Humanin rescues cultured rat cortical neurons from NMDA-induced toxicity through the alleviation of mitochondrial dysfunction

Abstract

N-methyl-D-aspartate (NDMA) receptor-mediated excitotoxicity has been implicated in a variety of pathological situations such as Alzheimer’s disease (AD) and Parkinson’s disease. However, no effective treatments for the same have been developed so far. Humanin (HN) is a 24-amino acid peptide originally cloned from the brain of patients with AD and it prevents stress-induced cell death in many cells/tissues. In our previous study, HN was found to effectively rescue rat cortical neurons. It is still not clear whether HN protects the neurons through the attenuation of mitochondrial dysfunction. In this study, excitatory toxicity was induced by NMDA, which binds the NMDA receptor in primarily cultured rat cortical neurons. We found that NMDA (100 μmol/L) dramatically induced the decrease of cell viability and caused mitochondrial dysfunction. Pretreatment of the neurons with HN (1 μmol/L) led to significant increases of mitochondrial succinate dehydrogenase (SDH) activity and membrane potential. In addition, HN pretreatment significantly reduced the excessive production of both reactive oxygen species (ROS) and nitric oxide (NO). Thus, HN could attenuate the excitotoxicity caused by the overactivation of the NMDA receptor through the alleviation of mitochondrial dysfunction.

Murine maternal dietary restriction affects neural Humanin expression and cellular profile

“…Similar findings have been seen with adult models of stroke and amyotrophic lateral sclerosis (Matsuoka, Hashimoto, Aiso, & Nishimoto, ; Xu, Chua, Gao, Hamdy, & Chua, ). HN's protective properties have also been demonstrated in cell culture using models of hypoxia, toxins, and conditions of oxidative stress (Cui et al, ; Men, Zhang, Yang, & Gao, ; Sreekumar et al, ; Zhao, Wang, Li, Zhao, & Zhang, ). A common theme in these studies is the promotion of cell survival under stressful conditions such as energy deficit and cellular degeneration/apoptosis.…”

Humanin levels in human seminal plasma and spermatozoa are related to sperm quality

“…It is well established that reactive oxygen species (ROS), which are mainly generated in the mitochondrial respiratory chain, impair sperm production, motility, membrane, and DNA integrity and also influence sperm capacitation (Christova et al ., ; Henkel et al ., ; Brouwers et al ., ; Aitken et al ., ; Lee et al ., ). Humanin has been reported to prevent ROS accumulating in cardiomyocytes (Blasco et al ., ), cortical neurons (Cui et al ., ), retinal pigment epithelium (Minasyan et al ., ), and rat pancreatic beta cells (Paharkova et al ., ), etc. Pre‐treatment with humanin analog can exert cardiologically protective effects against myocardial ischemia and reperfusion injury in mouse models (Muzumdar et al ., ).…”

Humanin Attenuates NMDA-Induced Excitotoxicity by Inhibiting ROS-dependent JNK/p38 MAPK Pathway

“…These suggest that the mechanism of HN neuroprotection in rat cortical neuron maybe through antagonism of the NMDA receptor. Nonetheless, there is also a conflicting report showing that HN failed to inhibit intracellular Ca 2+ overload triggered by NMDA [ 23 , 30 ]. The reason for the discrepancy is unclear, but one possibility could be due to different concentrations of HN used between these two studies.…”

“…Recently, evidence has revealed that HN has a broader spectrum of neuroprotective activity [ 21 , 22 ]. For example, HN has been shown to rescue neurons from NMDA-induced toxicity [ 23 , 24 ]. However, it remains sketchy that the neuroprotection of HN is mediated by the MAPK signals.…”