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(Stroke. 2006;37:2613.)
© 2006 American Heart Association, Inc.

Original Contributions

Humanin Is a Novel Neuroprotective Agent Against Stroke

From the Department of Pharmacology (X.X., B.H.L.C.) and the Cecile Cox Quillen Laboratory of Geriatric Research (X.X., C.C.C., J.G., R.C.H., B.H.L.C.), James H. Quillen College of Medicine, East Tennessee State University, James H. Quillen Veterans Affairs Medical Center, Johnson City, Tenn.

Correspondence to Balvin H. L. Chua, PhD, PO Box 70,432, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614. E-mail chua{at}mail.etsu.edu

Background and Purpose— Humanin (HN) is a 24-amino acid peptide best known for its ability to protect neurons from damage caused by Alzheimer disease-related proteins. This study examines the neuroprotective effects of HNG (a potent form of HN) on focal cerebral ischemia/reperfusion injury in mice.

Methods— Mice underwent middle cerebral artery occlusion for 75 minutes followed by 24-hour reperfusion. Mice were pretreated with 0.1 µg HNG (intracerebroventricularly) 30 minutes before ischemia; posttreated at 0, 2, 4, and 6 hours after ischemia; or pretreated with 1 µg HNG (intraperitoneally) 1 hour before ischemia. Neurological deficits and cerebral infarct volume were evaluated. Neuronal apoptosis and activated poly(ADP-ribose) polymerase expression were measured by TUNEL and Western blot analysis, respectively. Activated ERKs were examined by Western blot analysis.

Results— Pretreatment with 0.1 µg HNG (intracerebroventricularly) 30 minutes before ischemia reduced cerebral infarct volume from 56.2±3.0% to 26.1±1.4% (P<0.01). HNG posttreatment after 4 hours of reperfusion reduced cerebral infarct volume to 45.6±2.6% (P<0.05). Pretreatment with 1 µg HNG (intraperitoneally) 1 hour before ischemia or posttreatment after 2 hours of reperfusion reduced cerebral infarct volume significantly. HNG also significantly improved neurological function and inhibited both neuronal apoptosis as well as poly(ADP-ribose) polymerase activation. A significant decrease of phospho-ERK was observed in mice treated with HNG, whereas phospho-JNK and phospho-p38 levels were not altered.

Conclusions— Our results demonstrate that HNG protects against cerebral ischemia/reperfusion injury in mice. HNG offers neuroprotection in vivo at least in part by inhibiting ERK activation. These findings suggest a potential therapeutic role for HNG in the treatment of stroke.

Key Words: cerebral ischemia • humanin • MAP kinase • neuroprotection • stroke