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

Venkat, Poornima; Yan, Tao; Chopp, Michael; Zacharek, Alex; Ning, Ruizhuo; Slyke, Paul Van; Dumont, Daniel; Landschoot-Ward, Julie; Liu, Liang; Chen, Jieli

doi:10.1177/0963689718791568

Cited by 32 publications

(44 citation statements)

References 52 publications

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“…CCL2 is a pro-inflammatory chemokine that plays an important role in inflammatory reactions under various neurological conditions, such as stroke, Alzheimer’s disease, and multiple sclerosis [ 17 ]. CCL2 is constitutively present in the normal brain and within neurons, astrocytes, and endothelial cells; however, it is upregulated during a stroke [ 17 , 18 , 19 ]. Increases in CCL2 level induce the recruitment of various inflammatory cells to the brain and disruption of the BBB after stroke [ 10 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke

Lee

Jung

et al. 2020

IJMS

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Although intravenous administration of mesenchymal stem cells (MSCs) is effective for experimental stroke, low engraftment and the limited functional capacity of transplanted cells are critical hurdles for clinical applications. C–C motif chemokine ligand 2 (CCL2) is associated with neurological repair after stroke and delivery of various cells into the brain via CCL2/CCR2 (CCL2 receptor) interaction. In this study, after CCL2-overexpressing human umbilical cord-derived MSCs (hUC-MSCs) were intravenously transplanted with mannitol in rats with middle cerebral arterial occlusion, we compared the differences between four different treatment groups: mannitol + CCL2-overexpressing hUC-MSCs (CCL2-MSC), mannitol + naïve hUC-MSCs (M-MSC), mannitol only, and control. At four-weeks post-transplantation, the CCL2-MSC group showed significantly better functional recovery and smaller stroke volume relative to the other groups. Additionally, we observed upregulated levels of CCR2 in acute ischemic brain and the increase of migrated stem cells into these areas in the CCL2-MSC group relative to the M-MSC. Moreover, the CCL2-MSC group displayed increased angiogenesis and endogenous neurogenesis, decreased neuro-inflammation but with increased healing-process inflammatory cells relative to other groups. These findings indicated that CCL2-overexpressing hUC-MSCs showed better functional recovery relative to naïve hUC-MSCs according to the increased migration of these cells into brain areas of higher CCR2 expression, thereby promoting subsequent endogenous brain repair.

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Section: Discussionmentioning

confidence: 99%

Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke

Lee

Jung

et al. 2020

IJMS

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“…A range of studies have found protective effects of ANG-1 on BBB function. Meng et al [92] demonstrated that ANG-1 overexpression reduced BBB leakage, while exogenous ANG-1 or ANG-1 mimetic peptides suppressed BBB damage [93,94], in animal models of focal embolic cerebral ischemia. In subarachnoid hemorrhage rats, the administration of exogenous ANG-1 reduced BBB leakage [95].…”

Section: Regulation Of Bbb Function By Astrocyte-derived Factorsmentioning

confidence: 99%

Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

Michinaga

Kōyama

2019

IJMS

206

143

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The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed.

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“…Recent data in a model of diabetic stroke demonstrates that Vasculotide has neuroprotective properties including protection from BBB breakdown and significant reductions in markers of neuroinflammation [18]. These improvements correlated with increased functioning when assessed by blinded observer for neurological severity score (NSS) [18]. In organs other than the brain, Vasculotide was found to decrease vascular endothelial cell permeability in sepsis, endotoxemia, ionizing radiation damage, tumor cell extravasation, influenza, acute kidney injury, dermatitis, pneumonia and hemorrhagic shock [16,17,[19][20][21][22][23][24][25][26].…”

Section: Ivyspringmentioning

confidence: 99%

Vasculotide restores the blood-brain barrier after focused ultrasound-induced permeability in a mouse model of Alzheimer's disease

Lynch¹,

Heinen²,

Markham-Coultes³

et al. 2021

Int. J. Med. Sci.

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Focused ultrasound (FUS) is used to locally and transiently induce blood-brain barrier (BBB) permeability, allowing targeted drug delivery to the brain. The purpose of the current study is to evaluate the potential of Vasculotide to accelerate the recovery of the BBB following FUS disruption in the TgCRND8 mouse model of amyloidosis, characteristic of Alzheimer's disease (AD). Accelerating the restoration of the BBB post-FUS would represent an additional safety procedure, which could be beneficial for clinical applications. Methods: TgCRND8 mice and their non-transgenic littermates were treated with Vasculotide (250 ng, intraperitoneal) every 48 hours for 3 months. BBB permeability was induced using FUS, in presence of intravenously injected microbubbles, in TgCRND8 and non-transgenic mice, and confirmed at time 0 by MRI enhancement using the contrast agent gadolinium. BBB closure was assessed at 6, 12 and 20 hours by MRI. In a separate cohort of animals, BBB closure was assessed at 24-hours post-FUS using Evans blue injected intravenously and followed by histological evaluation. Results: Chronic Vasculotide administration significantly reduces the ultra-harmonic threshold required for FUS-induced BBB permeability in the TgCRND8 mice. In addition, Vasculotide treatment led to a faster restoration of the BBB following FUS in TgCRND8 mice. BBB closure after FUS is not significantly different between TgCRND8 and non-transgenic mice. BBB permeability was assessed by gadolinium up to 20-hours post-FUS, demonstrating 87% closure in Vasculotide treated TgCRND8 mice, as opposed to 52% in PBS treated TgCRND8 mice, 58% in PBS treated non-transgenic mice, and 74% in Vasculotide treated non-transgenic mice. In both TgCRND8 mice and non-transgenic littermates the BBB was impermeable to Evans blue dye at 24-hours post-FUS. Conclusion: Vasculotide reduces the pressure required for microbubble ultra-harmonic onset for FUS-induced BBB permeability and it accelerates BBB restoration in a mouse model of amyloidosis, suggesting its potential clinical utility to promote vascular health, plasticity and repair in AD.

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

Abstract: Decreased neuroinflammation and reduced BBB leakage may contribute, at least in part, to vasculotide-induced neuroprotective effects after stroke in T1DM rats.

Cited by 32 publications

References 52 publications

Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke

Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke

Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

Vasculotide restores the blood-brain barrier after focused ultrasound-induced permeability in a mouse model of Alzheimer's disease

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