Abstract
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.
Highlights
Glutamate is a primary excitatory amino acid neurotransmitter in mammalian central nervous system (CNS) and activation of glutamate receptors including N-methyl-D-aspartate (NMDA) receptor plays crucial roles in neural development, synaptic plasticity, transmission, learning and memory [1,2]
We found that preincubation of cortical neurons with HN
It has been reported that HN exerts protective effects via its putative receptor on the cell membrane, including G protein-coupled receptors, formyl peptide-receptor-like (FPRL)-1 and 2 [31,32]; and a trimeric receptor complex composed of ciliary neurotrophic factor receptor α (CNTFR), gp130, and the IL-27 receptor subunit, WSX-1.7 [33]; and the gp130 receptor [24]. These findings suggest that different mechanisms underlie the HN neuroprotection in different cells in vitro
Summary
Glutamate is a primary excitatory amino acid neurotransmitter in mammalian central nervous system (CNS) and activation of glutamate receptors including N-methyl-D-aspartate (NMDA) receptor plays crucial roles in neural development, synaptic plasticity, transmission, learning and memory [1,2]. NNMMDDAA--IInndduucceedd MMAAPPKKss AAccttiivvaattiioonn wweerree AAtttteennuuaatteedd bbyy HHNN oorr NNAACC MiMnAAFPPigTTKKuoossrfwefwuu4arras,ttshhpeeeexhrxraoameesmvpvinaahinlelouuderaadyattleteaavttttaihhvoreeainoriiuilnnoesvvvupooeselllvsvprieeeoommrdfioseJeNdnnosfttKtoooimafffntMeMdimaAAfpetPPe3ra8KKfNssMteMiirAnnDNPttAhMKheeaDfdoeeAxmlxlccoiaiinwttdooisemtttoodrixxanbiiticciysoiitttnrNyya,,(MtztitehohDrneeoAp(hpzhhwteoooreoss2rpp4ehhhhsoot)io.rgryyAn2llia4safittscihihooa)onn.nwAtoolnysff hshigohwenr aitn3 ,F6i,g1u2reh, 4a,ndph24oshpthhoarnytlhataitoinn tlheveeulnstroefatJeNdKconantrdol pgr3o8upM(AzePrKo hf)o, lwloiwtheadmbayximNaMl aDcAtivawtieorne asitg1n2ifhicaafnttelryNhMighDeAr attre3at,m6,e1n2t (hp,
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