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Aggf1 Attenuates Neuroinflammation and BBB Disruption Via PI3K/Akt/NF-Κb Pathway After Subarachnoid Hemorrhage in Rats

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Aggf1 Attenuates Neuroinflammation and BBB Disruption Via PI3K/Akt/NF-Κb Pathway After Subarachnoid Hemorrhage in Rats Zhu et al. Journal of Neuroinflammation (2018) 15:178 https://doi.org/10.1186/s12974-018-1211-8 RESEARCH Open Access Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats Qiquan Zhu1,2, Budbazar Enkhjargal2, Lei Huang2,4, Tongyu Zhang2, Chengmei Sun2, Zhiyi Xie2, Pei Wu2, Jun Mo2, Jiping Tang2, Zongyi Xie1* and John H. Zhang2,3,4* Abstract Background: Neuroinflammation and blood-brain barrier (BBB) disruption are two critical mechanisms of subarachnoid hemorrhage (SAH)-induced brain injury, which are closely related to patient prognosis. Recently, angiogenic factor with G-patch and FHA domain 1 (Aggf1) was shown to inhibit inflammatory effect and preserve vascular integrity in non-nervous system diseases. This study aimed to determine whether Aggf1 could attenuate neuroinflammation and preserve BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective roles. Methods: Two hundred forty-nine male Sprague-Dawley rats were subjected to the endovascular perforation model of SAH. Recombinant human Aggf1 (rh-Aggf1) was administered intravenously via tail vein injection at 1 h after SAH induction. To investigate the underlying neuroprotection mechanism, Aggf1 small interfering RNA (Aggf1 siRNA) and PI3K-specific inhibitor LY294002 were administered through intracerebroventricular (i.c.v.) before SAH induction. SAH grade, neurological score, brain water content, BBB permeability, Western blot, and immunohistochemistry were performed. Results: Expression of endogenous Aggf1 was markedly increased after SAH. Aggf1 was primarily expressed in endothelial cells and astrocytes, as well as microglia after SAH. Administration of rh-Aggf1 significantly reduced brain water content and BBB permeability, decreased the numbers of infiltrating neutrophils, and activated microglia in the ipsilateral cerebral cortex following SAH. Furthermore, rh-Aggf1 treatment improved both short- and long-term neurological functions after SAH. Meanwhile, exogenous rh-Aggf1 significantly increased the expression of PI3K, p-Akt, VE-cadherin, Occludin, and Claudin-5, as well as decreased the expression of p-NF-κB p65, albumin, myeloperoxidase (MPO), TNF-α, and IL-1β. Conversely, knockdown of endogenous Aggf1 aggravated BBB breakdown, inflammatory response and neurological impairments at 24 h after SAH. Additionally, the protective roles of rh-Aggf1 were abolished by LY294002. Conclusions: Taken together, exogenous Aggf1 treatment attenuated neuroinflammation and BBB disruption, improved neurological deficits after SAH in rats, at least in part through the PI3K/Akt/NF-κB pathway. Keywords: Angiogenic factor with G patch and FHA domains 1, Neuroinflammation, Blood-brain barrier, Subarachnoid hemorrhage * Correspondence: [email protected]; [email protected] 1Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China 2Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhu et al. Journal of Neuroinflammation (2018) 15:178 Page 2 of 13 Background with the guideline for the Care and Use of Laboratory Aneurysmal subarachnoid hemorrhage (SAH) is a devastat- Animals by National Institutes of Health. Two hundred ing cerebrovascular disease with a high rate of mortality forty-nine male Sprague-Dawley rats (Indianapolis, IN, and disability [1]. Neuroinflammation and blood-brain bar- USA) weighing 300–320 g were used, and they were rier (BBB) disruption have been recognized as important housed in a light- and temperature-controlled room with pathological processes in early brain injury (EBI) after SAH unlimited access to food and water. [2–4]. Neuroinflammatory responses are characterized by resident microglial and astrocyte activation, infiltration of SAH model peripheral leukocytes, and release of pro-inflammatory me- The endovascular perforation model was induced as diators, which exacerbate BBB disruption that further amp- previously described [20]. Briefly, rats were intubated lifies inflammatory response and worsens neurological and maintained with 3% isoflurane anesthesia in the impairments [5]. Therefore, developing a protective strategy air. Rodents were placed in a supine position, and the against neuroinflammation and BBB disruption may be ef- neck was opened with a sharp scalpel in the midline. fective for patients with SAH. After localization of the appropriate vessels, a sharp- Angiogenic factor with G patch and FHA domains 1 ened 3-cm, 4–0 nylon suture was inserted into the (Aggf1, also known as VG5Q) was initially identified as a left internal carotid artery through the external ca- vascular endothelium-derived protein and promoted angio- rotid artery and the common carotid bifurcation. The genesis as strongly as vascular endothelial growth factor A suture was advanced until resistance was reached, fur- (VEGFA) [6]. Mounting evidence suggested that Aggf1 ex- ther advanced in order to puncture the vessel, and erts multiple roles in various pathological processes, includ- then immediately withdrawn after artery perforation. ing embryogenesis, tumorigenesis, cirrhosis, apoptosis, The sham-operated group underwent the same pro- inflammation, and autophagy [7–12]. Aggf1 was proved to cedure without an endovascular puncture. After re- reduce the release of inflammatory molecules in myocardial moval of the suture, the skin incision was sutured ischemia model [13]. Moreover, an in vivo study revealed and the rats were housed individually in heated cages that Aggf1 exerts anti-inflammatory property through sup- until recovery. pressing TNF-α-induced endothelial activation in a mouse model of hindlimb ischemia [14]. Previous study demon- Experimental design strated exogenous Aggf1 treatment could increase vessel Animals were randomly assigned to five separate experi- density and improve blood flow after limb ischemia in mice ments as described (Fig. 1). The experimental group in- [15]. Aggf1 maintained vascular integrity by inhibiting formation was blinded to the surgeon and researchers VE-cadherin phosphorylation in myocardial ischemia/re- who performed the neurobehavioral tests and Western perfusion models [16]. Despite the well-established roles for blot/immunofluorescence as well as data analysis. Aggf1 in inflammation and vascular integrity, the effects of Aggf1 on neuroinflammation and BBB integrity after SAH Experiment 1 have not been investigated. The time course of endogenous Aggf1 in the ipsilateral The activation of PI3K/Akt/NF-κB pathway is involved (left) cerebral cortex was measured by Western blot ana- in the stabilization of BBB integrity by increasing the lysis. Double immunofluorescence staining was per- expression of tight junction proteins and the alleviation of formed to characterize the cellular localization of Aggf1 inflammation via decreasing inflammatory mediators in at 24 h after SAH. stroke and neurodegenerative disease [17–19]. Recent studies showed that Aggf1 possessed the protective Experiment 2 roles by activating PI3K/Akt pathway in myocardial To assess the effects of recombinant human Aggf1 ischemia-reperfusion injury and in cell cultures [16]. (rh-Aggf1) on neuroinflammation, three doses of In the present study, we hypothesized that intravenous rh-Aggf1 (1, 3, 9 μg/rat; R&D Systems, USA) dissolved administration of recombinant human Aggf1 (rh-Aggf1) in normal saline (NS) were administered intravenously could attenuate neuroinflammation and BBB disruption via the tail vein at 1 h after SAH. Neurological scores, after SAH, as well as the protective effects of Aggf1 are SAH grade, and brain water content were measured at mediated through PI3K/Akt/NF-κB pathway. 24 h after SAH. Rats were randomly divided into five groups: sham, SAH+vehicle (normal saline, NS), SAH Methods +rh-Aggf1 (1 μg/rat), SAH+rh-Aggf1 (3 μg/rat), SAH Animals +rh-Aggf1 (9 μg/rat). Evans blue (EB) extravasation, neu- All procedures and protocols for this study were ap- trophil infiltration, and inflammatory factor molecules proved by the Institutional Animal Care and Use Com- expression were evaluated at 24 h after SAH in sham, mittee (IACUC) of Loma Linda University in accordance SAH+vehicle, and SAH+rh-Aggf1 (3 μg/rat). Zhu et al. Journal of Neuroinflammation (2018) 15:178 Page 3 of 13 Fig. 1 Experimental design and animal groups. Aggf1, angiogenic factor with G patch and FHA domains 1; DMSO, dimethyl sulfoxide; EB, Evans blue; IHC, immunohistochemistry; LY294002, PI3K inhibitor; SAH, subarachnoid hemorrhage; Scr siRNA, scrambled siRNA; WB, Western blot Experiment 3 rat) treatment. Neurobehavioral tests, brain water con- To evaluate the effects of rh-Aggf1 on long-term neuro- tent, immunofluorescence staining, and Western blot logical functions, the foot-fault test was conducted
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