188宝金博页面版

Acta Pha rmacol Sin 2009 Ma y； 30(5)： 522— 529 P rotec tiv e ef fec ts of com p ou n d F L Z ，a n ov el sy n th eti c an al og u e of ~u am osam i d e，on am y loi d． i n d u ced rat brain m itoch on dri also u am osam ~ e l~-am 1ol ， - dy sfu n ction in v itro u ce rat n ltoc on ri al F ang FA N G §，G eng． tao L IU Department o f Pharmacology, Institute o f Materia Medica， Chinese Academy o f Medical Sciences and Peking Union Medical College Beij ing 100054 C hina Ai m： The aim of the present study was to assess the effects of N-[2一 (4-hy droxypheny1 )ethy1 ]一 2一 (2， 5一 dimethoxypheny1 )一 3一 (3一 methoxy一 4一 hydroxypheny1) acrylamide (compound FLZ)， a novel synthetic analogue of squamosamide， on the dysfunct i on of rat brain mitochondria induced by A [~ 2 5 — 3 5 in vitro． M ethod s： Isolated rat brain mitoch ondria were in cubated with aged A B (卜100 pmol／ L )． The activities of ， anion (0 2一 )， and the lev els of glutathione (GSH) in mitochondria w ere examined．Mitochondria1 sw elling and the release of cy t ochrom e c from m itoch on dria w ere assesse d by biochem ical an d W estern blot m ethods， respe ctiv ely ． Results： Incubation of mitochondria with aged a p2 5 — 3 5 inhibited the activities of Q-ketoglutarate dehydrogenase fa— KGDH)， pyruv ate dehydrogenase (PDH ) and respiratory chain complex IV ．It also resulted in increased H2O2 and 0 2一product i on， and decrease d the G S H lev el in mitochond ria ．F u rthe rm ore ， it ind uced m itochondrial sw ellin g an d cy tochrom e c rele ase from the mitochondria． The addition of FLZ (100 pmol／ L) prior to treatment with Ap2 5 -3 5 significantly prevented these toxic ef f ects of A p25I35 on the mitochondria． C onclusion： FLZ has a protect i ve effect agai n st A D， ¨ 一 induced mitochondrial dysfunction n vitro． for 30 min in the presence and absence of FLZ ( 2 2 )．k e y m itoch on drial e nz y m es the prod uction of hy d rog en peroxide H O an d sup erox ide K eyw ords： compound FLZ ； ~-amyloid； mitochondrial dysfunction； mitochondrial key enzymes； cytochrome c Acta Pharmac ologica Sinica (2009) 30： 522-529； doi： 10． 1038／ aps． 2009． 45 I n tro d uc ti on M itoch ondria p lay an im portant role in the regulat ion of c ell surv iv a1 an d death．M any lines of ev id ence suggest th at mitoc hon drial dysfun ctio n is critica1 to th e p ath ogen esis of zheimer’s disease (AD) and other neurodegenerative disordersl 一 ．A dd ition ally , m ito ch on drial dy sfunc tion has been proposed as a hallmark of p— amyloid (Ap)一 induced n euronal toxicity in th e dev elo pm en t and p ath ogenesis of AD 【 J．T h erefore, anti— A D ph arm acological studies h ave foc used in tensiv ely o n th e p ot ent ial p rotectiv e effect s of stabilizing or resto ring mitoch ondrial f unction as a therapy C o rresp on d en ce to P rof G eng — tao L IU ． E— mail liugt@imm． ac． cn／ gtliu2002@yahoo． cor n Now at the Department of Pharmacology, School of Chinese M ateria Medica, Beijing University o f Chinese Medicine, Beijing 100029， Chinf l E — m ail ty fan gfan g@ey ou ． co r n R eceiv ed 2009— 02— 06 A c cep ted 2009． ． 03． ． 24 5 22 against A D ? ． T h e n atural p ro duc t squam o sam ide w as isolated from the leaves of Annona squamosa．Compound FLZ (N 一 [2一 (4-hydroxypheny1 )ethy1 ]一 2一 (2， 5一 dimethoxypheny1 )一 3一 (3一 methoxy-4一 hydroxypheny1 ) acrylamide) is a novel synthetic cy clic deriv ativ e of squamo sam ide w ith a m olecular w eigh t of449． 5(Figure 1)． Our previous studies demonstrated that compound FL Z protected against dopamin e·- and M pp ~． in·· duced ap op tosis in P C 1 2 and SH — SY SY cells．Thi s pro tective ef f ect is though t to b e th e result o f inhibition of cytoch rome c release from mito ch o nd ria an d sub sequ ent c asp ase一 3 activ ati o n [ ． In addition． our I， ivo studies also sh0w ed th at com p ound F L Z im p rov ed abn orm al beh aviors cau sed by th e fu nction al disturb anc e of dop amin ergic and ch olin— ergic n euron s．F urtherm oreJ th is comp oun d also im prov ed the prognosis of mouse Parkinson's models(created through treatment with MPTP)． Thus， FLZ possesses a strong neuro— p rotect iv e property ．In addit ionJ F L Z w as also sh ow n to A cta P harmac ologica Sinic a 0 2009 C P S and SIM M