TY - JOUR
T1 - Humanin attenuates NMDA-induced excitotoxicity by inhibiting ROS-dependent JNK/p38 MAPK pathway
AU - Yang, Xiaorong
AU - Zhang, Hongmei
AU - Wu, Jinzi
AU - Yin, Litian
AU - Yan, Liang Jun
AU - Zhang, Ce
N1 - Funding Information:
Funding: This research was funded by the National Natural Science Foundation of China [no. 31000481, and no. 81601167], the Natural Science Foundation of Shanxi Province, China [no. 2011011040-2], the Fund for Shanxi Key Subjects Construction [FSKSC], Shanxi “1331 Project” Key Subjects Construction [1331KSC], Key Laboratory of Cellular Physiology (Shanxi Medical University)in Shanxi Province, Science and Technology Innovation Project of Shanxi Province [201802061], and Research Project Supported by Shanxi Scholarship Council of China [2017–059].
Funding Information:
This research was funded by the National Natural Science Foundation of China [no. 31000481, and no. 81601167], the Natural Science Foundation of Shanxi Province, China [no. 2011011040-2], the Fund for Shanxi Key Subjects Construction [FSKSC], Shanxi “1331 Project” Key Subjects Construction [1331KSC], Key Laboratory of Cellular Physiology (Shanxi Medical University)in Shanxi Province, Science and Technology Innovation Project of Shanxi Province [201802061], and Research Project Supported by Shanxi Scholarship Council of China [2017–059]. We thank the other academic staff members in Ce Zhang’s group at Shanxi Medical University.
Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
KW - Excitotoxicity
KW - HN
KW - MAPKs
KW - NMDA
KW - Neuroprotection
KW - ROS
UR - http://www.scopus.com/inward/record.url?scp=85054051608&partnerID=8YFLogxK
U2 - 10.3390/ijms19102982
DO - 10.3390/ijms19102982
M3 - Article
C2 - 30274308
AN - SCOPUS:85054051608
SN - 1661-6596
VL - 19
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 10
M1 - 2982
ER -