MFGE8/Integrin β3 pathway alleviates apoptosis and inflammation in early brain injury after subarachnoid hemorrhage in rats.
BACKGROUND
Milk fat globule-epidermal growth factor-factor 8(MFGE8)/Integrin β3 pathway was reported to be involved in reducing oxidative stress and early brain injury after subarachnoid hemorrhage (SAH). In the present study, the potential effects of MFGE8 and its receptor Integrin β3 in the inhibition of apoptosis and neuroinflammation in early brain injury after SAH were investigated.


METHODS
Ninety-five (95) male Sprague-Dawley rats were used. The SAH model was induced by endovascular perforation. Recombinant human MFGE8 (rhMFGE8), MFGE8 small interfering RNA (siRNA) and Integrin β3 siRNA were injected intracerebroventricularly. SAH grade, neurologic scores, Western blots and immunofluorescence were employed to study the mechanisms of MFGE8 and its receptor Integrin β3, as well as neurological outcome.


RESULTS
SAH induced significant neuronal apoptosis and inflammation and exhibited neurological dysfunction in rats. Knockdown endogenous MFGE8 with siRNA significantly increased the protein levels of cleaved caspase 3 and IL-1β, accompanied with more neurological deficits. rhMFGE8 significantly reduced neural cell death in cortex, decreased cleaved caspase 3 and IL-1β expressions, and improved neurological functions 24h after SAH. The anti-apoptosis and anti-inflammation effects of rhMFGE8 were abolished by Integrin β3 siRNA.


CONCLUSIONS
MFGE8 could alleviate neurologic damage in early brain injury after SAH via anti-inflammation and anti-apoptosis effects. MFGE8 may serve as a promising therapeutic target for future management of SAH patients.
Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
Fei
F
Liu
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China; Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
Yujie
Y
Chen
Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
Qin
Q
Hu
Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
Bo
B
Li
Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
Junjia
J
Tang
Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
Yue
Y
He
Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
Zongduo
Z
Guo
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
Hua
H
Feng
Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
Jiping
J
Tang
Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA. Electronic address: johnzhang3910@yahoo.com.
John H
JH
Zhang
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001930:Brain Injuries / Q000188:drug therapy / Q000209:etiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D057967:Infusions, Intraventricular; D039661:Integrin beta3 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy / Q000401:mortality
D000954:Antigens, Surface; C000594089:IL1B protein, rat; D039661:Integrin beta3; D053583:Interleukin-1beta; C499941:MFGE8 protein, rat; D008894:Milk Proteins; D034741:RNA, Small Interfering; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase
Apoptosis; Early brain injury; Inflammation; MFGE8; Subarachnoid hemorrhage