Oxidative stress-responsive apoptosis inducing protein (ORAIP) plays a critical role in cerebral ischemia/reperfusion injury

• Published in: Scientific reports 2019-09, Vol.9 (1), p.13512-12, Article 13512
• Main Authors: Kishimoto, Masao, Suenaga, Jun, Takase, Hajime, Araki, Kota, Yao, Takako, Fujimura, Tsutomu, Murayama, Kimie, Okumura, Ko, Ueno, Ryu, Shimizu, Nobuyuki, Kawahara, Nobutaka, Yamamoto, Tetsuya, Seko, Yoshinori
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 13/95; 631/378/2607; 692/617/375/1370/534; 82/51; 82/80; 82/83; 96/35; 96/63; Animals; Apoptosis; Apoptosis - physiology; Apoptosis Regulatory Proteins - metabolism; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Cell Hypoxia - physiology; Cerebral blood flow; Cerebral infarction; Cerebrospinal fluid; Eukaryotic Translation Initiation Factor 5A; Humanities and Social Sciences; Hypoxia; Infarction, Middle Cerebral Artery - pathology; Initiation factor eIF-5A; Intracerebroventricular administration; Ischemia; Male; Monoclonal antibodies; multidisciplinary; Neurons; Neurons - metabolism; Oxidative stress; Oxidative Stress - physiology; Peptide Initiation Factors - genetics; Peptide Initiation Factors - metabolism; Rats; Rats, Inbred SHR; Reperfusion; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Stroke - pathology; Therapeutic applications; Thrombolysis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-50073-8

Oxidative stress is known to play a critical role in the pathogenesis of various disorders, especially in ischemia/reperfusion (I/R) injury. We identified an apoptosis-inducing humoral factor and named this novel post translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A) “oxidative stress-responsive apoptosis inducing protein” (ORAIP). The purpose of this study was to investigate the role of ORAIP in the mechanisms of cerebral I/R injury. Hypoxia/reoxygenation induced expression of ORAIP in cultured rat cerebral neurons, resulting in extensive apoptosis of these cells, which was largely suppressed by neutralizing anti-ORAIP monoclonal antibody (mAb) in vitro . Recombinant-ORAIP induced extensive apoptosis of cerebral neurons. Cerebral I/R induced expression of ORAIP in many neurons in a rat tandem occlusion model in vivo . In addition, we analyzed the effects of intracerebroventricular administration of neutralizing anti-ORAIP mAb on the development of cerebral infarction. Cerebral I/R significantly increased ORAIP levels in cerebrospinal fluid. Treatment with intracerebroventricular administration of neutralizing anti-ORAIP mAb reduced infarct volume by 72%, and by 55% even when started after reperfusion. These data strongly suggest that ORAIP plays a pivotal role and will offer a critical therapeutic target for cerebral I/R injury induced by thrombolysis and thrombectomy for acute ischemic stroke.