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      The Combination of Human Urinary Kallidinogenase and Mild Hypothermia Protects Adult Rats Against Hypoxic-Ischemic Encephalopathy-Induced Injury by Promoting Angiogenesis and Regeneration

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          Abstract

          Objectives: Human Urinary Kallidinogenase (HUK) is a tissue kallikrein that plays neuroprotective role in ischemic conditions via different mechanisms. Mild hypothermia (MH) is another robust neuroprotectant that reduces mortality but does not profoundly ameliorate the neurological outcome in hypoxic-ischemic encephalopathy (HIE) patients. However, whether the combination of HUK and MH can be used as a promising neuroprotective treatment in HIE is unknown.

          Methods: One-hundred and forty-four adult Wistar rats were randomly divided into five groups: Sham, HIE, HUK, MH and a combination of HUK and MH treatment. The HIE rat model was established by right carotid dissection followed by hypoxia aspiration. The survival curve was created within 7 days, and the neurological severity scores (NSS) were assessed at days 0, 1, 3, and 7. Nissl staining, Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), immunofluorescent staining and western blotting were used to evaluate neuronal survival, apoptosis and necrosis, tight-junction proteins Claudin-1 and Zonula occludens-1 (ZO-1), vascular endothelial growth factor (VEGF), doublecortex (DCX), bradykinin receptor B1 (BDKRB1), BDKRB2 and Ki67 staining.

          Results: The combined treatment rescued all HIE rats from death and had a best survival curve compared to HIE. The Combination also reduced the NSS scores after HIE at days 7, better than HUK or MH alone. The combination of HUK and MH reserved more cells in Nissl staining and inhibited neuronal apoptosis and necrosis as well as significantly attenuated HIE-induced decreases in claudin-1, ZO-1, cyclin D1 and BDKRB1/B2 in comparison to HUK or MH treatment alone. Moreover, the combined treatment increased the expression of VEGF and DCX as well as the number of Ki67-labeled cells.

          Conclusions: This study demonstrates that both HUK and MH are neuroprotective after HIE insult; however, the combined therapy with HUK and MH enhanced the efficiency and efficacy of either therapy alone in the treatment of HIE, at least partially by promoting angiogenesis and regeneration and rescuing tight-junction loss. The combination of HUK and MH seems to be a feasible and promising clinical strategy to alleviate cerebral injury following HIE insult.

          Highlights:

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            The combination of HUK and MH distinctly reduces neurological dysfunction in HIE rats.

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            HUK enhances the neuroprotective effects of MH in HIE.

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            MH attenuates tight-junction disruption, upregulates the BDKR B1/2, DCX and cyclin D1.

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            The combination of MH and HUK enhances the expressions of MH/HUK mediated-BDKR B1/2, DCX, cyclin D1 and Ki67 positive cells.

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          Most cited references 46

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          Doublecortin expression levels in adult brain reflect neurogenesis.

          Progress in the field of neurogenesis is currently limited by the lack of tools enabling fast and quantitative analysis of neurogenesis in the adult brain. Doublecortin (DCX) has recently been used as a marker for neurogenesis. However, it was not clear whether DCX could be used to assess modulations occurring in the rate of neurogenesis in the adult mammalian central nervous system following lesioning or stimulatory factors. Using two paradigms increasing neurogenesis levels (physical activity and epileptic seizures), we demonstrate that quantification of DCX-expressing cells allows for an accurate measurement of modulations in the rate of adult neurogenesis. Importantly, we excluded induction of DCX expression during physiological or reactive gliogenesis and excluded also DCX re-expression during regenerative axonal growth. Our data validate DCX as a reliable and specific marker that reflects levels of adult neurogenesis and its modulation. We demonstrate that DCX is a valuable alternative to techniques currently used to measure the levels of neurogenesis. Importantly, in contrast to conventional techniques, analysis of neurogenesis through the detection of DCX does not require in vivo labelling of proliferating cells, thereby opening new avenues for the study of human neurogenesis under normal and pathological conditions.
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            Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain.

            Formation of cerebral oedema caused by vascular leakage is a major problem in various injuries of the CNS, such as stroke, head injury and high-altitude illness. A common feature of all these disorders is the fact that they are associated with tissue hypoxia. Hypoxia has therefore been suggested to be an important pathogenic factor for the induction of vascular leakage in the brain. Vascular endothelial growth factor (VEGF) is known as the major inducer of angiogenesis. Originally, however, it was described as a vascular permeability factor. As VEGF gene expression was shown to be upregulated by hypoxia, increased VEGF expression may link hypoxia and vascular leakage in the CNS in vivo. To delineate the role of VEGF in vascular leakage in the brain, we studied the effect of hypoxia on VEGF expression and vascular permeability in the brains of mice in vivo. Hypoxic exposure led to a significant increase in the levels of VEGF mRNA and protein in mouse brain that correlated with the severity of the hypoxic stimulus. Measurement of vascular permeability using the fluorescent marker sodium fluorescein revealed a two-fold increase in fluorescence intensity in hypoxic brains, indicative of significant vascular leakage. Inhibition of VEGF activity by a neutralizing antibody completely blocked the hypoxia-induced increase in vascular permeability. In conclusion, our data show that VEGF is responsible for hypoxia-induced augmentation in vascular leakage following tissue hypoxia. Our findings might provide the basis for new therapeutic concepts for the treatment of cerebral oedema.
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              Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat.

              The immaturity of the CNS at birth greatly affects injury after stroke but the contribution of the blood-brain barrier (BBB) to the differential response to stroke in adults and neonates is poorly understood. We asked whether the structure and function of the BBB is disrupted differently in neonatal and adult rats by transient middle cerebral artery occlusion. In adult rats, albumin leakage into injured regions was markedly increased during 2-24 h reperfusion but leakage remained low in the neonates. Functional assays employing intravascular tracers in the neonates showed that BBB permeability to both large (70 kDa dextran) and small (3 kDa dextran), gadolinium (III)-diethyltriaminepentaacetic acid tracers remained largely undisturbed 24 h after reperfusion. The profoundly different functional integrity of the BBB was associated with the largely nonoverlapping patterns of regulated genes in endothelial cells purified from injured and uninjured adult and neonatal brain at 24 h (endothelial transcriptome, 31,042 total probe sets). Within significantly regulated 1266 probe sets in injured adults and 361 probe sets in neonates, changes in the gene expression of the basal lamina components, adhesion molecules, the tight junction protein occludin, and matrix metalloproteinase-9 were among the key differences. The protein expression of collagen-IV, laminin, claudin-5, occludin, and zonula occludens protein 1 was also better preserved in neonatal rats. Neutrophil infiltration remained low in acutely injured neonates but neutralization of cytokine-induced neutrophil chemoattractant-1 in the systemic circulation enhanced neutrophil infiltration, BBB permeability, and injury. The markedly more integrant BBB in neonatal brain than in adult brain after acute stroke may have major implications for the treatment of neonatal stroke.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                11 July 2018
                2018
                : 10
                Affiliations
                1Department of Neurology, Zhujiang Hospital of Southern Medical University , Guangzhou, China
                2Department of Rehabilitation, Zhujiang Hospital, Southern Medical University , Guangzhou, China
                3Department of General Intensive Care Unit of Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University , Guangzhou, China
                4Department of Neurosurgery, Zhujiang Hospital, Southern Medical University , Guangzhou, China
                5Department of Neurology, Nanfang Hospital, Southern Medical University , Guangzhou, China
                6Department of Microbiology & Immunology, School of Medicine, New York Medical College , Valhalla, NY, United States
                7Structural Genomics Consortium, Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON, Canada
                Author notes

                Edited by: Jiawei Zhou, Institute of Neuroscience, Shanghai Institutes for Biological Sciences (CAS), China

                Reviewed by: Ting-Ting Huang, Stanford University, United States; Liu Jun, Ruijin Hospital, China

                These authors have contributed equally to this work.

                Article
                10.3389/fnagi.2018.00196
                6050362
                Copyright © 2018 Gao, Xie, Zhu, Yu, Xian, Ouyang, Ji, Yang, Wen, Wang, Tong and Wang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 53, Pages: 15, Words: 10164
                Categories
                Neuroscience
                Original Research

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