Humanin attenuates NMDA-induced excitotoxicity by inhibiting ROS-dependent JNK/p38 MAPK pathway

Xiaorong Yang, Hongmei Zhang, Jinzi Wu, Litian Yin, Liang Jun Yan, Ce Zhang

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29 Scopus citations


Humanin (HN) is a novel 24-amino acid peptide that protects neurons against N-methyl-D-aspartate (NMDA)-induced toxicity. However, the contribution of the different mitogen-activated protein kinases (MAPKs) signals to HN neuroprotection against NMDA neurotoxicity remains unclear. The present study was therefore aimed to investigate neuroprotective mechanisms of HN. We analyzed intracellular Ca2+ levels, reactive oxygen species (ROS) production, and the MAPKs signal transduction cascade using an in vitro NMDA-mediated excitotoxicity of cortical neurons model. Results showed that: (1) HN attenuated NMDA-induced neuronal insults by increasing cell viability, decreasing lactate dehydrogenase (LDH) release, and increasing cell survival; (2) HN reversed NMDA-induced increase in intracellular calcium; (3) pretreatment by HN or 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, decreased ROS generation after NMDA exposure; (4) administration of HN or N-Acetyl-L-cysteine (NAC), a ROS scavenger, inhibited NMDA-induced JNK and p38 MAPK activation. These results indicated that HN reduced intracellular elevation of Ca2+ levels, which, in turn, inhibited ROS generation and subsequent JNK and p38 MAPK activation that are involved in promoting cell survival in NMDA-induced excitotoxicity. Therefore, the present study suggests that inhibition of ROS-dependent JNK/p38 MAPK signaling pathway serves an effective strategy for HN neuroprotection against certain neurological diseases.

Original languageEnglish
Article number2982
JournalInternational journal of molecular sciences
Issue number10
StatePublished - Oct 2018


  • Excitotoxicity
  • HN
  • MAPKs
  • NMDA
  • Neuroprotection
  • ROS


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