Role Of Caspase11 And TNFAIP3 Inflammatory Pathways In Neurotoxicity Induced By Methamphetamine

Background:Methamphetamine(METH)is one of the most abused drugs in the world,and the main effector is the central nervous system.METH can cause brain damage,mostly taget to dopaminergic neurons in the brain.Degeneration and necrosis of nerve cells can also lead to inflammatory damage of neuronal stromal cells,activation of astrocytes,aggregation of microglia,and release of inflammatory factors,induced glial scar hyperplasia and other changes.Among the many mechanisms of METH neurotoxic injury,the toxic effects of neuritic injury are not known clearly.Astrocytes,which are the most abundant glial cells in the central nervous system,have multiple functions and play an important role in the central nervous system and protecting neurons.When activated,they can induce microglia differentiation,produce more cytokines,and participate in inflammatory responses.Therefore,we speculate that astrocytes play an important role in METH neuroinflammatory injury.Studies have shown that the classical and non-classical inflammatory pathways composed of Toll like receptor(TLR),Caspasel 1 and NLRP3 inflammasome play an important role in the immune response.However,TLR4 causes excessive activation of the downstream NF-?B pathway,which may also be the cause of some autoim:mune diseases.As an endogenous inhibitor of NF-kB,A20 plays a key role in the regulation of inflammatory pathways and may become a therapeutic target for METH neurotoxicity.In summary,we conducted METH and astrocyte related research.Research purposes:This study is to investigate the mechanism of METH-induced astrocyte activation,changes in astrocyte inflammatory pathway and its role in neuronal toxicity and regulation strategies.Methods:Through the establishment of METH primary cultured astrocytes and U87MG cell model,METH exposed animals subacute poisoning model,through morphological,molecular biology,gene interference and overexpression technology,explore the inflammatory pathway TLR4-Expression levels of Caspasel 1-NLRP3 inflammatory bodies and A20-NF-kB.In addition,by establishing a model of METH-induced astrocyte-neuron co-culture,the interaction between the two cells under the action of METH was explored.Results:1.METH-induced astrocyte cytokines pro-inflammatory factors IL-1? and IL-18 are highly expressed.2.After primary cultured astrocytes are treated with METH,TLR4 can pass Myd88-dependent and non-dependent pathways.Mediates the increase of NF-icB into the nucleus,which mediates the increased transcription of Caspasel 1 pathway-related proteins.3.We established astrocyte-neuron co-culture combined with METH drug delivery model,and astrocytes can significantly reduce METH-induced neuronal apoptosis,autophagy,oxidative stress and DNA damage levels in the co-culture model.4.In the METH-infected cell model,A20 was found to be inhibited by establishing A20 overexpression and interference-stable cell lines.TRAF6 also inhibits the expression of downstream factors in the NF-kB pathway.Conclusions:1.Caspasel 1 promotes METH-induced proinflammatory cytokine expression via the inflammatory corpuscle;2.METH induces astrocyte activation via TLR4-NF-kB-Caspasel 1 pathway;3.METH-induced astrocytes after co-culture with neurons,neuronal apoptosis,autophagy and oxidative stress levels were significantly down-regulated;4.Astrocytes were activated by METH after the inflammatory pathway was activated,and A20 pathway was also activated.Moreover,after overexpression of astrocyte A20,the cell inflammatory pathway was significantly inhibited.