Noggin Protects Against Ischemic Brain Injury in Rodents

Children's Memorial Hospital, Chicago, Illinois, United States
Stroke (Impact Factor: 5.72). 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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    • "In contrast to a previous study [18], the viral expression of Noggin, an extracellular inhibitor of BMP2, BMP4 and BMP7, had no effect on the infarct size although we verified that the rAAV expressed Noggin was bioactive by decreasing the level of Smad phosphorpylation of HeLa cells. Besides the different time points for the analysis after MCAO (2 days in this study versus 14 days in [18]) a lower expression level of biological active Noggin in our system cannot be excluded. "
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    ABSTRACT: Bone morphogenic proteins (BMPs) promote the survival of neurons, suggesting a therapeutic application of BMPs in the treatment of acute and chronic neurodegenerative disorders. However, the application of recombinant BMPs in vivo is limited by their short half-life. To provide a continuous supply for functionally active BMPs, we expressed BMP7, BMP2 and the BMP inhibitor Noggin under the control of rAAV vectors in vivo. For visual control of rAAV-mediated BMP (v-BMP) expression we fused the secreted morphogenic polypeptides and the fluorescent reporter protein Venus via the 'ribosomal skip' promoting 2A peptide-bridge. In primary cortical neurons, the rAAV-expressed morphogenic polypeptides were efficiently released from the 2A-Venus fusion precursors, were secreted, correctly processed and functionally active as shown by their effects on Smad phosphorylation in HeLa cells and in primary neurons, by the protection of v-BMP7-transduced primary cortical neurons against oxidative stress, and by the activation of BMP responsive GFP in v-BMP2 transduced reporter mice. In the stroke model of middle cerebral artery occlusion rAAV-transduced v-BMP7 reduced the infarct size in mice. Polycistronic rAAV vectors encoding secreted polypeptides and 2A-linked reporter proteins are potential novel therapeutic tools for the treatment of neurological and neurodegenerative diseases. Using this technique we documented that rAAV delivery of BMP7 reduced ischemic cell death in mice.
    BMC Neuroscience 03/2014; 15(1):38. DOI:10.1186/1471-2202-15-38 · 2.67 Impact Factor
    • "Though most patients survive the initial stroke attack, they are at high risk for recurrent vascular events. Five years recurrence rate is about 30% after initial stroke episode.[2] At present, thrombolytic therapy with recombinant tissue plasminogen activator is the most effective treatment for acute ischemic stroke, but it has to be administered within 4.5 h of symptom onset. "
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    ABSTRACT: The aim of the study was to investigate the effects of LGB on cerebral ischemia-reperfusion (I/R) injury in rats and the mechanisms of action of LGB. The study involved extracting LGB from P. laciniata, exploring affects of LGB on brain ischemia and action mechanism at the molecular level. The cerebral ischemia reperfusion injury of middle cerebral artery occlusion was established. We measured brain histopathology and brain infarct rate to evaluate the effects of LGB on brain ischemia injury. The expressions of nerve growth factor (NGF) and neurotrophin-3 (NT-3) were also measured to investigate the mechanisms of action by the real-time polymerase chain reaction and immunohistochemistry. All results were mentioned as mean ± standard deviation. One-way analysis of variance was used to determine statistically significant differences among the groups. Values of P < 0.05 were considered to be statistically significant. Intraperitoneal injection of LGB at the dose of 12, 24, and 48 mg/kg after brain ischemia injury remarkably ameliorated the morphology of neurons and brain infarct rate (P < 0.05, P < 0.01). LGB significantly increased NGF and NT-3 mRNA (messenger RNA) and both protein expression in cerebral cortex at the 24 and 72 h after drug administration (P < 0.05, P < 0.01). LGB has a neuroprotective effect in cerebral I/R injury and this effect might be attributed to its upregulation of NGF and NT-3 expression ability in the brain cortex during the latter phase of brain ischemia.
    Indian Journal of Pharmacology 03/2014; 46(1):63-8. DOI:10.4103/0253-7613.125171 · 0.69 Impact Factor
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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.
    Journal of Neuroscience Research 08/2011; 89(8):1194-202. DOI:10.1002/jnr.22662 · 2.59 Impact Factor
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