Publications by authors named "Poornima Venkat"

41 Publications

Exosome treatment for stroke with diabetic comorbidity.

Neural Regen Res 2022 Feb;17(2):315-317

Department of Neurology, Henry Ford Hospital, Detroit; Department of Physics, Oakland University, Rochester, MI, USA.

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http://dx.doi.org/10.4103/1673-5374.319190DOI Listing
February 2022

Cardiac Dysfunction in a Mouse Vascular Dementia Model of Bilateral Common Carotid Artery Stenosis.

Front Cardiovasc Med 2021 11;8:681572. Epub 2021 Jun 11.

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

Cardiac function is associated with cognitive function. Previously, we found that stroke and traumatic brain injury evoke cardiac dysfunction in mice. In this study, we investigate whether bilateral common carotid artery stenosis (BCAS), a model that induces vascular dementia (VaD) in mice, induces cardiac dysfunction. Late-adult (6-8 months) C57BL/6J mice were subjected to sham surgery ( = 6) or BCAS ( = 8). BCAS was performed by applying microcoils (0.16 mm internal diameter) around both common carotid arteries. Cerebral blood flow and cognitive function tests were performed 21-28 days post-BCAS. Echocardiography was conducted in conscious mice 29 days after BCAS. Mice were sacrificed 30 days after BCAS. Heart tissues were isolated for immunohistochemical evaluation and real-time PCR assay. Compared to sham mice, BCAS in mice significantly induced cerebral hypoperfusion and cognitive dysfunction, increased cardiac hypertrophy, as indicated by the increased heart weight and the ratio of heart weight/body weight, and induced cardiac dysfunction and left ventricular (LV) enlargement, indicated by a decreased LV ejection fraction (LVEF) and LV fractional shortening (LVFS), increased LV dimension (LVD), and increased LV mass. Cognitive deficits significantly correlated with cardiac deficits. BCAS mice also exhibited significantly increased cardiac fibrosis, increased oxidative stress, as indicated by 4-hydroxynonenal and NADPH oxidase-2, increased leukocyte and macrophage infiltration into the heart, and increased cardiac interleukin-6 and thrombin gene expression. BCAS in mice without primary cardiac disease provokes cardiac dysfunction, which, in part, may be mediated by increased inflammation and oxidative stress.
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http://dx.doi.org/10.3389/fcvm.2021.681572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225957PMC
June 2021

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

Treatment with an Angiopoietin-1 mimetic peptide promotes neurological recovery after stroke in diabetic rats.

CNS Neurosci Ther 2021 01 21;27(1):48-59. Epub 2020 Dec 21.

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

Aim: Vasculotide (VT), an angiopoietin-1 mimetic peptide, exerts neuroprotective effects in type one diabetic (T1DM) rats subjected to ischemic stroke. In this study, we investigated whether delayed VT treatment improves long-term neurological outcome after stroke in T1DM rats.

Methods: Male Wistar rats were induced with T1DM, subjected to middle cerebral artery occlusion (MCAo) model of stroke, and treated with PBS (control), 2 µg/kg VT, 3 µg/kg VT, or 5.5 µg/kg VT. VT treatment was initiated at 24 h after stroke and administered daily (i.p) for 14 days. We evaluated neurological function, lesion volume, vascular and white matter remodeling, and inflammation in the ischemic brain. In vitro, we evaluated the effects of VT on endothelial cell capillary tube formation and inflammatory responses of primary cortical neurons (PCN) and macrophages.

Results: Treatment of T1DM-stroke with 3 µg/kg VT but not 2 µg/kg or 5.5 µg/kg significantly improves neurological function and decreases infarct volume and cell death compared to control T1DM-stroke rats. Thus, 3 µg/kg VT dose was employed in all subsequent in vivo analysis. VT treatment significantly increases axon and myelin density, decreases demyelination, decreases white matter injury, increases number of oligodendrocytes, and increases vascular density in the ischemic border zone of T1DM stroke rats. VT treatment significantly decreases MMP9 expression and decreases the number of M1 macrophages in the ischemic brain of T1DM-stroke rats. In vitro, VT treatment significantly decreases endothelial cell death and decreases MCP-1, endothelin-1, and VEGF expression under high glucose (HG) and ischemic conditions and significantly increases capillary tube formation under HG conditions when compared to non-treated control group. VT treatment significantly decreases inflammatory factor expression such as MMP9 and MCP-1 in macrophages subjected to LPS activation and significantly decreases IL-1β and MMP9 expression in PCN subjected to ischemia under HG conditions.

Conclusion: Delayed VT treatment (24 h after stroke) significantly improves neurological function, promotes vascular and white matter remodeling, and decreases inflammation in the ischemic brain after stroke in T1DM rats.
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http://dx.doi.org/10.1111/cns.13541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804913PMC
January 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

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

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

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

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

D-4F increases microRNA-124a and reduces neuroinflammation in diabetic stroke rats.

Oncotarget 2017 Nov 8;8(56):95481-95494. Epub 2017 Sep 8.

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

D-4F is an apolipoprotein-A1 mimetic peptide that promotes anti-inflammatory effects. MicroRNA-124 is the most abundant brain-specific microRNA and has anti-inflammatory effects. In this study, we investigated the therapeutic efficacy and mechanisms of D-4F treatment of stroke in type one diabetes mellitus (T1DM) rats. Male Wistar rats were induced with T1DM, subjected to embolic middle cerebral artery occlusion and treated with PBS or D-4F (1 mg/kg i.p.) at 2, 24 and 48 hours after stroke (n=8/group). A battery of function tests, brain blood barrier (BBB) integrity, white matter changes and microRNA expression were evaluated and . D-4F treatment in T1DM-stroke rats significantly improves functional outcome, decreases BBB leakage, increases tight junction protein expression, decreases white matter damage and inflammatory factor expression, while increasing anti-inflammatory M2 macrophage polarization in the ischemic brain. D-4F significantly increases microRNA-124a expression, and decreases matrix metalloproteinase-9, tumor necrosis factor-α and toll-like receptor-4 gene expression in the ischemic brain, and in primary cortical neuronal and microglial cultures. Inhibition of microRNA-124 in cultured primary cortical neurons and microglia attenuates D-4F induced anti-inflammatory effects and M2 macrophage polarization. D-4F treatment of T1DM-stroke increases microRNA-124 expression, promotes anti-inflammatory effects and M2 macrophage polarization, which may contribute to D-4F-induced improvement in neurological function, and BBB and white matter integrity.
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http://dx.doi.org/10.18632/oncotarget.20751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707036PMC
November 2017

Cell-based and pharmacological neurorestorative therapies for ischemic stroke.

Neuropharmacology 2018 05 1;134(Pt B):310-322. Epub 2017 Sep 1.

Department of Neurology, Henry Ford Hospital, Detroit, MI, 48202, USA; Gerontology Institute, Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, 300052, China. Electronic address:

Ischemic stroke remains one of most common causes of death and disability worldwide. Stroke triggers a cascade of events leading to rapid neuronal damage and death. Neuroprotective agents that showed promise in preclinical experiments have failed to translate to the clinic. Even after decades of research, tPA remains the only FDA approved drug for stroke treatment. However, tPA is effective when administered 3-4.5 h after stroke onset and the vast majority of stroke patients do not receive tPA therapy. Therefore, there is a pressing need for novel therapies for ischemic stroke. Since stroke induces rapid cell damage and death, neuroprotective strategies that aim to salvage or replace injured brain tissue are challenged by treatment time frames. To overcome the barriers of neuroprotective therapies, there is an increasing focus on neurorestorative therapies for stroke. In this review article, we provide an update on neurorestorative treatments for stroke using cell therapy such as bone marrow derived mesenchymal stromal cells (BMSCs), human umbilical cord blood cells (HUCBCs) and select pharmacological approaches including Minocycline and Candesartan that have been employed in clinical trials. This review article discusses the present understanding of mechanisms of neurorestorative therapies and summarizes ongoing clinical trials. This article is part of the Special Issue entitled 'Cerebral Ischemia'.
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http://dx.doi.org/10.1016/j.neuropharm.2017.08.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832535PMC
May 2018

Brain-Heart Interaction: Cardiac Complications After Stroke.

Circ Res 2017 Aug;121(4):451-468

From the Gerontology and Neurological Institute, Tianjin Medical University General Hospital, China (Z.C., T.Y., J.C.); Department of Neurology, Henry Ford Hospital, Detroit, MI (P.V., D.S., M.C., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).

Neurocardiology is an emerging specialty that addresses the interaction between the brain and the heart, that is, the effects of cardiac injury on the brain and the effects of brain injury on the heart. This review article focuses on cardiac dysfunction in the setting of stroke such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage. The majority of post-stroke deaths are attributed to neurological damage, and cardiovascular complications are the second leading cause of post-stroke mortality. Accumulating clinical and experimental evidence suggests a causal relationship between brain damage and heart dysfunction. Thus, it is important to determine whether cardiac dysfunction is triggered by stroke, is an unrelated complication, or is the underlying cause of stroke. Stroke-induced cardiac damage may lead to fatality or potentially lifelong cardiac problems (such as heart failure), or to mild and recoverable damage such as neurogenic stress cardiomyopathy and Takotsubo cardiomyopathy. The role of location and lateralization of brain lesions after stroke in brain-heart interaction; clinical biomarkers and manifestations of cardiac complications; and underlying mechanisms of brain-heart interaction after stroke, such as the hypothalamic-pituitary-adrenal axis; catecholamine surge; sympathetic and parasympathetic regulation; microvesicles; microRNAs; gut microbiome, immunoresponse, and systemic inflammation, are discussed.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.311170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553569PMC
August 2017

Blood-Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke.

J Am Heart Assoc 2017 06 1;6(6). Epub 2017 Jun 1.

Department of Neurology Research, Henry Ford Hospital, Detroit, MI

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http://dx.doi.org/10.1161/JAHA.117.005819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669184PMC
June 2017

MiR-126 Affects Brain-Heart Interaction after Cerebral Ischemic Stroke.

Transl Stroke Res 2017 08 19;8(4):374-385. Epub 2017 Jan 19.

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

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-126), and miR-126 knockout control (miR-126) 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-126 mice exhibited significantly decreased cardiac function and increased cardiomyocyte hypertrophy, fibrosis, and inflammatory factor expression after stroke compared to miR-126 stroke mice. Exosomes derived from endothelial cells of miR-126 (miR-126EC-Exo) mice exhibited significantly decreased miR-126 expression than exosomes derived from miR-126 (miR-126-EC-Exo) mice. Treatment of cardiomyocytes subjected to oxygen glucose deprivation with miR-126-EC-Exo exhibited significantly decreased hypertrophy than with miR-126EC-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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http://dx.doi.org/10.1007/s12975-017-0520-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604242PMC
August 2017

ABCA1/ApoE/HDL Pathway Mediates GW3965-Induced Neurorestoration After Stroke.

Stroke 2017 02 27;48(2):459-467. Epub 2016 Dec 27.

From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).

Background And Purpose: ATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke.

Methods: Middle-aged male specific brain ABCA1-deficient (ABCA1) and floxed-control (ABCA1) mice were subjected to distal middle-cerebral artery occlusion (dMCAo) and gavaged with saline or GW3965 (10 mg/kg) or intracerebral infusion of artificial cerebrospinal fluid or human plasma HDL3 in ABCA1 stroke mice, starting 24 hours after dMCAo and daily until euthanization 14 days after dMCAo.

Results: No differences in the blood level of total cholesterol and triglyceride and lesion volume were found among the groups. Compared with ABCA1 ischemic mice, ABCA1 ischemic mice exhibited impairment functional outcome and decreased ABCA1/ApoE expression and decreased gray/white matter densities in the ischemic boundary zone 14 days after dMCAo. GW3965 treatment of ABCA1 ischemic mice led to increased brain ABCA1/ApoE expression, concomitantly to increased blood HDL, gray/white matter densities and oligodendrocyte progenitor cell numbers in the ischemic boundary zone, as well as improved functional outcome 14 days after dMCAo. GW3965 treatment had negligible beneficial effects in ABCA1 ischemic mice. However, intracerebral infusion of human plasma HDL3 significantly attenuated ABCA1-induced deficits. In vitro, GW3965 treatment (5 μM) increased ABCA1/synaptophysin level and neurite/axonal outgrowth in primary cortical neurons derived from ABCA1 embryos, but not in neurons derived from ABCA1 embryos. HDL treatment (80 μg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1 embryos.

Conclusions: ABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke.
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http://dx.doi.org/10.1161/STROKEAHA.116.015592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263181PMC
February 2017
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