Publications by authors named "Jieli Chen"

138 Publications

Deficiency of Endothelial Nitric Oxide Synthase (eNOS) Exacerbates Brain Damage and Cognitive Deficit in A Mouse Model of Vascular Dementia.

Aging Dis 2021 Jun 1;12(3):732-746. Epub 2021 Jun 1.

1Department of Neurology, Henry Ford Hospital, Detroit, MI-48202, USA.

Vascular Dementia (VaD) accounts for nearly 20% of all cases of dementia. eNOS plays an important role in neurovascular remodeling, anti-inflammation, and cognitive functional recovery after stroke. In this study, we investigated whether eNOS regulates brain damage, cognitive function in mouse model of bilateral common carotid artery stenosis (BCAS) induced VaD. Late-adult (6-8 months) C57BL/6J and eNOS knockout (eNOS-/-) mice were subjected to BCAS (n=12/group) or sham group (n=8/group). BCAS was performed by applying microcoils to both common carotid arteries. Cerebral blood flow (CBF) and blood pressure were measured. A battery of cognitive functional tests was performed, and mice were sacrificed 30 days after BCAS. Compared to corresponding sham mice, BCAS in wild-type (WT) and eNOS-/- mice significantly: 1) induces short term, long term memory loss, spatial learning and memory deficits; 2) decreases CBF, increases ischemic cell damage, including apoptosis, white matter (WM) and axonal damage; 3) increases blood brain barrier (BBB) leakage, decreases aquaporin-4 (AQP4) expression and vessel density; 4) increases microglial, astrocyte activation and oxidative stress in the brain; 5) increases inflammatory factor interleukin-1 receptor-associated kinase-1(IRAK-1) and amyloid beta (Aβ) expression in brain; 6) increases IL-6 and IRAK4 expression in brain. eNOS-/-sham mice exhibit increased blood pressure, decreased iNOS and nNOS in brain compared to WT-sham mice. Compared to WT-BCAS mice, eNOS-/-BCAS mice exhibit worse vascular and WM/axonal damage, increased BBB leakage and inflammatory response, increased cognitive deficit, decreased iNOS, nNOS in brain. eNOS deficit exacerbates BCAS induced brain damage and cognitive deficit.
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http://dx.doi.org/10.14336/AD.2020.0523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139201PMC
June 2021

Multifaceted roles of pericytes-interorgan interactions.

Neural Regen Res 2021 May;16(5):982-983

Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.

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http://dx.doi.org/10.4103/1673-5374.297071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178774PMC
May 2021

HUCBC Treatment Improves Cognitive Outcome in Rats With Vascular Dementia.

Front Aging Neurosci 2020 18;12:258. Epub 2020 Aug 18.

Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.

: Vascular dementia (VaD) is the second common cause of dementia after Alzheimer's disease in older people. Yet, there are no FDA approved drugs specifically for VaD. In this study, we have investigated the therapeutic effects of human umbilical cord blood cells (HUCBC) treatment on the cognitive outcome, white matter (WM) integrity, and glymphatic system function in rats subject to a multiple microinfarction (MMI) model of VaD. : Male, retired breeder rats were subjected to the MMI model (800 ± 100 cholesterol crystals/300 μl injected into the internal carotid artery), and 3 days later were treated with phosphate-buffered saline (PBS) or HUCBC (5 × 10, i.v.). Sham rats were included as naïve control. Following a battery of cognitive tests, rats were sacrificed at 28 days after MMI and brains extracted for immunohistochemical evaluation and Western blot analysis. To evaluate the glymphatic function, fluorescent tracers (Texas Red dextran, MW: 3 kD and FITC-dextran, MW: 500 kD) was injected into the cisterna magna over 30 min at 14 days after MMI. Rats (3-4/group/time point) were sacrificed at 30 min, 3 h, and 6 h, and the tracer movement analyzed using laser scanning confocal microscopy. : Compared to control MMI rats, HUCBC treated MMI rats exhibit significantly improved short-term memory and long-term memory exhibited by increased discrimination index in novel object recognition task with retention delay of 4 h and improved novel odor recognition task with retention delay of 24 h, respectively. HUCBC treatment also improves spatial learning and memory as measured using the Morris water maze test compared to control MMI rats. HUCBC treatment significantly increases axon and myelin density increases oligodendrocyte and oligodendrocyte progenitor cell number and increases Synaptophysin expression in the brain compared to control MMI rats. HUCBC treatment of MMI in rats significantly improves glymphatic function by reversing MMI induced delay in the penetration of cerebrospinal fluid (CSF) into the brain parenchyma glymphatic pathways and reversing delayed clearance from the brain. HUCBC treatment significantly increases miR-126 expression in serum, aquaporin-4 (AQP4) expression around cerebral vessels, and decreases transforming growth factor-β (TGF-β) protein expression in the brain which may contribute to HUCBC induced improved glymphatic function. : HUCBC treatment of an MMI rat model of VaD promotes WM remodeling and improves glymphatic function which together may aid in the improvement of cognitive function and memory. Thus, HUCBC treatment warrants further investigation as a potential therapy for VaD.
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http://dx.doi.org/10.3389/fnagi.2020.00258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461871PMC
August 2020

Exosomes derived from bone marrow mesenchymal stem cells harvested from type two diabetes rats promotes neurorestorative effects after stroke in type two diabetes rats.

Exp Neurol 2020 12 2;334:113456. Epub 2020 Sep 2.

Neurology Research, Henry Ford Hospital, Detroit, MI 48202, USA. Electronic address:

Background And Purpose: Diabetes elevates the risk of stroke, promotes inflammation, and exacerbates vascular and white matter damage post stroke, thereby hindering long term functional recovery. Here, we investigated the neurorestorative effects and the underlying therapeutic mechanisms of treatment of stroke in type 2 diabetic rats (T2DM) using exosomes harvested from bone marrow stromal cells obtained from T2DM rats (T2DM-MSC-Exo).

Methods: T2DM was induced in adult male Wistar rats using a combination of high fat diet and Streptozotocin. Rats were subjected to transient 2 h middle cerebral artery occlusion (MCAo) and 3 days later randomized to one of the following treatment groups: 1) phosphate-buffered-saline (PBS, i.v), 2) T2DM-MSC-Exo, (3 × 10, i.v), 3) T2DM-MSC-Exo with miR-9 over expression (miR9+/+-T2DM-MSC-Exo, 3 × 10, i.v) or 4) MSC-Exo derived from normoglycemic rats (Nor-MSC-Exo) (3 × 10, i.v). T2DM sham control group is included as reference. Rats were sacrificed 28 days after MCAo.

Results: T2DM-MSC-Exo treatment does not alter blood glucose, lipid levels, or lesion volume, but significantly improves neurological function and attenuates post-stroke weight loss compared to PBS treated as well as Nor-MSC-Exo treated T2DM-stroke rats. Compared to PBS treatment, T2DM-MSC-Exo treatment of T2DM-stroke rats significantly 1) increases tight junction protein ZO-1 and improves blood brain barrier (BBB) integrity; 2) promotes white matter remodeling indicated by increased axon and myelin density, and increases oligodendrocytes and oligodendrocyte progenitor cell numbers in the ischemic border zone as well as increases primary cortical neuronal axonal outgrowth; 3) decreases activated microglia, M1 macrophages, and inflammatory factors MMP-9 (matrix mettaloproteinase-9) and MCP-1 (monocyte chemoattractant protein-1) expression in the ischemic brain; and 4) decreases miR-9 expression in serum, and increases miR-9 target ABCA1 (ATP-binding cassette transporter 1) and IGFR1 (Insulin-like growth factor 1 receptor) expression in the brain. MiR9+/+-T2DM-MSC-Exo treatment significantly increases serum miR-9 expression compared to PBS treated and T2DM-MSC-Exo treated T2DM stroke rats. Treatment of T2DM stroke with miR9+/+-T2DM-MSC-Exo fails to improve functional outcome and attenuates T2DM-MSC-Exo treatment induced white matter remodeling and anti-inflammatory effects in T2DM stroke rats.

Conclusions: T2DM-MSC-Exo treatment for stroke in T2DM rats promotes neurorestorative effects and improves functional outcome. Down regulation of miR-9 expression and increasing its target ABCA1 pathway may contribute partially to T2DM-MSC-Exo treatment induced white matter remodeling and anti-inflammatory responses.
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http://dx.doi.org/10.1016/j.expneurol.2020.113456DOI Listing
December 2020

SUMO1 Deficiency Exacerbates Neurological and Cardiac Dysfunction after Intracerebral Hemorrhage in Aged Mice.

Transl Stroke Res 2021 08 6;12(4):631-642. Epub 2020 Aug 6.

Department of Neurology, Henry Ford Hospital, Detroit, MI-48202, USA.

Small ubiquitin-like modifier 1 (SUMO1) reduces cardiac hypertrophy and induces neuroprotective effects. Previous studies have found that intracerebral hemorrhage (ICH) provokes cardiac deficit in the absence of primary cardiac diseases in mice. In this study, we tested the hypothesis that SUMO1 deficiency leads to worse brain and heart dysfunction after ICH and SUMO1 plays a key role in regulating brain-heart interaction after ICH in aged mice. Aged (18-20 months) female SUMO1 null (SUMO1) mice and wild-type (WT) C57BL/6 J mice were randomly divided into four groups (n = 8/group): (1) WT-sham group, (2) SUMO1-sham group, (3) WT-ICH group, and (4) SUMO1-ICH group. Cardiac function was measured by echocardiography. Neurological and cognitive functional tests were performed. Mice were sacrificed at 10 days after ICH for histological and immunohistochemically staining. Compared with WT-sham mice, WT-ICH mice exhibited (1) significantly (P < 0.05) decreased SUMO1 expression in heart tissue, (2) evident neurological and cognitive dysfunction as well as brain white matter deficits, (3) significantly increased cardiac dysfunction, and (4) inflammatory factor expression in the heart and brain. Compared with WT-ICH mice, SUMO1-ICH mice exhibited significantly increased: (1) brain hemorrhage volume, worse neurological and cognitive deficits, and increased white matter deficits; (2) cardiac dysfunction and cardiac fibrosis; (3) inflammatory response both in heart and brain tissue. Aged SUMO1-deficient female mice subjected to ICH not only exhibit increased neurological and cognitive functional deficit but also significantly increased cardiac dysfunction and inflammatory cell infiltration into the heart and brain. These data suggest that SUMO1 plays an important role in brain-heart interaction.
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http://dx.doi.org/10.1007/s12975-020-00837-6DOI Listing
August 2021

ABCA1/ApoE/HDL Signaling Pathway Facilitates Myelination and Oligodendrogenesis after Stroke.

Int J Mol Sci 2020 Jun 19;21(12). Epub 2020 Jun 19.

Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.

ATP-binding cassette transporter A1 (ABCA1) plays an important role in the regulation of apolipoprotein E (ApoE) and the biogenesis of high-density lipoprotein (HDL) cholesterol in the mammalian brain. Cholesterol is a major source for myelination. Here, we investigate whether ABCA1/ApoE/HDL contribute to myelin repair and oligodendrogenesis in the ischemic brain after stroke. Specific brain ABCA1-deficient (ABCA1) and ABCA1-floxed (ABCA1) control mice were subjected to permanent distal middle-cerebral-artery occlusion (dMCAo) and were intracerebrally administered (1) artificial mouse cerebrospinal fluid (CSF) as vehicle control, (2) human plasma HDL3, and (3) recombined human ApoE2 starting 24 h after dMCAo for 14 days. All stroke mice were sacrificed 21 days after dMCAo. The ABCA1-dMCAo mice exhibit significantly reduced myelination and oligodendrogenesis in the ischemic brain as well as decreased functional outcome 21 days after stroke compared with ABCA1 mice; administration of human ApoE2 or HDL3 in the ischemic brain significantly attenuates the deficits in myelination and oligodendrogenesis in ABCA1-dMCAo mice ( < 0.05, = 9/group). In vitro, ABCA1 reduces ApoE expression and decreases primary oligodendrocyte progenitor cell (OPC) migration and oligodendrocyte maturation; HDL3 and ApoE2 treatment significantly reverses ABCA1-induced reduction in OPC migration and oligodendrocyte maturation. Our data indicate that the ABCA1/ApoE/HDL signaling pathway contributes to myelination and oligodendrogenesis in the ischemic brain after stroke.
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http://dx.doi.org/10.3390/ijms21124369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352241PMC
June 2020

Emerging role of microRNAs in ischemic stroke with comorbidities.

Exp Neurol 2020 09 16;331:113382. Epub 2020 Jun 16.

Department of Neurology, Henry Ford Hospital, Detroit, MI, United States of America. Electronic address:

Ischemic stroke is one of the major causes of global disability and death. Comorbidities in stroke are not only risk factors for an increased incidence of stroke, but also adversely impact stroke outcome. Stroke patients with co-morbidities have worse deficit, long term disability and high mortality rate and extended hospitalization stay. MicroRNAs (miRNAs) are noncoding RNA molecules, and are emerging as key molecular mediators of ischemic stroke and other diseases. Thus, focusing on the treatment of stroke and its comorbidities with miRNAs appears to be particularly important. In this review article, we provide an overview of the common comorbidities of hypertension, diabetes mellitus (DM) and hyperlipidemia in ischemic stroke. We also discuss specific miRNAs, including miR-126, miR-223, and miR-124 which are important in regulating ischemic stroke and describetheir effects as related to stroke and comorbidities. In addition, we provide an overview of roles of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in stroke with comorbidities.
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http://dx.doi.org/10.1016/j.expneurol.2020.113382DOI Listing
September 2020

Multifaceted roles of pericytes in central nervous system homeostasis and disease.

J Cereb Blood Flow Metab 2020 07 24;40(7):1381-1401. Epub 2020 Mar 24.

Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.

Pericytes, the mural cells surrounding microcirculation, are gaining increasing attention for their roles in health and disease of the central nervous system (CNS). As an essential part of the neurovascular unit (NVU), pericytes are actively engaged in interactions with neighboring cells and work in synergy with them to maintain homeostasis of the CNS, such as maintaining the blood-brain barrier (BBB), regulating cerebral blood flow (CBF) and the glymphatic system as well as mediating immune responses. However, the dysfunction of pericytes may contribute to the progression of various pathologies. In this review, we discuss: (1) origin of pericytes and different pericyte markers; (2) interactions of pericytes with endothelial cells (ECs), astrocytes, microglia, oligodendrocytes, and neurons; (3) physiological roles of pericytes in the CNS; (4) effects of pericytes in different CNS diseases; (5) relationship of pericytes with extracellular vesicles (EVs) and microRNAs (miRs); (6) recent advances in pericytes studies and future perspective.
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http://dx.doi.org/10.1177/0271678X20911331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308511PMC
July 2020

CD133+Exosome Treatment Improves Cardiac Function after Stroke in Type 2 Diabetic Mice.

Transl Stroke Res 2021 02 20;12(1):112-124. Epub 2020 Mar 20.

Department of Neurology, Henry Ford Hospital, Detroit, MI, 48202, USA.

Cardiac complications post-stroke are common, and diabetes exacerbates post-stroke cardiac injury. In this study, we tested whether treatment with exosomes harvested from human umbilical cord blood derived CD133+ cells (CD133+Exo) improves cardiac function in type 2 diabetes mellitus (T2DM) stroke mice. Adult (3-4 m), male, BKS.Cg-m+/+Lepr/J (db/db, T2DM) and non-DM (db+) mice were randomized to sham or photothrombotic stroke groups. T2DM-stroke mice were treated with phosphate-buffered saline (PBS) or CD133+Exo (20 μg, i.v.) at 3 days after stroke. T2DM sham and T2DM+CD133+Exo treatment groups were included as controls. Echocardiography was performed, and mice were sacrificed at 28 days after stroke. Cardiomyocyte hypertrophy, myocardial capillary density, interstitial fibrosis, and inflammatory factor expression were measured in the heart. MicroRNA-126 expression and its target gene expression were measured in the heart. T2DM mice exhibit significant cardiac deficits such as decreased left ventricular ejection fraction (LVEF) and shortening fraction (LVSF), increased left ventricular diastolic dimension (LVDD), and reduced heart rate compared to non-DM mice. Stroke in non-DM and T2DM mice significantly decreases LVEF compared to non-DM and T2DM-sham, respectively. Cardiac dysfunction is worse in T2DM-stroke mice compared to non-DM-stroke mice. CD133+Exo treatment of T2DM-stroke mice significantly improves cardiac function identified by increased LVEF and decreased LVDD compared to PBS treated T2DM-stroke mice. In addition, CD133+Exo treatment significantly decreases body weight and blood glucose but does not decrease lesion volume in T2DM-stroke mice. CD133+Exo treatment of T2DM mice significantly decreases body weight and blood glucose but does not improve cardiac function. CD133+Exo treatment in T2DM-stroke mice significantly decreases myocardial cross-sectional area, interstitial fibrosis, transforming growth factor beta (TGF-β), numbers of M1 macrophages, and oxidative stress markers 4-HNE (4-hydroxynonenal) and NADPH oxidase 2 (NOX2) in heart tissue. CD133+Exo treatment increases myocardial capillary density in T2DM-stroke mice as well as upregulates endothelial cell capillary tube formation in vitro. MiR-126 is highly expressed in CD133+Exo compared to exosomes derived from endothelial cells. Compared to PBS treatment, CD133+Exo treatment significantly increases miR-126 expression in the heart and decreases its target gene expression such as Sprouty-related, EVH1 domain-containing protein 1 (Spred-1), vascular cell adhesion protein (VCAM), and monocyte chemoattractant protein 1 (MCP1) in the heart of T2DM-stroke mice. CD133+Exo treatment significantly improves cardiac function in T2DM-stroke mice. The cardio-protective effects of CD133+Exo in T2DM-stroke mice may be attributed at least in part to increasing miR-126 expression and decreasing its target protein expression in the heart, increased myocardial capillary density and decreased cardiac inflammatory factor expression.
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http://dx.doi.org/10.1007/s12975-020-00807-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502550PMC
February 2021

Brain-Derived Microparticles (BDMPs) Contribute to Neuroinflammation and Lactadherin Reduces BDMP Induced Neuroinflammation and Improves Outcome After Stroke.

Front Immunol 2019 26;10:2747. Epub 2019 Nov 26.

Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.

Microparticles (MPs, ~size between 0.1 and 1 mm) are lipid encased containers derived from intact cells which contain antigen from the parent cells. MPs are involved in intercellular communication and regulate inflammation. Stroke increases secretion of brain derived MP (BDMP) which activate macrophages/microglia and induce neuroinflammation. Lactadherin (Milk fat globule-EGF factor-8) binds to anionic phospholipids and extracellular matrices, promotes apoptotic cell clearance and limits pathogenic antigen cross presentation. In this study, we investigate whether BDMP affects stroke-induced neuroinflammation and whether Lactadherin treatment reduces stroke initiated BDMP-induced neuroinflammation, thereby improving functional outcome after stroke. Middle aged (8-9 months old) male C57BL/6J mice were subjected to distal middle cerebral artery occlusion (dMCAo) stroke, and BDMPs were extracted from ischemic brain 24 h after dMCAo by ultracentrifugation. Adult male C57BL/6J mice were subjected to dMCAo and treated via tail vein injection at 3 h after stroke with: (A) +PBS ( = 5/group); (B) +BDMPs (1.5 × 10, = 6/group); (C) +Lactadherin (400 μg/kg, = 5/group); (D) ++Lactadherin ( = 6/group). A battery of neurological function tests were performed and mice sacrificed for immunostaining at 14 days after stroke. Blood plasma was used for Western blot assay. Our data indicate: (1) treatment of Stroke with BDMP significantly increases lesion volume, neurological deficits, blood brain barrier (BBB) leakage, microglial activation, inflammatory cell infiltration (CD45, microglia/macrophages, and neutrophils) into brain, inflammatory factor (TNFα, IL6, and IL1β) expression in brain, increases axon/white matter (WM) damage identified by decreased axon and myelin density, and increases inflammatory factor expression in the plasma when compared to PBS treated stroke mice; (2) when compared to PBS and BDMP treated stroke mice, Lactadherin and BDMP+Lactadherin treatment significantly improves neurological outcome, and decreases lesion volume, BBB leakage, axon/WM injury, inflammatory cell infiltration and inflammatory factor expression in the ischemic brain, respectively. Lactadherin treatment significantly increases anti-inflammatory factor (IL10) expression in ischemic brain and decreases IL1β expression in plasma compared to PBS and BDMP treated stroke mice, respectively. BDMP increases neuroinflammation and aggravates ischemic brain damage after stroke. Thus, Lactadherin exerts anti-inflammatory effects and improves the clearance of MPs to reduce stroke and BDMP induced neurological deficits.
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http://dx.doi.org/10.3389/fimmu.2019.02747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968774PMC
November 2020

Spleen associated immune-response mediates brain-heart interaction after intracerebral hemorrhage.

Exp Neurol 2020 05 24;327:113209. Epub 2020 Jan 24.

Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA. Electronic address:

Background And Purpose: Intracerebral hemorrhage (ICH) patients frequently encounter cardiovascular complications which may contribute to increased mortality and poor long term outcome. ICH induces systemic oxidative stress and activates peripheral immune responses which are involved in the pathological cascade leading to cardiac dysfunction and heart failure after ICH. We have previously reported that ICH induces progressive cardiac dysfunction in mice without primary cardiac diseases. In this study, we have investigated the role of immune response in mediating cardiac dysfunction post ICH in mice.

Methods: Adult male C57BL/6 J mice were randomly assigned to the following groups (n = 8/group): 1) sham control; 2) ICH; 3) splenectomy with ICH (ICH + Spx); 4) splenectomy alone (Spx). Echocardiography was performed at 7 and 28 days after ICH. A battery of neurological and cognitive tests were performed. Flow cytometry, western blot and immunostaining were used to test mechanisms of ICH induced cardiac dysfunction.

Results: Compared to sham control mice, Spx alone does not induce acute (7 day) or chronic (28 day) cardiac dysfunction. ICH induces significant neurological and cognitive deficits, as well as acute and chronic cardiac dysfunction compared to sham control mice. Mice subjected to ICH + Spx exhibit significantly improved neurological and cognitive function compared to ICH mice. Mice with ICH + Spx also exhibit significantly improved acute and chronic cardiac function compared to ICH mice indicated by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), decreased cardiac fibrosis, decreased cardiomyocyte hypertrophy, decreased cardiac infiltration of immune cells and decreased expression of inflammatory factor and oxidative stress in the heart.

Conclusions: Our study demonstrates that splenectomy attenuates ICH-induced neurological and cognitive impairment as well as ICH-induced cardiac dysfunction in mice. Inflammatory cell infiltration into heart and immune responses mediated by the spleen may contribute to ICH-induce acute and chronic cardiac dysfunction and pathological cardiac remodeling.
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http://dx.doi.org/10.1016/j.expneurol.2020.113209DOI Listing
May 2020

Brain-kidney interaction: Renal dysfunction following ischemic stroke.

J Cereb Blood Flow Metab 2020 02 25;40(2):246-262. Epub 2019 Nov 25.

Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.

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http://dx.doi.org/10.1177/0271678X19890931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370616PMC
February 2020

ApoA-I Mimetic Peptide Reduces Vascular and White Matter Damage After Stroke in Type-2 Diabetic Mice.

Front Neurosci 2019 25;13:1127. Epub 2019 Oct 25.

Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.

Diabetes leads to an elevated risk of stroke and worse functional outcome compared to the general population. We investigate whether L-4F, an economical ApoA-I mimetic peptide, reduces neurovascular and white-matter damage in db/db type-2 diabetic (T2DM) stroke mice. L-4F (16 mg/kg, subcutaneously administered initially 2 h after stroke and subsequently daily for 4 days) reduced hemorrhagic transformation, decreased infarct-volume and mortality, and treated mice exhibited increased cerebral arteriole diameter and smooth muscle cell number, decreased blood-brain barrier leakage and white-matter damage in the ischemic brain as well as improved neurological functional outcome after stroke compared with vehicle-control T2DM mice ( < 0.05, = 11/group). Moreover, administration of L-4F mitigated macrophage infiltration, and reduced the level of proinflammatory mediators tumor necrosis factor alpha (TNFα), high-mobility group box-1 (HMGB-1)/advanced glycation end-product receptor (RAGE) and plasminogen activator inhibitor-1 (PAI-1) in the ischemic brain in T2DM mice ( < 0.05, = 6/group). , L-4F treatment did not increase capillary-like tube formation in mouse-brain endothelial cells, but increased primary artery explant cell migration derived from C57BL/6-aorta 1 day after middle cerebral artery occlusion (MCAo), and enhanced neurite-outgrowth after 2 h of oxygen-glucose deprivation and axonal-outgrowth in primary cortical neurons derived from the C57BL/6-embryos subjected to high-glucose condition. This study suggests that early treatment with L-4F provides a potential strategy to reduce neuroinflammation and vascular and white-matter damage in the T2DM stroke population.
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http://dx.doi.org/10.3389/fnins.2019.01127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823666PMC
October 2019

Immune response mediates the cardiac damage after subarachnoid hemorrhage.

Exp Neurol 2020 01 30;323:113093. Epub 2019 Oct 30.

Neurology, Henry Ford Hospital, Detroit MI-48202, USA.

Cardiac dysfunction is a common adverse effect of subarachnoid hemorrhage (SAH). Autopsy of SAH patients shows immunocyte infiltration into the heart. In this study, a SAH model of endovascular perforation was performed in adult male mice in order to test whether SAH causes cardiac dysfunction in non-primary cardiac disease young adult male mice and whether immune response mediates SAH induced cardiac and neurological deficit. Splenectomy was performed on a subpopulation of mice one week prior to induction of the SAH. Neurological functional tests, transthoracic Doppler echocardiography, immunofluorescent staining, and flow cytometry were performed to investigate neurological and cardiac function and immune/inflammatory effects of SAH in mice with or without splenectomy. We found that SAH significantly induces ventricular fibrillation and cardiac dysfunction identified by significantly reduced left ventricular ejection fraction, left ventricular fractional shortening, decreased heart rate, as well as increased macrophage and neutrophil infiltration into heart and inflammatory factor expression in the heart compared to sham control mice. SAH also induces neurological deficit, increases astrocyte and microglial activity, and inflammatory cell infiltration into brain as well as up-regulates inflammatory factor expression in the brain tissue. Splenectomy not only significantly improves neurological function, but also reduces cardiac dysfunction compared to SAH alone mice. Splenectomy in SAH mice significantly reduces inflammatory cell infiltration, and decreases NADPH oxidase-2 and macrophage chemokine protein-1 expression in heart and brain when compared to non-splenectomy SAH mice. Our data suggest that, SAH induces acute cardiac dysfunction in non-primary cardiac disease mice. Secondary immune response may play an important role in mediating brain-heart damage after SAH.
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http://dx.doi.org/10.1016/j.expneurol.2019.113093DOI Listing
January 2020

Role of Regulatory T cells in Atorvastatin Induced Absorption of Chronic Subdural Hematoma in Rats.

Aging Dis 2019 Oct 1;10(5):992-1002. Epub 2019 Oct 1.

1Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin, China.

Chronic subdural hematoma (CSDH) is a neurological disorder with a substantial recurrence rate. Atorvastatin is an effective drug for treating hyperlipidemia and known to improve neurological outcome after intracerebral hemorrhage. Previous studies have reported that atorvastatin treatment promotes hematoma absorption in CSDH, while the underlying mechanisms remain unclear. In this study, we investigated whether the anti-inflammatory effects of atorvastatin mediate absorption of CSDH. 144 male, Wistar rats (6 months old) were randomly divided into the following groups: 1) sham surgery control, 2) treatment: CSDH + atorvastatin, and 3) vehicle control: CSDH + saline. Atorvastatin or saline was orally administered daily for 19 days after CSDH procedure. A T2WI MRI was used to evaluate CSDH volume changes during the time course of the study. Flow cytometry and immunohistochemical staining were used to measure the number of regulatory T cells (Treg). ELISA was used to measure cytokine level in the hematoma border. Neurological function and cognitive outcome were evaluated using Foot-Fault test and Morris Water Maze test, respectively. When compared to saline treatment, atorvastatin treatment accelerated the absorption of CSDH as indicated by decreased hematoma volume in T2WI MRI data on 14 and 21 day after CSDH (P<0.05). Atorvastatin treatment significantly increased the number of Treg in circulation and hematoma border from 3 to 21 day after CSDH. Atorvastatin treatment significantly decreased the levels of interleukins (IL-6 and IL-8) and tumor necrosis factor-α (TNF-α), but increased IL-10 level in the hematoma border. Atorvastatin treatment also improved neurological function and cognitive outcome compared to vehicle treated group. Atorvastatin induced anti-inflammatory responses and increased Treg in circulation and brain which may contribute to the accelerated CSDH absorption in rats.
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http://dx.doi.org/10.14336/AD.2018.0926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764728PMC
October 2019

Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice.

Aging Dis 2019 Aug 1;10(4):770-783. Epub 2019 Aug 1.

2Neurology, Henry Ford Hospital, Detroit, MI, USA.

Tissue plasminogen activator (tPA) is a serine protease primarily involved in mediating thrombus breakdown and regulating catabolism of amyloid-beta (Aβ). The aim of this study is to investigate age-dependent decline of endogenous tPA and the effects of tPA decline on glymphatic function and cognitive outcome in mice. Male, young (3m), adult (6m) and middle-aged (12m) C57/BL6 (wild type) and tPA knockout (tPA) mice were subject to a battery of cognitive tests and white matter (WM) integrity, neuroinflammation, and glymphatic function were evaluated. Adult WT mice exhibit significantly decreased brain tPA level compared to young WT mice and middle-aged WT mice have significantly lower brain tPA levels than young and adult WT mice. Middle-aged WT mice exhibit significant neuroinflammation, reduced WM integrity and increased thrombin deposition compared to young and adult mice, and increased blood brain barrier (BBB) permeability and reduced cognitive ability compared to young WT mice. In comparison to adult WT mice, adult tPA mice exhibit significant BBB leakage, decreased dendritic spine density, increased thrombin deposition, neuroinflammation, and impaired functioning of the glymphatic system. Compared to age-matched WT mice, adult and middle-aged tPA mice exhibit significantly increased D-Dimer expression and decreased perivascular Aquaporin-4 expression. Compared to age-matched WT mice, young, adult and middle-aged tPA mice exhibit significant cognitive impairment, axonal damage, and increased deposition of amyloid precursor protein (APP), Aβ, and fibrin. Endogenous tPA may play an important role in contributing to aging induced cognitive decline, axonal/WM damage, BBB disruption and glymphatic dysfunction in the brain.
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http://dx.doi.org/10.14336/AD.2018.0816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675536PMC
August 2019

MiR-126 Mediates Brain Endothelial Cell Exosome Treatment-Induced Neurorestorative Effects After Stroke in Type 2 Diabetes Mellitus Mice.

Stroke 2019 10 9;50(10):2865-2874. Epub 2019 Aug 9.

From the Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., C.C., M.C., A.Z., F.W., J.L.-W., Y.S., J.C.).

Background and Purpose- Stroke patients with type 2 diabetes mellitus (T2DM) exhibit increased vascular and white matter damage and have worse prognosis compared with nondiabetic stroke patients. We investigated the neurorestorative effects of exosomes derived from mouse brain endothelial cells (EC-Exo) as treatment for stroke in T2DM mice and investigated the role of miR-126 in mediating EC-Exo-derived therapeutic benefits in T2DM-stroke mice. Methods- Adult, male BKS.Cg-m+/+Lepr/J (T2DM) mice were subjected to photothrombotic stroke model. T2DM mice were intravenously injected at 3 days after stroke with (1) PBS; (2) liposome mimic (vehicle control, 3×10); (3) EC-Exo (3×10); (4) knockdown of miR-126 in EC-Exo (miR-126 EC-Exo, 3×10). Behavioral and cognitive tests were performed, and mice were sacrificed at 28 days after stroke. Results- Compared with non-DM stroke mice, T2DM-stroke mice exhibit significantly decreased serum and brain tissue miR-126 expression. Endothelial cells and EC-Exo contain high levels of miR-126 compared with other cell types or exosomes derived from other types of cells, respectively (smooth muscle cells, astrocytes, and marrow stromal cells). Compared with PBS or liposome mimic treatment, EC-Exo treatment of T2DM-stroke mice significantly improves neurological and cognitive function, increases axon density, myelin density, vascular density, arterial diameter, as well as induces M2 macrophage polarization in the ischemic boundary zone. MiR-126 EC-Exo treatment significantly decreases miR-126 expression in serum and brain, as well as attentuates EC-Exo treatment-induced functional improvement and does not significantly increase axon and myelin density, vascular density, arterial diameter or induce M2 macrophage polarization in T2DM-stroke mice. In vitro, EC-Exo treatment significantly increases primary cortical neuron axonal outgrowth and increases endothelial capillary tube formation whereas miR-126 EC-Exo attentuates EC-Exo induced capillary tube formation and axonal outgrowth. Conclusions- EC-Exo treatment of stroke promotes neurorestorative effects in T2DM mice. MiR-126 may mediate EC-Exo-induced neurorestorative effects in T2DM mice. Visual Overview- An online visual overview is available for this article.
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http://dx.doi.org/10.1161/STROKEAHA.119.025371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756941PMC
October 2019

RP001 hydrochloride improves neurological outcome after subarachnoid hemorrhage.

J Neurol Sci 2019 Apr 5;399:6-14. Epub 2019 Feb 5.

Neurology, Henry Ford Hospital, Detroit MI-48202, USA. Electronic address:

Subarachnoid hemorrhage (SAH) results in neurological damage, acute cardiac damage and has a high mortality rate. Immunoresponse in the acute phase after SAH plays a key role in mediating vasospasm, edema, inflammation and neuronal damage. The S1P/S1PR pathway impacts multiple cellular functions, exerts anti-inflammatory and anti-apoptotic effects, promotes remyelination, and improves outcome in several central nervous system (CNS) diseases. RP001 hydrochloride is a novel S1PR agonist, which sequesters lymphocytes within their secondary tissues and prevents infiltration of immune cells into the CNS thereby reducing immune response. In this study, we investigated whether RP001 attenuates neuronal injury after SAH by reducing inflammation. S1PRs, specifically S1PR not only exerts anti-inflammatory effects, but also decreases heart rate and induces atrioventricular conduction abnormalities. Therefore, we also tested whether RP001 treatment of SAH regulates cardiac functional outcome. Male adult C57BL/6 mice were subjected to SAH, and neurological function tests, echocardiography, and immunohistochemical analysis were performed. SAH induces neurological deficits and acute cardiac dysfunction compared to sham control mice. Treatment of SAH with a low-dose of RP001 induces better neurological outcome and cardiac function compared to a high-dose of RP001. Low-dose-RP001 treatment significantly decreases apoptosis, white matter damage, blood brain barrier permeability, microglial/astrocyte activation, macrophage chemokine protein-1, matrix metalloproteinase-9 and NADPH oxidase-2 expression in the brain compared to SAH control mice. Our findings indicate that low-dose of RP001 alleviates neurological damage after SAH, in part by decreasing neuroinflammation.
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http://dx.doi.org/10.1016/j.jns.2019.02.005DOI Listing
April 2019

Sildenafil treatment of vascular dementia in aged rats.

Neurochem Int 2019 07 25;127:103-112. Epub 2018 Dec 25.

Department of Neurology, Henry Ford Hospital, Detroit, MI, 48202, USA. Electronic address:

Background: and purpose: In this study, we employed a multiple microinfarction (MMI) based vascular dementia (VaD) model in aged rats and tested the therapeutic effects of Sildenafil, a phosphodiesterase type 5 inhibitor, on cognitive decline, white matter damage, autophagy and inflammatory response associated with VaD.

Methods: Male, aged (16-18 months) Wistar rats were subjected to MMI (800 ± 100, 70-100 μm cholesterol crystals injected into the internal carotid artery) and treated with or without Sildenafil (2 mg/kg, i.p) starting at 24 h after MMI daily for 28 days. Four experimental groups were employed: Sham control, Sham + Sildenafil, MMI, and MMI + Sildenafil. A battery of cognitive tests were performed and rats were sacrificed at 28 days after MMI for immunohistochemical evaluation and PCR assay.

Results: Sildenafil treatment in aged MMI rats significantly improves short term memory evaluated by the novel object recognition test and improves spatial learning and memory in the Morris water maze test compared to aged control MMI rats. Sildenafil treatment of aged MMI rats significantly increases axon and myelin density in the corpus callosum and white matter bundles in the striatum, increases oligodendrocyte and oligodendrocyte progenitor cell number in the corpus callosum, cortex and striatum, and increases synaptic protein expression in the cortex and striatum compared to aged control MMI rats. In addition, Sildenafil treatment of MMI in aged rats significantly decreases Beclin1 expression and inflammatory factors Monocyte chemoattractant protein-1 and Interleukin-1β expression in brain. Sildenafil treatment in aged rats does not improve cognitive outcome compared to aged sham control rats.

Conclusions: Sildenafil treatment of MMI in aged rats significantly improves cognition and memory at 1 month after MMI. Sildenafil treatment increases axon and myelin density, increases Synaptophysin expression, decreases autophagic activity and exerts anti-inflammatory effects which in concert may contribute to cognitive improvement in aged rats subjected to MMI.
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http://dx.doi.org/10.1016/j.neuint.2018.12.015DOI Listing
July 2019

Intracerebral Hemorrhage Induces Cardiac Dysfunction in Mice Without Primary Cardiac Disease.

Front Neurol 2018 20;9:965. Epub 2018 Nov 20.

Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.

Intracerebral hemorrhage (ICH) is a life threatening stroke subtype and a worldwide health problem. In this study, we investigate brain-heart interaction after ICH in mice and test whether ICH induces cardiac dysfunction in the absence of primary cardiac disease. We also investigate underlying mechanisms such as oxidative stress and inflammatory responses in mediating cardiac dysfunction post-ICH in mice. Male, adult (3-4 m) C57BL/6J mice were subjected to sham surgery or ICH using an autologous blood injection model ( = 16/group). Cardiac function was evaluated at 7 and 28 days after ICH using echocardiography ( = 8/group per time point). Western blot and immunostaining analysis were employed to assess oxidative stress and inflammatory responses in the heart. Mice subjected to ICH exhibited significantly decreased cardiac contractile function measured by left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) at 7 and 28 days after ICH compared to sham-control mice ( < 0.05). ICH induced cardiac dysfunction was significantly worse at 28 days than at 7 days after ICH ( < 0.05). ICH in mice significantly increased cardiomyocyte apoptosis, inflammatory factor expression and inflammatory cell infiltration in heart tissue, and induced cardiac oxidative stress at 7 days post-ICH compared to sham-control mice. Compared to sham-control mice, ICH-mice also exhibited significantly increased ( < 0.05) cardiomyocyte hypertrophy and cardiac fibrosis at 28 days after ICH. ICH induces significant and progressive cardiac dysfunction in mice. ICH increases cardiac oxidative stress and inflammatory factor expression in heart tissue which may play key roles in ICH-induced cardiac dysfunction.
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http://dx.doi.org/10.3389/fneur.2018.00965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256175PMC
November 2018

Inflammatory responses mediate brain-heart interaction after ischemic stroke in adult mice.

J Cereb Blood Flow Metab 2020 06 22;40(6):1213-1229. Epub 2018 Nov 22.

Neurology, Henry Ford Hospital, Detroit, MI, USA.

Stroke induces cardiac dysfunction which increases post stroke mortality and morbidity particularly in aging population. Here, we investigated the effects of inflammatory responses as underlying mediators of cardiac dysfunction after stroke in adult mice. Adult (eight-to-nine months) male C57BL/6 mice were subjected to photothrombotic stroke. To test whether immunoresponse to stroke leads to cardiac dysfunction, splenectomy was performed with stroke. Immunohistochemistry, flow cytometry, PCR, ELISA and echocardiography were performed. We found marginal cardiac dysfunction at acute phase and significant cardiac dysfunction at chronic phase of stroke as indicated by significant decrease of left ventricular ejection fraction (LVEF) and shortening fraction (LVSF). Stroke significantly increases macrophage infiltration into the heart and increases IL-1β, IL-6, MCP-1, TGF-β and macrophage-associated inflammatory cytokine levels in the heart as well as induces cardiac-fibrosis and hypertrophy. Splenectomy with stroke significantly reduces macrophage infiltration into heart, decreases inflammatory factor expression in the heart, decreases cardiac hypertrophy and fibrosis, as well as significantly improves cardiac function compared to non-splenectomized adult stroke mice. Therefore, cerebral ischemic stroke in adult mice induces chronic cardiac dysfunction and secondary immune response may contribute to post stroke cardiac dysfunction.
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http://dx.doi.org/10.1177/0271678X18813317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238382PMC
June 2020

Administration of Downstream ApoE Attenuates the Adverse Effect of Brain ABCA1 Deficiency on Stroke.

Int J Mol Sci 2018 Oct 28;19(11). Epub 2018 Oct 28.

Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.

The ATP-binding cassette transporter member A1 (ABCA1) and apolipoprotein E (ApoE) are major cholesterol transporters that play important roles in cholesterol homeostasis in the brain. Previous research demonstrated that specific deletion of brain-ABCA1 (ABCA1) reduced brain grey matter (GM) and white matter (WM) density in the ischemic brain and decreased functional outcomes after stroke. However, the downstream molecular mechanism underlying brain ABCA1-deficiency-induced deficits after stroke is not fully understood. Adult male ABCA1 and ABCA1-floxed control mice were subjected to distal middle-cerebral artery occlusion and were intraventricularly infused with artificial mouse cerebrospinal fluid as vehicle control or recombinant human ApoE2 into the ischemic brain starting 24 h after stroke for 14 days. The ApoE/apolipoprotein E receptor 2 (ApoER2)/high-density lipoprotein (HDL) levels and GM/WM remodeling and functional outcome were measured. Although ApoE2 increased brain ApoE/HDL levels and GM/WM density, negligible functional improvement was observed in ABCA1-floxed-stroke mice. ApoE2-administered ABCA1 stroke mice exhibited elevated levels of brain ApoE/ApoER2/HDL, increased GM/WM density, and neurogenesis in both the ischemic ipsilateral and contralateral brain, as well as improved neurological function compared with the vehicle-control ABCA1 stroke mice 14 days after stroke. Ischemic lesion volume was not significantly different between the two groups. In vitro supplementation of ApoE2 into primary cortical neurons and primary oligodendrocyte-progenitor cells (OPCs) significantly increased ApoER2 expression and enhanced cholesterol uptake. ApoE2 promoted neurite outgrowth after oxygen-glucose deprivation and axonal outgrowth of neurons, and increased proliferation/survival of OPCs derived from ABCA1 mice. Our data indicate that administration of ApoE2 minimizes the adverse effects of ABCA1 deficiency after stroke, at least partially by promoting cholesterol traffic/redistribution and GM/WM remodeling via increasing the ApoE/HDL/ApoER2 signaling pathway.
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http://dx.doi.org/10.3390/ijms19113368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274914PMC
October 2018

Role of microRNA-126 in vascular cognitive impairment in mice.

J Cereb Blood Flow Metab 2019 12 14;39(12):2497-2511. Epub 2018 Sep 14.

Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.

Vascular dementia (VaD) affects cognition and memory. MicroRNA-126 (miR-126) is an angiogenic microRNA that regulates vascular function. In this study, we employ a multiple microinfarction (MMI) model to induce VaD in mice, and investigate VaD-induced cognitive dysfunction, white matter (WM) damage, glymphatic dysfunction and the role of miR-126 in mediating these effects. Male six-to eight-months old C57/BL6 mice (WT) were subject to MMI model, and cerebral blood flow (CBF), vessel patency, glymphatic function, cognitive function, and serum miR-126 expression were measured. Mice were sacrificed at 28 days after MMI. To investigate the role of miR-126 in VaD, cognitive function, water channel integrity and glymphatic function were assessed in male, six-to eight months old conditional-knockout endothelial cell miR-126 (miR-126), and control (miR-126) mice. MMI in WT mice induces significant cognitive deficits, decreases CBF and vessel patency; evokes astrocytic and microglial activation, increases inflammation, axonal/WM damage; decreases synaptic plasticity and dendritic spine density, instigates water channel and glymphatic dysfunction, and decreases serum miR-126 expression. MiR-126 mice exhibit significant cognitive impairment, decreased CBF, myelin density and axon density, increased inflammation, and significant water channel and glymphatic dysfunction compared to miR-126 mice. Reduction of endothelial miR-126 expression may mediate cognitive impairment in MMI-induced VaD.
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http://dx.doi.org/10.1177/0271678X18800593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893975PMC
December 2019

Angiopoietin-1 Mimetic Peptide Promotes Neuroprotection after Stroke in Type 1 Diabetic Rats.

Cell Transplant 2018 12 20;27(12):1744-1752. Epub 2018 Aug 20.

1 Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.

Angiopoietin-1 (Ang1) mediates vascular maturation and immune response. Diabetes decreases Ang1 expression and disrupts Ang1/Tie2 signaling activity. Vasculotide is an Ang1 mimetic peptide, and has anti-inflammatory effects. In this study, we test the hypothesis that vasculotide treatment induces neuroprotection and decreases inflammation after stroke in type 1 diabetic (T1DM) rats. T1DM rats were subjected to embolic middle cerebral artery occlusion (MCAo) and treated with: 1) phosphate buffered saline (PBS); 2) vasculotide (3µg/kg, i.p. injection) administered half an hour prior to MCAo and at 8 and 24 hours after MCAo. Rats were sacrificed at 48 h after MCAo. Neurological function, infarct volume, hemorrhage, blood brain barrier (BBB) permeability and neuroinflammation were measured. Vasculotide treatment of T1DM-MCAo rats significantly improves functional outcome, decreases infarct volume and BBB permeability, but does not decrease brain hemorrhagic transformation compared with PBS-treated T1DM-MCAo rats. In the ischemic brain, Vasculotide treatment significantly decreases apoptosis, number of cleaved-caspase-3 positive cells, the expression of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF-α). Western blot analysis shows that vasculotide significantly decreases expression of receptor for advanced glycation end products (RAGE), MCP-1 and TNF-α in the ischemic brain compared with T1DM-MCAo rats. Vasculotide treatment in cultured primary cortical neurons (PCN) significantly decreases TLR4 expression compared with control. Decreased neuroinflammation and reduced BBB leakage may contribute, at least in part, to vasculotide-induced neuroprotective effects after stroke in T1DM rats.
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http://dx.doi.org/10.1177/0963689718791568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300775PMC
December 2018

Immune Response Mediates Cardiac Dysfunction after Traumatic Brain Injury.

J Neurotrauma 2019 02 4;36(4):619-629. Epub 2018 Sep 4.

3 Department of Neurology, Henry Ford Hospital , Detroit, Michigan.

Cardiovascular complications are common after traumatic brain injury (TBI) and are associated with increased morbidity and mortality. In this study, we investigated the possible role of the immune system in mediating cardiac dysfunction post-TBI in mice. Adult male C57BL/6J mice were subjected to a TBI model of controlled cortical impact (CCI) with or without splenectomy (n = 20/group). Splenectomy was performed immediately prior to induction of TBI. Cardiac function was measured using echocardiography prior to and after TBI. Neurological and cognitive functional tests and flow cytometry and immunostaining were performed. TBI mice exhibited significant cardiac dysfunction identified by decreased left ventricular ejection fraction and fractional shortening at 3 and 30 days post-TBI. In addition, these mice exhibited significantly increased cardiomyocyte apoptosis, inflammation, and oxidative stress at 3 and 30 days post-TBI, as well as cardiac hypertrophy and fibrosis and ventricular dilatation at 30 days after TBI. TBI mice subjected to splenectomy showed significantly improved cardiac function, and decreased cardiac fibrosis, oxidative stress, cardiomyocyte apoptosis, and infiltration of immune cells and inflammatory factor expression in the heart compared with TBI control mice. TBI mice exhibited severe neurological and cognitive function deficits. However, splenectomy did not improve neurological and cognitive functional outcome after TBI compared with the TBI control group. TBI induces immune cell infiltration and inflammatory factor expression in the heart as well as cardiac dysfunction. Splenectomy decreases heart inflammation and improves cardiac function after TBI. Immune response may contribute to TBI-induced cardiac dysfunction.
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http://dx.doi.org/10.1089/neu.2018.5766DOI Listing
February 2019

APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats.

Aging Dis 2018 Jun 1;9(3):453-466. Epub 2018 Jun 1.

2Department of Neurology, Henry Ford hospital, Detroit, MI, USA.

APX3330 is a selective inhibitor of APE1/Ref-1 redox activity. In this study, we investigate the therapeutic effects and underlying mechanisms of APX3330 treatment in type one diabetes mellitus (T1DM) stroke rats. Adult male Wistar rats were induced with T1DM and subjected to transient middle cerebral artery occlusion (MCAo) and treated with either PBS or APX3330 (10mg/kg, oral gavage) starting at 24h after MCAo, and daily for 14 days. Rats were sacrificed at 14 days after MCAo and, blood brain barrier (BBB) permeability, ischemic lesion volume, immunohistochemistry, cell death assay, Western blot, real time PCR, and angiogenic ELISA array were performed. Compared to PBS treatment, APX3330 treatment of stroke in T1DM rats significantly improves neurological functional outcome, decreases lesion volume, and improves BBB integrity as well as decreases total vessel density and VEGF expression, while significantly increases arterial density in the ischemic border zone (IBZ). APX3330 significantly increases myelin density, oligodendrocyte number, oligodendrocyte progenitor cell number, synaptic protein expression, and induces M2 macrophage polarization in the IBZ of T1DM stroke rats. Compared to PBS treatment, APX3330 treatment significantly decreases plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 and matrix metalloproteinase 9 (MMP9) and receptor for advanced glycation endproducts expression in the ischemic brain of T1DM stroke rats. APX3330 treatment significantly decreases cell death and MMP9 and PAI-1 gene expression in cultured primary cortical neurons subjected to high glucose and oxygen glucose deprivation, compared to untreated control cells. APX3330 treatment increases M2 macrophage polarization and decreases inflammatory factor expression in the ischemic brain as well as promotes neuroprotective and neurorestorative effects after stroke in T1DM rats.
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http://dx.doi.org/10.14336/AD.2017.1130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988600PMC
June 2018

Exosome-mediated amplification of endogenous brain repair mechanisms and brain and systemic organ interaction in modulating neurological outcome after stroke.

J Cereb Blood Flow Metab 2018 12 11;38(12):2165-2178. Epub 2018 Jun 11.

1 Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.

Ischemic stroke is caused by a regional interruption of cerebral blood flow to the brain. Rigorous pre-clinical and clinical research has made landmark progress in stroke treatment using thrombolytics and endovascular thrombectomy. Although numerous successful neuroprotective therapeutic agents for ischemic stroke have been reported in pre-clinical studies, most of them failed in clinical testing. Persistent pre-clinical research has demonstrated that the ischemic brain is not only passively dying but is also actively recovering. Within the neurovascular niche in the peri-infarct tissue, repair mechanisms thrive on the interactions between the neural and vascular compartments. In this review, we discuss exogenous therapy using mesenchymal stromal cell-derived exosomes to amplify endogenous brain repair mechanisms and to induce neurorestorative effects after stroke. Emerging evidence indicates that multiple communication axes between the various organs such as the brain, heart, kidney and gut, and whole body immune response mediated by the spleen can also affect stroke outcome. Therefore, in this review, we summarize this evidence and initiate a discussion on the potential to improve stroke outcome by amplifying multiple brain repair mechanisms after stroke, and by targeting peripheral organs and downstream events to enhance recovery in the injured brain and promote over all well being.
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http://dx.doi.org/10.1177/0271678X18782789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282218PMC
December 2018

Exosome Therapy for Stroke.

Stroke 2018 05 18;49(5):1083-1090. Epub 2018 Apr 18.

From the Department of Neurology, Henry Ford Hospital, Detroit, MI (J.C., M.C.)

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http://dx.doi.org/10.1161/STROKEAHA.117.018292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028936PMC
May 2018

Cell-Based and Exosome Therapy in Diabetic Stroke.

Stem Cells Transl Med 2018 06 2;7(6):451-455. Epub 2018 Mar 2.

Neurology Henry Ford Hospital, Detroit, Michigan, USA.

Stroke is a global health concern and it is imperative that therapeutic strategies with wide treatment time frames be developed to improve neurological outcome in patients. Patients with diabetes mellitus who suffer a stroke have worse neurological outcomes and long-term functional recovery than nondiabetic stroke patients. Diabetes induced vascular damage and enhanced inflammatory milieu likely contributes to worse post stroke outcomes. Diabetic stroke patients have an aggravated pathological cascade, and treatments that benefit nondiabetic stroke patients do not necessarily translate to diabetic stroke patients. Therefore, there is a critical need to develop therapeutics for stroke specifically in the diabetic population. Stem cell based therapy for stroke is an emerging treatment option with wide therapeutic time window. Cell-based therapies for stroke promote endogenous central nervous system repair and neurorestorative mechanisms such as angiogenesis, neurogenesis, vascular remodeling, white matter remodeling, and also modulate inflammatory and immune responses at the local and systemic level. Emerging evidence suggests that exosomes and their cargo microRNA mediate cell therapy derived neurorestorative effects. Exosomes are small vesicles containing protein and RNA characteristic of its parent cell. Exosomes are transported by biological fluids and facilitate communication between neighboring and remote cells. MicroRNAs, a class of naturally occurring, small noncoding RNA sequences, contained within exosomes can regulate recipient cell's signaling pathways and alter protein expression either acting alone or in concert with other microRNAs. In this perspective article, we summarize current knowledge and highlight the promising future of cell based and exosome therapy for stroke and specifically for diabetic stroke. Stem Cells Translational Medicine 2018;7:451-455.
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http://dx.doi.org/10.1002/sctm.18-0014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980126PMC
June 2018

Generation and functional characterization of a conditional Pumilio2 null allele.

J Biomed Res 2018 Nov;32(5):434-441

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.

The highly conserved RNA binding protein PUF (Pumilio/FBF) family is present throughout eukaryotes from yeast to mammals, with critical roles in development, fertility and the nervous system. However, the function of the mammalian PUF family members remains underexplored. Our previous study reported that a gene-trap mutation of Pum2 results in a smaller testis but does not impact fertility and viability. Although the gene-trap mutation disrupted the key functional domain of PUM protein-PUM-HD (Pumilio homology domain), but still produced a chimeric Pum2-β-geo protein containing part of PUM2, raising a question if such a chimeric protein may provide any residual function or contribute to the reproductive phenotype. Here, we report the generation of a conditional PUM2 allele, when knocked out, producing no residual PUM2 and hence a complete loss-of-function allele. We also uncovered small but significant reduction of male fertility and viability in the mutants, suggesting requirement of PUM2 for male fertility and viability.
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http://dx.doi.org/10.7555/JBR.32.20170117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283824PMC
November 2018
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