Humanin is a novel neuroprotective agent against stroke

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 mu g HNG (intracerebroventricularly) 30 minutes before ischemia; posureated at 0, 2, 4, and 6 hours after ischemia; or pretreated with 1 mu g 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 mu g 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 mu g 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.