The Role And Mechanism Of LCN2 In Methamphetamine-Induced Neurotoxicity

BackgroundMethamphetamine(METH),also known as amphedroxyn,is a pure white crystal with an ice-like appearance,also known as "ice".Because of its relatively simple synthesis,lower cost,and easier addiction,METH has become the first most widely abused illicit drug in China.METH can mainly damage to the structure and function of the central nervous system,causing neurodegeneration and necrosis of neurons.Our previous research showed that oxidative stress plays an important role in METH neurotoxicity,and endoplasmic reticulum stress activation promotes METH-induced neurotoxicity.Meanwhile,the Lipocalin-2(LCN2)gene obtained by chip expression profiling expressed significantly higher than the control group.LCN2 can not only transport small mocular through the cell membrane but also regulate cell death and proliferation and play an important role in various neurodegenerative diseases Endoplasmic reticulum stress is involved in regulating LCN2 expression and promoting cell apoptosis.However,the role of LCN2 in METH-induced neurotoxicity and detail mechanism underlying METH-induced neuronal damage need further research.ObjectivesTo investigate the role and mechanism of LCN2 in METH-induced neurotoxicity,providing a theoretical basis for the study the mechanism of METH-induced neurotoxicity.MethodsThrough the establishment of METH primary cultured astrocytes and primary cultured neurons cell model,METH-exposed animal model,using Western blot,immunofluorescence,RT-qPCR,ELISA to detect whether LCN2-LCN2R and endoplasmic reticulum stress are involved in METH-induced neurotoxicity.Meanwhile,through establishing an astrocyte-neuron coculture model,to explore the interaction between the two cells after METH exposure.Results1.METH induced LCN2 high expression in vivo and in vitro.LCN2 is mainly expressed in astrocytes but not in neurons.2.Astrocyte-derived LCN2 after METH exposure bound to LCN2R expressed in neurons to induce neuronal apoptosis.3 METH-induced neurons cocultured astrocytes increased astrocyte-derived LCN2 expression and secretion to contribute to METH-induced neurotoxicity.4.METH induced ROS-PERK-eIF2α signal pathway to regulate astrocyte-derived LCN2 expression.ConclusionMETH-induced high expression of astrocyte-derived LCN2 upregulated by ROS-PERK-eIF2α signal pathway and bound to LCN2R expressed in neurons were involved in neuronal apoptosis.LCN2-LCN2R play an important role in the interaction between astrocytes and neurons after METH exposure,which may be a potential therapeutic in METH-induced neurotoxicity.