5　NSA ID s的其它作用机制

有人将吲哚美辛应用于老年受试者,发现能加强感觉运动协调和增强短期记忆。长期给予阿司匹林或塞来昔布可以提高老年动物的学习能力。N 2甲基2D2天冬氨酸(N 2meth2yl2D2aspartate,NMDA)受体NR2B 亚型在老年鼠中下降,与行为学实验中的动作障碍相互关联。避免NR2B亚型随年龄减少的治疗也能减轻记忆缺失。Mesches等[ 27 ] 给老年Fischer 344大鼠2 mon的舒林酸治疗,结果显示舒林酸本身,而非其抗COX活性的硫化物形式,可以减轻水迷宫实验中学习和记忆缺失,机制可能是减缓NMDA受体亚型NR1和NR2B的降低,并预防致炎细胞因子IL21β的增加。Kukar等[ 28 ]在淀粉样斑沉淀形成之前给Tg2576小鼠R - 氟布洛芬,然后进行Morris水迷宫实验,结果发现小鼠的空间学习能力提高。另外还有人认为NSA IDs对羟基有黏附作用,可消除自由基,从而减轻AD的炎症反应。

总之, NSA IDs可通过作用于COX、Aβ、PPARγ、NF2κB、改善认知等对AD具有一定保护作用,但所用剂量比常用量要大,严重的胃肠道不良反应限制了传统NSA IDs用于AD的长期治疗。因此,开发疗效更高、特异性更强、安全性和耐受性更好的非甾体类抗炎药物,对于控制AD的进展和症状改善有着广阔的应用前景。

参考文献:

[ 1 ] 　Townsend K P, Pratico D. Novel therapeutic opportunities forAlzheimer′s disease: focus on nonsteroidal anti2inflammatory drugs[ J ]. FASEB J , 2005, 19 (12) : 1592 - 601.

[ 2 ] 　McGeer P L,McGeer E G. NSA IDs and Alzheime disease: Ep ide2miological, animalmodel and clinical studies[ J ]. N eurobiolAging,2007, 28 (5) : 639 - 47.

[ 3 ] 　张　纯,吴　青,陈　燕. 选择性COX22抑制剂NS2398诱导白血病细胞凋亡的作用机制[ J ]. 中国药理学通报, 2007, 23 ( 7) :899 - 902.

[ 3 ] 　Zhang C,Wu Q, Chen Y. Effect of selective cyclooxygenase22 in2hibitorNS2398 on cell apop tosis in K562 cells and its underlyingmechanism[ J ]. Chin Pharm acol B ull, 2007, 23 (7) : 899 - 902.

[ 4 ] 　李淑惠,李晓辉. 炎症介质与消炎药[M ] / /张庆柱主编. 分子药理学. 北京:高等教育出版社, 2007: 468 - 9.

[ 4 ] 　Li S H, Li X H. Mediators of inflammation and anti2inflamatorydrug [M ] / /Zhang Q Z editor. M olecular Pharm acology. Beijing:Higher Education Press, 2007: 468 - 9.

[ 5 ] 　Nogawa S, TakaoM, Suzuki S, et al. COX22 exp ression in brains ofpatientswith familial Alzheimer′s disease[ J ]. Int Congress Series,2003, 1252: 363 - 72.

[ 6 ] 　GiovanniniM G, Scali C, Prosperi C, et al. Beta2amyloid2inducedinflammation and cholinergic hypofunction in the rat brain in vivo:involvement of the p38MAPK pathway[ J ]. N eurobiolD is, 2002, 11(2) : 257 - 74.

[ 7 ] 　Yermakova A V, O′Banion M K. Downregulation of neuronal cy2clooxygenase22 exp ression in end stage Alzheimer′s disease [ J ].N eurobiol Aging, 2001, 22 (6) : 823 - 36.

[ 8 ] 　Avramovich Y, Amit T, Youdim M B. Non2steroidal Anti2inflam2matory Drugs Stimulate Secretion of Non2amyloidogenic PrecursorProtein[ J ]. J B iol Chem , 2002, 277 (35) : 31466 - 73.

[ 9 ] 　Weggen S, Eriksen J L, Das P, et al. A subset of NSA IDs loweramyloidogenic Aβ42 independently of cyclooxygenase activity[ J ].N ature, 2001, 414 (6860) : 212 - 6.

[ 10 ] Lleo A,Berezovska O, HerlL, et al. Nonsteroidal anti2inflammatorydrugs lowerAbeta42 and change p resenilin 1 conformation[ J ]. N atM ed, 2004, 10 (10) : 1065 - 6.

[ 11 ] Yan Z, Yuan S, Baolin L, et al. Nonsteroidal Anti2InflammatoryDrugs Can LowerAmyloidogenic Aβ42 by Inhibiting Rho[ J ]. Sci2ence, 2003, 302 (5648) : 1215 - 17.

[ 12 ] HirohataM,Ono K,Naiki H, et al. Non2steroidal anti2inflammatorydrugs have anti2amyloidogenic effects forAlzheimer′sβ2amyloid fi2brils in vitro[ J ]. N europharm acology, 2005, 49 (7) : 1088 - 99.

[ 13 ] Wilcock DM , Jantzen P T ,LiQ, et al. Amyloidβ vaccination, butnot nitro2nonsteroidal anti2inflammatory drug treatment, increasesvascular amyloid and microhemorrhage while both reduce paren2chymal amyloid[ J ]. N euroscience, 2007, 144: 950 - 60.

[ 14 ] Morihara T, Teter B, Yang F, et al. Ibup rofen Supp resses Interleu2kin21 Induction of Pro2Amyloidogenicα12Antichymotryp sin to Aβmeliorate2Amyloid (Aβ) Pathology in Alzheimer′s Models [ J ].N europsychopharm acology, 2005, 30 (6) : 1111 - 20.

[ 15 ] Quinn J,Montine T,Morrow J, et al. Inflammation and cerebralamyloidosis are disconnected in an animal model of Alzheimer’sdisease[ J ]. J N euroimm unol, 2003, 137 (122) : 32 - 41.

[ 16 ] Imbimbo B P,Del Giudice E, CenacchiV, et al. In vitro and in vi2vo p rofiling of CHF5022 and CHF5074 Twoβ2amyloid1242 lower2ing agents[ J ]. Pharm acol Res, 2007, 55 (4) : 318 - 28.

[ 17 ] Iwata R, Kitagawa K, Zhang N Y, et al. Non2steroidal anti2inflam2matory drugs p rotect amyloidβ p rotein2induced increase in the in2tracellular Cl2concentration in cultured rat hippocampal neurons[ J ]. N eurosci Lett, 2004, 367 (2) : 156 - 59.

[ 18 ] 张慧灵,顾振纶,秦正红. PPARs与神经退行性疾病[ J ]. 中国药理学通报, 2006, 22 (4) : 397 - 402.

[ 18 ] Zhang H L, Gu ZL,Qin Z H. PPARs and nerodegenerative disease[ J ]. Chin Pharm acol B ull, 2006, 22 (4) : 397 - 402.

[ 19 ] Csastre M, Dewachter I, Rossner S, et al. NSA IDs rep ress BACE1gene p romoter activity by activation of the peroxisome p rolifera2toractivated recep tor2γ ( PPARγ) [ J ]. Proc N atl Acad Sci USA,2006, 103 (2) : 443 - 8.

[ 20 ] Rossner S, Sastre M, Bourne K, et al. Transcrip tional and transla2tional regulation of BACE1 exp ression2Imp lications forAlzheimer′sdisease[ J ]. Prog N eurobiol, 2006, 79 (2) : 95 - 111.

[ 21 ] Neve R L,McPhie D L. The cell cycle as a therapeutic target forAlzheimer′s disease[ J ]. Pharm acology & Therapeutics, 2006, 111:99 - 113.

[ 22 ] Inestrosa N C, Godoy J A,Quintanilla R A, et al. Peroxisome p ro2liferator2activated recep torγis exp ressed in hippocampal neuronsand its activation p revents β2amyloid neurodegeneration: role ofWnt signaling[ J ]. Exp Cell Res, 2005, 304 (1) : 91 - 104.

[ 23 ] d′Abramo C,Massone S, Zingg J M, et al. Role of peroxisome pro2liferator2activated recep tor gamma in amyloid p recursor p rotein p ro2cessing and amyloid beta2mediated cell death [ J ]. B iochem J ,2005, 391 (3) : 693 - 8.

[ 24 ] Camacho I E, SerneelsL, Sp ittaels K, et al. Peroxisome p roliferator2activated recep tor2γ induces a clearance mechanism for the amy2loid2βpep tide[ J ]. J N eurosci, 2004, 24 (48) : 10908 - 17. [ 25 ] 陈云波,张大鹏,冯　梅,等. 人参皂苷Rg1对Aβ25235诱导的神经细胞核因子2κB活化的影响[ J ]. 中国药理学通报, 2007, 23(5) : 612 - 7.

[ 25 ] Chen Y B, Zhang D P, FengM, et al. Effects of Ginsenoside Rg1on the activation of NF2κB in neuronal cells induced by Aβ25235[ J ]. Chin Pharm acol B ull, 2007, 23 (5) : 612 - 7.

[ 26 ] Trojanowski J Q,Lee V M, Pratico D. Modulation of nuclear factor2kappa B activity by indomethacin influences A beta levels but notA beta p recursor p rotein metabolism in a model ofAlzheimer′s dis2ease[ J ]. Am J Pathol, 2004, 165: 2197 - 2206.

[ 27 ] MeschesM H, Gemma C,VengLM, et al. Sulindac imp rovesmem2ory and increasesNMDA recep tor subunits in aged Fischer 344 rats[ J ]. N eurobi Aging, 2004, 25 (3) : 315 - 24.

[ 28 ] Kukar T, Prescott S, Eriksen J L, et al. Chronic administration of R2flurbip rofen attenuates learning impairments in transgenic amyloidp recursor p rotein mice[ J ]. BMC N eurosci, 2007, 8: 54 - 65.