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Blood substitution therapy rescues the brain of mice from ischemic damage.

ABSTRACT: Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage.

SUBMITTER: Ren X

PROVIDER: S-EPMC7447645 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Blood substitution therapy rescues the brain of mice from ischemic damage.

Ren Xuefang X Hu Heng H Farooqi Imran I Simpkins James W JW

Nature communications 20200825 1

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescenc ...[more]

PMID: 32843630

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Project description:BackgroundAdropin is a peptide encoded by the energy homeostasis-associated gene (Enho) that is highly expressed in the brain. Aging and stroke are associated with reduced adropin levels in the brain and plasma. We showed that treatment with synthetic adropin provides long-lasting neuroprotection in permanent ischemic stroke. However, it is unknown whether the protective effects of adropin are observed in aged animals following cerebral ischemia/reperfusion. We hypothesized that adropin provides neuroprotection in aged mice subjected to transient middle cerebral artery occlusion.MethodsAged (18-24 months old) male mice were subjected to 30 minutes of middle cerebral artery occlusion followed by 48 hours or 14 days of reperfusion. Sensorimotor (weight grip test and open field) and cognitive tests (Y-maze and novel object recognition) were performed at defined time points. Infarct volume was quantified by 2,3,5-triphenyltetrazolium chloride staining at 48 hours or Cresyl violet staining at 14 days post-middle cerebral artery occlusion. Blood-brain barrier damage, tight junction proteins, and MMP-9 (matrix metalloproteinase-9) were assessed 48 hours after middle cerebral artery occlusion by ELISA and Western blots.ResultsGenetic deletion of Enho significantly increased infarct volume and worsened neurological function, whereas overexpression of adropin dramatically reduced stroke volume compared to wild-type controls. Postischemic treatment with synthetic adropin peptide given at the onset of reperfusion markedly reduced infarct volume, brain edema, and significantly improved locomotor function and muscular strength at 48 hours. Delayed adropin treatment (4 hours after the stroke onset) reduced body weight loss, infarct volume, and muscular strength dysfunction, and improved long-term cognitive function. Postischemic adropin treatment significantly reduced blood-brain barrier damage. This effect was associated with reduced MMP-9 and preservation of tight junction proteins by adropin treatment.ConclusionsThese data unveil a promising neuroprotective role of adropin in the aged brain after transient ischemic stroke via reducing neurovascular damage. These findings suggest that poststroke adropin therapy is a potential strategy to minimize brain injury and improve functional recovery in ischemic stroke patients.

Project description:ObjectiveOur previous results showed that icariin (ICA) could inhibit apoptosis and provide neuroprotection against hypoxic-ischemic brain damage (HIBD) in neonatal mice, but the specific mechanism of its neuroprotective effect remains unknown. This study aims at exploring whether ICA plays a neuroprotective role in apoptosis inhibition by regulating autophagy through the estrogen receptor α (ERα)/estrogen receptor β (ERβ) pathway in neonatal mice with HIBD.MethodsA neonatal mouse model of HIBD was constructed in vivo, and an oxygen and glucose deprivation (OGD) model in HT22 cells from the hippocampal neuronal system was constructed in vitro. The effects of ICA pretreatment on autophagy and the expression of ERα and ERβ were detected in vitro and in vivo, respectively. ICA pretreatment was also supplemented with the autophagy inhibitor 3-methyladenine (3-MA), ERα inhibitor methylpiperidino pyrazole (MPP), and ERβ inhibitor 4-(2-phenyl-5,7-bis (trifluoromethyl) pyrazolo [1,5-a] pyramidin-3-yl) phenol (PHTPP) to further detect whether ICA pretreatment can activate the ERα/ERβ pathway to promote autophagy and reduce HIBD-induced apoptosis to play a neuroprotective role against HIBD in neonatal mice.ResultsICA pretreatment significantly promoted autophagy in HIBD mice. Treatment with 3-MA significantly inhibited the increase in autophagy induced by ICA pretreatment, reversed the neuroprotective effect of ICA pretreatment, and promoted apoptosis. Moreover, ICA pretreatment significantly increased the expression levels of the ERα and ERβ proteins in HIBD newborn mice. Both MPP and PHTPP administration significantly inhibited the expression levels of the ERα and ERβ proteins activated by ICA pretreatment, reversed the neuroprotective effects of ICA pretreatment, inhibited the increase in autophagy induced by ICA pretreatment, and promoted apoptosis.ConclusionICA pretreatment may promote autophagy by activating the ERα and ERβ pathways, thus reducing the apoptosis induced by HIBD and exerting a neuroprotective effect on neonatal mice with HIBD.

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Blood substitution therapy rescues the brain of mice from ischemic damage.

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Blood substitution therapy rescues the brain of mice from ischemic damage.

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