Noggin Protects Against Ischemic Brain Injury in Rodents

Children's Memorial Hospital, Chicago, Illinois, United States
Stroke (Impact Factor: 6.02). 12/2009; 41(2):357-62. DOI: 10.1161/STROKEAHA.109.565523
Source: PubMed

ABSTRACT Bone morphogenetic proteins and their receptors are expressed in adult brains, and their expression levels increase after cerebral ischemia. The brain also expresses an inhibitor of bone morphogenetic protein signaling, noggin, but the role of noggin in ischemic disease outcome has not been studied.
We used transgenic mice overexpressing noggin to assess whether inhibition of bone morphogenetic protein signaling affects ischemic injury responses after permanent middle cerebral artery occlusion.
Transgenic mice overexpressing noggin mice had significantly smaller infarct volumes and lower motor deficits compared to wild-type mice. CD11b(+) and IBA1(+) microglia along with oligodendroglial progenitors were significantly increased in transgenic mice overexpressing noggin mice at 14 days after permanent middle cerebral artery occlusion.
These results provide genetic evidence that overexpression of noggin reduces ischemic brain injury after permanent middle cerebral artery occlusion via enhanced activation of microglia and oligodendrogenesis.

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Available from: Lixin Kan, Jan 15, 2014
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    • "Recent research with the transgenic mouse showed that overexpression of Noggin alleviated ischemic brain injury after permanent MCAo via enhanced activation of microglia and oligodenrogenesis (Samanta et al., 2010). "
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    ABSTRACT: Early intervention with intravenous administration of bone marrow stromal cells (BMSCs) reduces infarction size and ameliorates functional deficits in rat ischemia models. Noggin, an inhibitor of bone morphogenetic protein (BMP), has been demonstrated to provide protection from ischemic disease. In the present work, we hypothesize that administering Noggin-transfected BMSCs enhances BMSC-induced brain repair after cerebral ischemia. We compared the effects of BMSCs alone and Noggin-transfected BMSCs (Noggin-BMSCs) systematically delivered into the middle cerebral artery occlusion (MCAo) rat model. Noggin expression in BMSCs was achieved using adenoviral infection together with a green fluorescent protein (GFP) vector to monitor transduction efficiency and facilitate posttransplantation tracking. BMSCs and Noggin-BMSCs were intravenously injected into the rats 6 hr after MCAo. At 7 days after MCAo, the GFP-expressing BMSCs and Noggin-BMSCs were found primarily in the ischemic penumbra, which indicated that the intravenously delivered cells survived and reached in the lesion site. Both BMSC and Noggin-BMSC treatment significantly promoted neurogenesis in the ipsilateral subventrical zone (SVZ), reduced infarct volume, and led to functional improvement compared with the control group. Moreover, these beneficial effects were significantly greater in the Noggin-BMSC-treated group compared with BMSCs alone treatment (P < 0.05). Noggin expression in the ischemic hemisphere was significantly increased in the Noggin-BMSC-treated group as revealed by enzyme-linked immunosorbent assay (ELISA) at 7 days after MCAo compared with BMSC-treated and control groups (P < 0.05). These results indicate that transfection of Noggin in BMSCs enhances BMSC-induced neuroprotective effects when administered intravenously during the acute phase after stroke.
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    • "Moreover, administration of BMP6 and BMP7 prior to adult stroke decreases infarct volumes and neurologic deficits (Chang et al., 2003; Chang et al., 2002; Wang et al., 2001). However the BMP antagonist noggin decreases infarct size and improves motor function in an adult stroke model (Samanta et al. 2010). There are several possible explanations for these apparently divergent findings. "
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    ABSTRACT: Hypoxia-ischemia (HI) in the neonate leads to white matter injury and subsequently cerebral palsy. We find that expression of bone morphogenetic protein 4 (BMP4) increases in the neonatal mouse brain after unilateral common carotid artery ligation followed by hypoxia. Since signaling by the BMP family of factors is a potent inhibitor of oligodendroglial differentiation, we tested the hypothesis that antagonism of BMP signaling would prevent loss of oligodendroglia (OL) and white matter in a mouse model of perinatal HI. Perinatal HI was induced in transgenic mice in which the BMP antagonist noggin is overexpressed during oligodendrogenesis (pNSE-Noggin). Following perinatal HI, pNSE-Noggin mice had more oligodendroglial progenitor cells (OPCs) and more mature OL compared to wild type (WT) animals. The increase in OPC numbers did not result from proliferation but rather from increased differentiation from precursor cells. Immunofluorescence studies showed preservation of white matter in lesioned pNSE-Noggin mice compared to lesioned WT animals. Further, following perinatal HI, the pNSE-Noggin mice were protected from gait deficits. Together these findings indicate that the BMP-inhibitor noggin protects from HI-induced loss of oligodendroglial lineage cells and white matter as well as loss of motor function.
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