Dataset Information

Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke.

ABSTRACT:

Background and purpose

The restoration of blood-flow following cerebral ischemia incites a series of deleterious cascades that exacerbate neuronal injury. Pharmacologic inhibition of the C3a-receptor ameliorates cerebral injury by attenuating post-ischemic inflammation. Recent reports also implicate C3a in the modulation of tissue repair, suggesting that complement may influence both injury and recovery at later post-ischemic time-points.

Methods

To evaluate the effect of C3a-receptor antagonism on post-ischemic neurogenesis and neurological outcome in the subacute period of stroke, transient focal cerebral ischemia was induced in adult male C57BL/6 mice treated with multiple regimens of a C3a receptor antagonist (C3aRA).

Results

Low-dose C3aRA administration during the acute phase of stroke promotes neuroblast proliferation in the subventricular zone at 7 days. Additionally, the C3a receptor is expressed on T-lymphocytes within the ischemic territory at 7 days, and this cellular infiltrate is abrogated by C3aRA administration. Finally, C3aRA treatment confers robust histologic and functional neuroprotection at this delayed time-point.

Conclusions

Targeted complement inhibition through low-dose antagonism of the C3a receptor promotes post-ischemic neuroblast proliferation in the SVZ. Furthermore, C3aRA administration suppresses T-lymphocyte infiltration and improves delayed functional and histologic outcome following reperfused stroke. Post-ischemic complement activation may be pharmacologically manipulated to yield an effective therapy for stroke.

SUBMITTER: Ducruet AF

PROVIDER: S-EPMC3383680 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke.

Ducruet Andrew F AF Zacharia Brad E BE Sosunov Sergey A SA Gigante Paul R PR Yeh Mason L ML Gorski Justin W JW Otten Marc L ML Hwang Richard Y RY DeRosa Peter A PA Hickman Zachary L ZL Sergot Paulina P Connolly E Sander ES

PloS one 20120626 6

<h4>Background and purpose</h4>The restoration of blood-flow following cerebral ischemia incites a series of deleterious cascades that exacerbate neuronal injury. Pharmacologic inhibition of the C3a-receptor ameliorates cerebral injury by attenuating post-ischemic inflammation. Recent reports also implicate C3a in the modulation of tissue repair, suggesting that complement may influence both injury and recovery at later post-ischemic time-points.<h4>Methods</h4>To evaluate the effect of C3a-rece ...[more]

PMID: 22761695

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Project description:We investigated the effects of PACAP treatment, and endogenous PACAP deficiency, on infarct volume, neurological function, and the cerebrocortical transcriptional response in a mouse model of stroke, middle cerebral artery occlusion (MCAO). PACAP-38 administered i.v. or i.c.v. 1 h after MCAO significantly reduced infarct volume, and ameliorated functional motor deficits measured 24 h later in wild-type mice. Infarct volumes and neurological deficits (walking faults) were both greater in PACAP-deficient than in wild-type mice, but treatment with PACAP reduced lesion volume and neurological deficits in PACAP-deficient mice to the same level of improvement as in wild-type mice. A 35,546-clone mouse cDNA microarray was used to investigate cortical transcriptional changes associated with cerebral ischemia in wild-type and PACAP-deficient mice, and with PACAP treatment after MCAO in wild-type mice. 229 known (named) transcripts were increased (228) or decreased (1) in abundance at least 50% following cerebral ischemia in wild-type mice. 49 transcripts were significantly up-regulated only at 1 h post-MCAO (acute response transcripts), 142 were up-regulated only at 24 h post-MCAO (delayed response transcripts) and 37 transcripts were up-regulated at both times (sustained response transcripts). More than half of these are transcripts not previously reported to be altered in ischemia. A larger percentage of genes up-regulated at 24 hr than at 1 hr required endogenous PACAP, suggesting a more prominent role for PACAP in later response to injury than in the initial response. This is consistent with a neuroprotective role for PACAP in late response to injury, i.e., even when administered 1 hr or more after MCAO. Putative injury effector transcripts regulated by PACAP include beta-actin, midline 2, and metallothionein 1. Potential neuroprotective transcripts include several demonstrated to be PACAP-regulated in other contexts. Prominent among these were transcripts encoding the PACAP-regulated gene Ier3, and the neuropeptides enkephalin, substance P (tachykinin 1), and neurotensin.

Project description:Patients with acute ischemic stroke (AIS) present an increased incidence of systemic inflammatory response syndrome and release of Troponin T coinciding with cardiac dysfunction. The nature of the cardiocirculatory alterations remains obscure as models to investigate systemic interferences of the brain-heart-axis following AIS are sparse. Thus, this study aims to investigate acute cardiocirculatory dysfunction and myocardial injury in mice after reperfused AIS. Ischemic stroke was induced in mice by transient right-sided middle cerebral artery occlusion (tMCAO). Cardiac effects were investigated by electrocardiograms, 3D-echocardiography, magnetic resonance imaging (MRI), invasive conductance catheter measurements, histology, flow-cytometry, and determination of high-sensitive Troponin T (hsTnT). Systemic hemodynamics were recorded and catecholamines and inflammatory markers in circulating blood and myocardial tissue were determined by immuno-assay and flow-cytometry. Twenty-four hours following tMCAO hsTnT was elevated 4-fold compared to controls and predicted long-term survival. In parallel, systolic left ventricular dysfunction occurred with impaired global longitudinal strain, lower blood pressure, reduced stroke volume, and severe bradycardia leading to reduced cardiac output. This was accompanied by a systemic inflammatory response characterized by granulocytosis, lymphopenia, and increased levels of serum-amyloid P and interleukin-6. Within myocardial tissue, MRI relaxometry indicated expansion of extracellular space, most likely due to inflammatory edema and a reduced fluid volume. Accordingly, we found an increased abundance of granulocytes, apoptotic cells, and upregulation of pro-inflammatory cytokines within myocardial tissue following tMCAO. Therefore, reperfused ischemic stroke leads to specific cardiocirculatory alterations that are characterized by acute heart failure with reduced stroke volume, bradycardia, and changes in cardiac tissue and accompanied by systemic and local inflammatory responses.

Dataset Information

Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke.

Background and purpose

Methods

Results

Conclusions

Publications

Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke.

Similar Datasets

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