神经退行性疾病的药物作用新靶点的研究进展

[13]　OrmrodD,WellingtonK,WagstaffAJ.Valdecoxib[J].Drugs,2002,62(14):2059.[14]　SchleuningWD.VampirebatplasminogenactivatorDSPA-Alpha-1(Desmoteplase):athrombolyticdrugoptimizedbynaturalselection[J].Haemostasis,2001,31(3):118.[15]　MolkanenT,TyynelaJ,HelinJ,etal.EnhancedactivationofboundplasminogenonStaphylococcusaureusbystaphylokinase[J].FEBSLett,2002,517(1～3):72.[16]　GibsonCM,MurphySA,MarbleSJ,etal.Combinationtherapywithabciximabreducesangiographicallyevidentthrombusinacutemyocar-dialinfarction:aTIMI14substudy[J].Circulation,2001,103(21):2550.(:2003-05-11):,,　　＊:,,　　Tel/Fax:[phone]　　E-mail:[e-mail]神经退行性疾病的药物作用新靶点的研究进展耿兴超,蒲小平＊(,100083):　分析国内外关于神经退行性疾病的药物作用靶点的最新研究进展,为该类疾病的治疗提供新的思路。　综述近几年的国内外文献。　近2年来研究神经退行性疾病有了很大的突破,在基因、受体、酶、离子通道等水平都有新治疗靶点的发现。　发现的药物新靶点,能够开发成为治疗神经退行性疾病的新药物。:神经退行性疾病;新靶点;治疗:R943.42　　　:A　　　:1001-2494(2005)04-0251-04　　20,、,。,、、、、,。,、,,。,(Alzheimer'sdisease,AD)、(Parkinson'sdisease,PD)(Amyotrophiclateralsclerosis,ALS)。,,2。1　(AD)1.1　tau蛋白相关靶点研究,tauAD。,,tau,β-(guanosinetriphosphate,GTP)tau。ADtau,GTP,,,,。(PP)-2Atau。(PP)-2Atau[1]。AD,tauAD,[2]。AD,1(Prolyliso-merase1,Pin1)tauphospho-Thr231。Pin1tau。Pin1tau,Pin1AD。,Pin1D1,G1,。Pin1G0/G1,,AD[3]。-5(cyclin-dependentkinase5,cdk5),p25AD,p25cdk5。p25/cdk5tau。p25/cdk5tau,cdk5[4]。1.2　淀粉样肽相关靶点β-(beta-amyloidpeptide,Abe-ta)AD。Abeta,3(APP,PS1PS2),Abeta42(FAD)。AbetaAD,AbetaAD。Abeta(amyloidprecursorprotein,APP)I。,β-γ-secretaseAPPAbeta。β-γ-secretase,Abeta[5]。·251·20052404　　　　　　　　　　ChinPharmJ,2005February,Vol.40No.4,JohnsHopkinsBACE1(beta-siteAPPcleavingenzyme1)ββ-secretase,。,BACE1,β-secretase,β。BACE1AD[6]。,。(5-aminoacidbeta-shectbreakerpeptide,iAbeta5P),AD[7]。,,10,,。AD。,,,,,[8]。,[9],AD。1.3　谷氨酸受体相关靶点AD,,[10]。,,。,AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionicacid),,。,,AMPA[11]。[12]。Ca2+Ca2+。,。Urushitani[13],NMDA(N-methyl-D-aspartate)Ca2+。。1.4　线粒体相关靶点,、,。,[14]。KeioIkuoNishi-motoAD,Humanin。16srRNA,AD。,HumaninmRNA,。HumaninmRNAAD[15]。,AD。1.5　其他相关靶点,-2(fi-broblastgrowthfactor-2,FGF-2)-2(microtubule-associatedprotein2),tau。(),AD,FGF-2。,8～12。ADFGF-2,,-2[16]。,,,。。AD。,[17]。5-,。5-,5-HT-moduline5-HT1B。5-HT-moduline5-。5-HT-moduline,,,。5-HT-moduline5-HT,5-HT-moduline,AD[18]。2　(PD)2.1　多巴胺受体相关靶点、、、。G,。105。D1D2,D3,D4D5。,,[19]。,D3,,D2。,D2D3。·252·ChinPharmJ,2005February,Vol.40No.4　　　　　　　　　　　20052404PDD3,D3PD。,。D3PD,[20]。2.2　烟碱型乙酰胆碱受体相关靶点PD。(nicotinicacetylcholinereceptors,nAChRs),PD,CtxMII[α3()α6nAChR]。,MPTP(1-methl-4-phenyl-1,2,3,6-te-trahydropyridine)PD。,125I-α-CtxMII,()。,125I-epibatidine,125I-α-CtxMIInAChR。α3()α6nAChRPD[21]。2.3　其他相关靶点A2A,。MPTP,A2APD,PD[22]。,A2APD。A2A6-OH。A2A,MPTP。A2A,。,,,A2APD。PDα-synuclein。Petrucelliα-synuclein。α-synucleinPD。α-synucleinPD,PDα-synuclein。HEK293,α-synuclein。MPTP,α-synuclein。,MPTP,β-synuclein。α-synuclein,,α-synucleinMPTPPD[23]。MPTP,MPTP、3,4-。MPTP(tyrosinehy-droxylase,TH)(MAP2),(glialfibrillaryacidicprotein,GFAP)。THMAP2,MPTP。,MPTP3d,GFAP。PD[24]。,3,4-(3,4-dihydroxypheny-lacetaldehyde,DOPAL)PD[25]。DADOPALPD。PDα-synuclein,DAα-synuclein。PDI,IDOPALDA。,DOPAL。DOPALPD。3　ALS,,,AMPA/Ca2+。I(mGlu),,,ImGlu3-(3-HPG)。mGlu5,mGlu1a。,ALS,mGlu1a。Glu1aALS[26]。。。,Nogo。Fournier[27]Nogo,Nogo。,Rho(RhoGTP),(BDNF)。,。RhoGTP。,、、·253·20052404　　　　　　　　　　ChinPharmJ,2005February,Vol.40No.4、,,,AD,PDALS,,。,,,,、,,。[1]　IqbalK,Alonso-AdelC,El-AkkadE,etal.PharmacologicaltargetstoinhibitAlzheimerneurofibrillarydegeneration[J].JNeuralTransm,2002,(62):309.[2]　LauLF,SchachterJB,SeymourPA,etal.Tauproteinphosphoryla-tionasatherapeutictargetinAlzheimer'sdisease[J].CurrTopMedChem,2002,2(4):395.[3]　HamdaneM,SmetC,SamboAV,etal.Pin1:atherapeutictargetinAlzheimerneurodegeneration[J].JMolNeurosci,2002,19(3):275.[4]　LauLF,SeymourPA,SannerMA,etal.Cdk5asadrugtargetforthetreatmentofAlzheimer'sdisease[J].JMolNeurosci,2002,19(3):267.[5]　TsaiJY,WolfeMS,XiaW.Thesearchforgamma-secretaseandde-velopmentofinhibitors[J].CurrMedChem,2002,9(11):1087.[6]　VassarR.Beta-Secretase(BACE)asadrugtargetforAlzheimer'sdisease[J].AdvDrugDelivRev,2002,54(12):1589.[7]　AdessiC,FrossardMJ,BoissardC,etal.PharmacologicalprofilesofpeptidedrugcandidatesforthetreatmentofAlzheimer'sdisease[J].JBiolChem,2003,278(16):13905.[8]　MatsuokaY,SaitoM,LaFrancoisJ,etal.Noveltherapeuticap-proachforthetreatmentofAlzheimer'sdiseasebyperipheraladminis-trationofagentswithanaffinitytobeta-amyloid[J].JNeurosci,2003,23(1):29.[9]　PasinettiGM.Cyclooxygenaseasatargetfortheantiamyloidogenicac-tivitiesofnonsteroidalanti-inflammatorydrugsinAlzheimer'sdisease[J].Neurosignals,2002,11(5):293.[10]　LeeHG,ZhuX,GhanbariHA,etal.Differentialregulationofgluta-matereceptorsinAlzheimer'sdisease[J].Neurosignals,2002,11(5):282.[11]　ZengL,LuL,MullerM,etal.Structure-basedfunctionaldesignofchemicalligandsforAMPA-subtypeglutamatereceptors[J].JMolNeurosci,2002,19(1～2):113.[12]　KleinRC,CastellinoFJ.ActivatorsandinhibitorsoftheionchanneloftheNMDAreceptor[J].CurrDrugTargets,2001,2(3):323.[13]　BleichS,RomerK,WiltfangJ,etal.Glutamateandtheglutamatereceptorsystem:atargetfordrugaction[J].IntJGeriatrPsychia-try,2003,18(Suppl1):33.[14]　ParraD,GonzalezA,MuguetaC,etal.Laboratorya