes by real-time PCR. Forty-eight hours after ischemia ST1942 treatment significantly counteracted ischemia-induced activation of IL-1b, TNFa, and Bax, and enhanced the expression of the antiapoptotic gene, Bcl-2, showing in vivo anti-inflammatory and antiapoptotic actions. The microglial activation/macrophage recruitment in the ischemic lesion was strongly prevented in mice receiving ST1942. In neuron-microglia cocultures, ST1942 significantly counteracted LPS-induced cytotoxicity. Binding data and experiments on microglial cell cultures indicate that the anti-inflammatory effect of ST1942 may be due to its action on 5-HT2B receptors, thus highlighting the possibility that this 5-HT receptor subtype may represent a novel target for neuroprotective drugs in ischemic injury.

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C1-inhibitor protects against brain ischemia–reperfusion injury via inhibition of cell recruitment and inflammation

Cited by 88 publications

References 41 publications

Therapeutic Targeting of Classical and Lectin Pathways of Complement Protects from Ischemia-Reperfusion-Induced Renal Damage

Therapeutic Targeting of Classical and Lectin Pathways of Complement Protects from Ischemia-Reperfusion-Induced Renal Damage

Long-lasting protection in brain trauma by endotoxin preconditioning

2-Aminotetraline Derivative Protects from Ischemia/Reperfusion Brain Injury with a Broad Therapeutic Window

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