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Front. Neurol. | doi: 10.3389/fneur.2018.00096

MFGE8 Pretreatment Attenuates Apoptosis and Inflammation via the Integrin β3 Pathway after Surgical Brain Injury in Rats

  • 1Third Xiangya Hospital, Central South University, China
  • 2Zhuzhou Central Hospital, China
  • 3Southwest Hospital, Third Military Medical University, China
  • 4Loma Linda University, United States

Iatrogenic brain injury inevitably occurs in neurosurgical operations, leading to brain edema, ischemia, intracranial hematoma, and other postoperative complications, eventually worsening neurological outcomes of patients. If apoptotic cells are not rapidly eliminated by phagocytic engulfment, they may communicate with surrounding cells to undergo secondary necrosis and releasing toxic signals. Recent studies have shown that MFGE8, which promotes phagocytosis and inhibits inflammation, is an endogenous protective factor in response to brain infarction, Alzheimer’s disease, subarachnoid hemorrhage, and prion disease. In the present study, we sought to investigate the different effects of both pretreated- and posttreated- rhMFGE8 for the surgical brain injury (SBI) rat model and potential involvement of its receptor Integrinβ3 for apoptosis and neuroinflammation after SBI. One hundred and sixty-seven male rats were employed in the preset study. Experiment 1 was performed to evaluate neurological scores and MFGE8, cleaved caspase-3 (CC3) and Interleukine-1 beta (IL-1β) levels at 3, 24 and 120 h after SBI. Experiment 2 was performed to evaluate the effects of rhMFGE8 pretreatment (10 min before SBI) and rhMFGE8 post-treatment (6 h after SBI) on brain edema at 24 and 72 h after SBI. Experiment 3 was performed to evaluate the potential anti-apoptotic and anti-inflammatory effects of rhMFGE8 pretreatment and post-treatment. Experiment 4 sought to investigate the involvement of the integrin β3 signal in the effects of MFGE8 pretreatment. Our data showed rhMFGE8 pretreatment alleviated neurological deficits and decreased brain water content and apoptotic cells in the SBI model, which exhibited neurological dysfunction, apoptosis and inflammation. Meanwhile, MFGE8 siRNA, which inhibited endogenous MFGE8 expression, significantly increased IL-1β, TUNEL positive cells and cleaved caspase-3. Furthermore, knockdown of its receptor integrin β3 by siRNA abolished the effects of rhMFGE8 in the SBI model. In conclusion, we found that rhMFGE8 pretreatment effectively alleviated neurological deficits and decreased brain water content and apoptotic cells in the SBI model through the MFGE8/integrinβ3 pathway, and treatment time was an important factor in achieving curative effects. Therefore, MFGE8 pretreatment may serve as a promising therapeutic strategy for SBI patients.

Keywords: Milk fat globule-epidermal growth factor-factor 8, surgical brain injury, Apoptosis, Inflammation, Integrin β3

Received: 23 Jul 2017; Accepted: 09 Feb 2018.

Edited by:

Firas H. Kobeissy, University of Florida, United States

Reviewed by:

Karim A. Sarhane, University of Toledo, United States
Wael M. Mohamed, International Islamic University Malaysia, Malaysia
Corina Bondi, University of Pittsburgh, United States  

Copyright: © 2018 Xiao, Li, Chen, Zuo, Rashid, He, Feng, Zhang and Liu. 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 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.

* Correspondence: Dr. Fei Liu, Third Xiangya Hospital, Central South University, Changsha, China,