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SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature.

ABSTRACT: Copper/zinc superoxide dismutase (CuZnSOD; SOD1) is widely considered as a potential therapeutic candidate for pathologies involving oxidative stress, but its application has been greatly hindered by delivery issues. In our previous study, nanoformulated SOD1 (cl-nanozyme) was shown to decrease infarct volume and improve sensorimotor functions after a single intravenous (IV) injection in a rat middle cerebral artery occlusion (MCAO) model of ischemia/reperfusion (I/R) injury (stroke). However, it remained unclear how cl-nanozyme was able to deliver SOD1 to the brain and exert therapeutic efficacy. The present study aims to answer this question by exploring micro-distribution pattern of cl-nanozyme in the rat brain after stroke. Immunohistochemistry studies demonstrated cl-nanozyme co-localization with fibrin along damaged arteries and capillaries in the ischemic hemisphere. We further found that cl-nanozyme can be cross-linked into thrombi formed after I/R injury in the brain, and this effect is independent of animal species (rat/mouse) used for modeling I/R injury. This work is also the first report reinforcing therapeutic potential of cl-nanozyme in a well-characterized mouse MCAO model of I/R injury.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC4684498 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature.

Jiang Yuhang Y Brynskikh Anna M AM S-Manickam Devika D Kabanov Alexander V AV

Journal of controlled release : official journal of the Controlled Release Society 20150618

Copper/zinc superoxide dismutase (CuZnSOD; SOD1) is widely considered as a potential therapeutic candidate for pathologies involving oxidative stress, but its application has been greatly hindered by delivery issues. In our previous study, nanoformulated SOD1 (cl-nanozyme) was shown to decrease infarct volume and improve sensorimotor functions after a single intravenous (IV) injection in a rat middle cerebral artery occlusion (MCAO) model of ischemia/reperfusion (I/R) injury (stroke). However, i ...[more]

PMID: 26093094

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Project description:Prenatal glucocorticoids prevent germinal matrix hemorrhage in premature infants. The underlying mechanism, however, is elusive. Germinal matrix is enriched with angiogenic vessels exhibiting paucity of pericytes and glial fibrillary acidic protein-positive astrocyte end feet. Therefore, we asked whether glucocorticoid treatment would suppress angiogenesis and enhance periendothelial coverage by pericytes and glial fibrillary acidic protein-positive end feet in the germinal matrix microvasculature.We treated pregnant rabbits with intramuscular betamethasone and delivered pups prematurely by cesarean section at E29 (term=32 days). Endothelial turnover, vascular density, pericyte coverage, glial fibrillary acidic protein-positive end feet, cell death, and growth factors orchestrating angiogenesis, including vascular endothelial growth factor, angiopoietins, transforming growth factor-beta, and platelet-derived growth factor-B, were compared between betamethasone-treated and untreated pups. Similar comparisons were done between autopsy materials from premature infants exposed and unexposed to prenatal glucocorticoids.Antenatal glucocorticoid treatment reduced endothelial proliferation, vascular density, and vascular endothelial growth factor expression in the germinal matrix of both rabbits and humans. The pericyte coverage was greater in glucocorticoid-treated rabbit pups and human infants than in controls, but not the glial fibrillary acidic protein-positive end feet coverage. Transforming growth factor-beta, but not angiopoietins and platelet-derived growth factor-B, were elevated in glucocorticoid-treated rabbit pups compared with controls. Betamethasone treatment induced apoptosis, neuronal degeneration, and gliosis in rabbit pups. However, there was no evidence of increased cell death in glucocorticoid-exposed human infants.Prenatal glucocorticoid suppresses vascular endothelial growth factor and elevates transforming growth factor-beta levels, which results in angiogenic inhibition, trimming of neovasculature, and enhanced pericyte coverage. These changes contribute to stabilizing the germinal matrix vasculature, thereby reducing its propensity to hemorrhage. Prenatal glucocorticoid exposure does not induce neural cell death in humans, unlike rabbits.

Project description:Cardiovascular diseases are approximately three times higher in patients with neurological deficits than in patients without neurological deficits. MicroRNA-126 (MiR-126) facilitates vascular remodeling and decreases fibrosis and is emerging as an important factor in the pathogenesis of cardiovascular diseases and cerebral stroke. In this study, we tested the hypothesis that decreased miR-126 after ischemic stroke may play an important role in regulating cardiac function. Wild-type (WT), specific conditional-knockout endothelial cell miR-126 (miR-126EC-/-), and miR-126 knockout control (miR-126fl/fl) mice were subjected to distal middle cerebral artery occlusion (dMCAo) (n = 10/group). Cardiac hemodynamics and function were measured using transthoracic Doppler echocardiography. Mice were sacrificed at 28 days after dMCAo. WT mice subjected to stroke exhibited significantly decreased cardiac ejection fraction and increased myocyte hypertrophy, fibrosis as well as increased heart inflammation, infiltrating macrophages, and oxidative stress compared to non-stroke animals. Stroke significantly decreased serum and heart miR-126 expression and increased miR-126 target genes, vascular cell adhesion protein-1, and monocyte chemotactic protein-1 gene, and protein expression in the heart compared to non-stroke mice. MiR-126EC-/- mice exhibited significantly decreased cardiac function and increased cardiomyocyte hypertrophy, fibrosis, and inflammatory factor expression after stroke compared to miR-126fl/fl stroke mice. Exosomes derived from endothelial cells of miR-126EC-/- (miR-126EC-/-EC-Exo) mice exhibited significantly decreased miR-126 expression than exosomes derived from miR-126fl/fl (miR-126fl/fl-EC-Exo) mice. Treatment of cardiomyocytes subjected to oxygen glucose deprivation with miR-126fl/fl-EC-Exo exhibited significantly decreased hypertrophy than with miR-126EC-/-EC-Exo treatment. Ischemic stroke directly induces cardiac dysfunction. Decreasing miR-126 expression may contribute to cardiac dysfunction after stroke in mice.

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SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature.

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SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature.

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