Humanin Is a Novel Neuroprotective Agent Against Stroke

Abstract

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 g HNG (intracerebroventricularly) 30 minutes before ischemia; posttreated at 0, 2, 4, and 6 hours after ischemia; or pretreated with 1 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 g HNG (intracerebroventricularly) 30 minutes before ischemia reduced cerebral infarct volume from 56.2Ϯ3.0% to 26.1Ϯ1.4% (PϽ0.01). HNG posttreatment after 4 hours of reperfusion reduced cerebral infarct volume to 45.6Ϯ2.6% (PϽ0.05). Pretreatment with 1 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.

SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

“…Second, given that htHNR belongs to the interleukin-6 receptor family, which activates ERK signaling (53), it is likely that the binding of Humanin to htHNR activates intracellular signals via ERK independently of STAT3. Third, phosphoinositide 3 kinase-and Akt-mediated signaling is activated by Humanin in a mouse stroke model (10). Finally, the signals activated by the Humanin binding to Humanin receptors other than htHNR, such as Bax (29) and formyl peptide receptor-like protein 1 (30), may also contribute to the protective effect of Humanin.…”

“…2-4 for review). Humanin also suppresses cell death in a variety of non-AD-related in vitro and in vivo cell death models; for example, serum deprivation-induced death of several cell types including PC12 neuronal cells (5), primary peripheral lymphocytes (6), K562 myeloblasts (7), and cultured islet ␤ cells (8), as well as death of Leydig cells during the first wave of spermatogenesis (9), ischemia-induced neuronal death in a mouse ischemic stroke model (10,11), gonadotropin-releasing hormone antagonist-induced death of testicular germ cells (12), ischemic death of myocardiocytes (13), and oxidized LDL-induced death of vascular endothelial cells (14). Humanin has other functions aside from inhibition of cell death.…”

Leptin Attenuates Cerebral Ischemia Injury through the Promotion of Energy Metabolism via the PI3K/Akt Pathway

“…Focal cerebral ischemia/reperfusion injury was induced by the unilateral middle cerebral artery occlusion (MCAO) model as described previously. 9 Briefly, mice were anesthetized with pentobarbital sodium (60 mg/kg, intraperitoneally), and their skin was sterilized. The common carotid artery, the external carotid artery, and the internal carotid artery on the right side were exposed through a ventral midline neck incision.…”

Humanin Derivatives Inhibit Necrotic Cell Death in Neurons

“…Previous publications have highlighted the protective effects of humanin peptides in a brain ischemia reperfusion model for stroke, by using middle cerebral artery occlusion (13). In this model, the main pathway of cellular demise occurs via a caspase-mediated pathway and not via classical necrosis (47).…”

“…Humanin expression in humans has been shown to decrease with age, which suggests a possible causal relationship between decreased humanin and the onset of "old age" diseases such as AD and type 2 diabetes (10). Humanin can suppress apoptotic cell death stemming from various insults, such as AD-related amyloid β (Aβ), serum deprivation and ischemia reperfusion (11)(12)(13). Design of peptides with higher activity was performed by systematic screening of peptides based on the amino acid sequence of humanin, which resulted in several derivatives with higher antiapoptotic activity (9,14,15).…”