NP-20 Tetramethylpyrazine Nitrone Activates PGC-1α/Nrf2 Pathway to Prevent Neurodegeneration in Experimental Models of Parkinson’s Disease  

作　　者：ZHANG Zai-jun GUO Bao-jian ZHENG Cheng-you WANG Yu-qiang 

机构地区：[1]Institute of New Drug Research,Jinan University College of Pharmacy,Guangzhou,510632,China

出　　处：《神经药理学报》2018年第4期117-118,共2页Acta Neuropharmacologica

摘　　要：Objective:Disease-modifying therapies are not available for Parkinson’s disease(PD)and several trials targeting individual pathways implicated in PD pathogenesis have failed.We hypothesize that a potentially more powerful strategy is the molecule targeting multiple signaling cascades involved in PD.TBN is the conjugate of natural product tetramethylpyrazine(TMP)and the nitrone group of a neuroprotective agent NXY-059.The neuroprotective effects of TBN have been verifi ed in various models of transient and permanent ischemic stroke,traumatic brain injury,as well as optic nerve injury through multifunctional mechanisms.The objective of present study was to inverstigate the therapeutic effi cay and mechanisms of TBN on PD models.Methods:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model,unilateral intrastriatal injection of 6-hydroxydopamine(6-OHDA)-induced rat model,and transgenic mice overexpression of human A53T mutantα-synuclein were used to evaluate TBN’s therapeutic efficacy and elucidate its mechanisms of action.Results:TBN takes the best of the Chinese medicine TMP,which has superior capability penetrating the blood-brain barrier(BBB),and the nitrone,which potently scavenging free radicals.As a result,TBN effi ciently penetrates the BBB delivering free radical scavenging nitrone to the brain to afford protection to neuronal cells.TBN treatment partially restores motor impairment,increases content of DA and its metabolites,and reduces loss of hydroxylase positive(TH+)neurons in SNpc of 6-OHDA and MPTP-induced and transgenic rodent PD models.Most intriguing is that TBN signifi cantly preserves motor function and reduces serum level of alpha-synuclein by 85%in A53T alpha-synuclein transgenic mice after 8 weeks’treatment.TBN also specifi cally suppresses MPTP intoxication-induced serum and mRNA levels of TNF-alpha and IL-6 in both wild-type and Rag1-/-immune deficient mice.Mechanistic studies show that TBN targeting PGC-1alpha and Nrf2 activation(to increase PGC-1alpha and Nrf2 transcr

关 键 词：Experimental PGC-1Α treatment Α-SYNUCLEIN multiple expression strategy effects 

分 类 号：TP368.5[自动化与计算机技术—计算机系统结构]