The neuroprotection of humanin on hypoxia/ischemia injury

Xingshun Xu¹, Chun-Feng Liu¹, Balvin Chua²

1. Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu 215123, China 2. Cecile Cox Quillen Laboratory of Geriatrics, James H. Quillen School of Medicine, East Tennessee State University, Johnson City, TN 37614, USA

Humanin is a high potent 24-amino acid peptide best known for its ability to protect neurons from damage caused by Alzheimer disease-related proteins in different cell and animal models. In this study, we examined the protective effects of Gly14-humanin (HNG), a derivative of humanin, on oxygen/glucose deprivation (OGD)-induced cell death and cerebral ischemia injury in mice. Our results demonstrated that HNG suppressed neuronal cell death, reduced infarct volume and improved neurological deficits in a middle cerebral artery occlusion model in mice, even if HNG was administered (i.c.v.) several hours after ischemia induction. Further study indicated that HNG achieved anti-apoptotic effects by decreasing cleaved poly(ADP-ribose)-polymerase (PARP, a marker of caspase activity), inhibiting extracellular signal regulated kinase (ERK) activation and activating PI3K/Akt signal pathways. Intraperitoneal injection of HNG also reduced cerebral infarct volume in mice, suggesting that HNG could cross the BBB and enter the ischemic area. In addition, the combination treatment of HNG and necrostain-1, a specific necroptosis inhibitor, had significantly synergistic protection on hypoxia/cerebral ischemia injury in vitro and in vivo, providing a novel therapeutic strategy for the treatment of stroke by combining anti-apoptosis and anti-necroptosis therapy.  In summary, our data demonstrated that this small neuropeptide is a promising reagent in the clinical application for the treatment of stroke.