药学学报, 2013, 48(12): 1743-1754
引用本文:
沈娇宁, 徐刘昕, 王蕊. 环氧合酶、脂氧酶及其靶向药物与阿尔茨海默病的防治[J]. 药学学报, 2013, 48(12): 1743-1754.
SHEN Jiao-ning, XU Liu-xin, WANG Rui. Cyclooxygenases, lipoxygenases, their targeted drugs and the prevention of Alzheimer’s disease[J]. Acta Pharmaceutica Sinica, 2013, 48(12): 1743-1754.

环氧合酶、脂氧酶及其靶向药物与阿尔茨海默病的防治
沈娇宁, 徐刘昕, 王蕊
华东理工大学药学院, 上海市新药设计重点实验室, 上海 200237
摘要:
许多研究显示,炎症与阿尔茨海默病(Alzheimer’s disease,AD)的发生发展关系密切。有证据表明长期服用非甾体抗炎药(non-steroidal anti-inflammatory drugs,NSAIDs)能够减轻AD病人或老年人认知能力的 下降。花生四烯酸(arachidonic acid,AA)代谢网络所产生的炎症介质,与很多炎症相关的疾病有关。脂氧酶(lipoxygenase,LOX)和环氧合酶(cyclooxygenase,COX)是AA网络中的两个关键酶,它们催化产生的类花生酸类物质(eicosanoids)有重要的促炎功能和许多生物活性,对AD的进程产生重要影响。虽然尚有不同的观点及互相矛盾的证据,但COX与LOX仍是当前研究AD发病机制和治疗药物的热点领域。本文主要对近年COX和LOX研究进展,尤其是与中枢神经系统功能及与AD发病的关系,以及LOX和COX作为药物干预靶点用于防治AD的可能性进行综述。
关键词:    脂氧酶      环氧合酶      花生四烯酸      阿尔茨海默病      β-淀粉样蛋白     
Cyclooxygenases, lipoxygenases, their targeted drugs and the prevention of Alzheimer’s disease
SHEN Jiao-ning, XU Liu-xin, WANG Rui
School of Pharmacy, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China
Abstract:
Many studies have shown that chronic inflammation occurs in the brain of patients with Alzheimer's disease (AD). It is well known that long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) can alleviate the cognitive decline of AD patient and elderly. Several inflammatory cytokines produced in the metabolism of arachidonic acid (AA) are closely related to inflammatory diseases. Lipoxygenases (LOXs) and cyclooxygenases (COXs) play a crucial role in the AA network, the products eicosanoids have an important impact on the progression of AD. Although there are many arguments and conflicting evidence, currently LOXs and COXs are still the hot topics in the research on AD pathogenesis and drug development. Here, we review the progress in research on COXs and LOXs, including their actions on CNS and their association with AD, and explore the feasibility of LOXs and COXs as targets for the drugs to prevent and/or treat AD.
Key words:    lipoxygenase    cyclooxygenase    arachidonic acid    Alzheimer’s disease    Aβ   
收稿日期: 2013-07-12
基金项目: 国家自然科学基金资助项目(81072627);教育部111项目(B07023);浦江人才计划(11PJ1402300);上海市科学技术委员会上海市新药设计重点实验室资助项目(11DZ2260600);上海市科学技术委员会重点项目(12431900901).
通讯作者: 王蕊
Email: ruiwang@ecust.edu.cn
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参考文献:
[1] Sanchez-Mejia RO, Mucke L. Phospholipase A2 and arachidonic acid in Alzheimer's disease[J]. Biochim Biophys Acta, 2010, 1801: 784-790.
[2] Listi F, Caruso C, Lio D, et al. Role of cyclooxygenase-2 and 5-lipoxygenase polymorphisms in Alzheimer's disease in a population from northern Italy: implication for pharmacogenomics[J]. J Alzheimers Dis, 2010, 19: 551-557.
[3] Tang WL, He MX, Yang B, et al. Association study of polymorphisms in the cyclooxygenase-2 gene and Alzheimer's disease risk in Chinese[J]. Neurol Sci, 2013, 34: 695-699.
[4] Choi SH, Bosetti F. Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid[J]. Aging (Albany NY), 2009, 1: 234-244.
[5] Choi SH, Aid S, Caracciolo L, et al. Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease[J]. J Neurochem, 2013, 124: 59-68.
[6] Firuzi O, Zhuo JM, Chinnici CM, et al. 5-Lipoxygenase gene disruption reduces amyloid-beta pathology in a mouse model of Alzheimer's disease[J]. FASEB J, 2008, 22: 1169-1178.
[7] Chu J, Praticò D. Pharmacologic blockade of 5-lipoxygenase improves the amyloidotic phenotype of an Alzheimer's disease transgenic mouse model[J]. Am J Pathol, 2011, 178: 1762-1769.
[8] Chu J, Giannopoulos PF, Ceballos-Diaz C, et al. Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice[J]. Mol Neurodegener, 2012, 7: 1.
[9] Succol F, Praticò D. A role for 12/15 lipoxygenase in the amyloid beta precursor protein metabolism[J]. J Neurochem, 2007, 103: 380-387.
[10] Yang HX, Zhuo JM, Chu J, et al. Amelioration of the Alzheimer's disease phenotype by absence of 12/15-lipoxygenase[J]. Biol Psychiatry, 2010, 68: 922-929.
[11] Yao Y, Clark CM, Trojanowski JQ, et al. Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment[J]. Ann Neurol, 2005, 58: 623-626.
[12] Imbimbo BP, Solfrizzi V, Panza F. Are NSAIDs useful to treat Alzheimer's disease or mild cognitive impairment?[J]. Front Aging Neurosci, 2010, 2: 1.
[13] Hayden KM, Zandi PP, Khachaturian AS, et al. Does NSAID use modify cognitive trajectories in the elderly? The Cache county study[J]. Neurology, 2007, 69: 275-282.
[14] Harizi H, Corcuff JB, Gualde N. Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology[J]. Trends Mol Med, 2008, 14: 461-469.
[15] Ueeda M, Doumei T, Takaya Y, et al. Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction[J]. Heart Vessels, 2011, 26: 145-152.
[16] Bederska-Łojewska D, Orczewska-Dudek S, Pieszka M. Metabolism of arachidonic acid, its concentration in animal products and influence on inflammatory processes in the human body[J]. Ann Animal Sci, 2013, 13: 177-194.
[17] Querfurth HW, LaFerla FM. Alzheimer's disease[J]. N Engl J Med, 2010, 362: 329-344.
[18] Sanchez-Mejia RO, Newman JW, Toh S, et al. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease[J]. Nat Neurosci, 2008, 11: 1311-1318.
[19] Esposito G, Giovacchini G, Liow JS, et al. Imaging neuroinflammation in Alzheimer's disease with radiolabeled arachidonic acid and PET[J]. J Nucl Med, 2008, 49: 1414-1421.
[20] Chalimoniuk M, Stolecka A, Cakala M, et al. Amyloid beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells[J]. Acta Biochim Pol, 2007, 54: 611-623.
[21] Amtul Z, Uhrig M, Wang L, et al. Detrimental effects of arachidonic acid and its metabolites in cellular and mouse models of Alzheimer's disease: structural insight[J]. Neurobiol Aging, 2012, 33: 821-831.
[22] Rao JS, Rapoport SI, Kim HW. Altered neuroinflammatory, arachidonic acid cascade and synaptic markers in postmortem Alzheimer's disease brain[J]. Transl Psychiatry, 2011, 1: 31.
[23] Mrak RE. Neuropathology and the neuroinflammation idea[J]. J Alzheimers Dis, 2009, 18: 473-481.
[24] Sastre M, Gentleman SM. NSAIDs: how they work and their prospects as therapeutics in Alzheimer's disease[J]. Front Aging Neurosci, 2010, 2: 20.
[25] Weggen S, Rogers M, Eriksen J. NSAIDs: small molecules for prevention of Alzheimer's disease or precursors for future drug development?[J]. Trends Pharmacol Sci, 2007, 28: 536-543.
[26] Imbimbo BP. An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer's disease[J]. Expert Opin Investig Drugs, 2009, 18: 1147-1168.
[27] McKee AC, Carreras I, Hossain L, et al. Ibuprofen reduces Abeta, hyperphosphorylated tau and memory deficits in Alzheimer mice[J]. Brain Res, 2008, 1207: 225-236.
[28] Aashish P, Tarun S, Pallavi B. Drug-induced hepatotoxicity: a review[J]. J Appl Pharm Sci, 2012, 2: 233-243.
[29] Jaturapatporn D, Isaac MG, McCleery J, et al. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease[J]. Cochrane Database Syst Rev, 2012, 2: CD006378.
[30] Aid S, Silva AC, Candelario-Jalil E, et al. Cyclooxygenase-1 and-2 differentially modulate lipopolysaccharide-induced blood-brain barrier disruption through matrix metalloproteinase activity[J]. J Cereb Blood Flow Metab, 2010, 30: 370-380.
[31] Choi SH, Aid S, Bosetti F. The distinct roles of cyclooxygenase-1 and-2 in neuroinflammation: implications for translational research[J]. Trends Pharmacol Sci, 2009, 30: 174-181.
[32] Garcia-Bueno B, Serrats J, Sawchenko PE. Cerebrovascular cyclooxygenase-1 expression, regulation, and role in hypothalamic-pituitary-adrenal axis activation by inflammatory stimuli[J]. J Neurosci, 2009, 29: 12970-12981.
[33] Aid S, Bosetti F. Targeting cyclooxygenases-1 and-2 in neuroinflammation: therapeutic implications[J]. Biochimie, 2011, 93: 46-51.
[34] Aid S, Bosetti F. Gene expression of cyclooxygenase-1 and Ca(2+)-independent phospholipase A(2) is altered in rat hippocampus during normal aging[J]. Brain Res Bull, 2007, 73: 108-113.
[35] Choi SH, Aid S, Choi U, et al. Cyclooxygenases-1 and-2 differentially modulate leukocyte recruitment into the inflamed brain[J]. Pharmacogenomics J, 2010, 10: 448-457.
[36] Matousek SB, Hein AM, Shaftel SS, et al. Cyclooxygenase-1 mediates prostaglandin E2 elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1 beta expression[J]. J Neurochem, 2010, 114: 247-258.
[37] Dargahi L, Nasiraei-Moghadam S, Abdi A, et al. Cyclooxygenase (COX)-1 activity precedes the COX-2 induction in A beta-induced neuroinflammation[J]. J Mol Neurosci, 2011, 45: 10-21.
[38] Hoozemans JJ, Rozemuller JM, van Haastert ES, et al. Cyclooxygenase-1 and-2 in the different stages of Alzheimer's disease pathology[J]. Curr Pharm Des, 2008, 14: 1419-1427.
[39] Aid S, Langenbach R, Bosetti F. Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2[J]. J Neuroinflammation, 2008, 5: 17.
[40] Ferretti MT, Bruno MA, Ducatenzeiler A, et al. Intracellular A beta-oligomers and early inflammation in a model of Alzheimer's disease[J]. Neurobiol Aging, 2012, 33: 1329-1342.
[41] Blanco A, Alvarez S, Fresno M, et al. Amyloid-beta induces cyclooxygenase-2 and PGE2 release in human astrocytes in NF-kappa B dependent manner[J]. J Alzheimers Dis, 2010, 22: 493-505.
[42] Carrero I, Gonzalo MR, Martin B, et al. Oligomers of beta-amyloid protein (A beta 1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1beta, tumour necrosis factor-alpha, and a nuclear factor kappa-B mechanism in the rat brain[J]. Exp Neurol, 2012, 236: 215-227.
[43] Medeiros R, Figueiredo CP, Pandolfo P, et al. The role of TNF-alpha signaling pathway on COX-2 upregulation and cognitive decline induced by beta-amyloid peptide[J]. Behav Brain Res, 2010, 209: 165-173.
[44] Yin LL, Li W, Chu YQ, et al. ERK pathway activation is required for amyloid-beta(1-40)-induced neurotoxicity of THP-1 human monocytes towards SK-N-SH neuroblastoma[J]. Brain Res, 2011, 1378: 9-17.
[45] Ramin M, Azizi P, Motamedi F, et al. Inhibition of JNK phosphorylation reverses memory deficit induced by beta-amyloid (1-42) associated with decrease of apoptotic factors[J]. Behav Brain Res, 2011, 217: 424-431.
[46] Rickle A, Bogdanovic N, Volkman I, et al. Akt activity in Alzheimer's disease and other neurodegenerative disorders[J]. Neuroreport, 2004, 15: 955-959.
[47] Stark DT, Bazan NG. Synaptic and extrasynaptic NMDA receptors differentially modulate neuronal cyclooxygenase-2 function, lipid peroxidation, and neuroprotection[J]. J Neurosci, 2011, 31: 13710-13721.
[48] Niemoller TD, Bazan NG. Docosahexaenoic acid neurolipi­domics[J]. Prostaglandins Other Lipid Mediat, 2010, 91: 85-89.
[49] Jiang J, Ganesh T, Du Y, et al. Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor[J]. Proc Natl Acad Sci USA, 2010, 107: 2307-2312.
[50] Hoshino T, Namba T, Takehara M, et al. Prostaglandin E2 stimulates the production of amyloid-beta peptides through internalization of the EP4 receptor[J]. J Biol Chem, 2009, 284: 18493-18502.
[51] Abe T, Kunz A, Shimamura M, et al. The neuroprotective effect of prostaglandin E2 EP1 receptor inhibition has a wide therapeutic window, is sustained in time and is not sexually dimorphic[J]. J Cereb Blood Flow Metab, 2009, 29: 66-72.
[52] Zhen GH, Kim YT, Li RC, et al. PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease[J]. Neurobiol Aging, 2012, 33: 2215-2219.
[53] Shi J, Johansson J, Woodling NS, et al. The prostaglandin E-2 E-prostanoid 4 receptor exerts anti-inflammatory effects in brain innate immunity[J]. J Immunol, 2010, 184: 7207-7218.
[54] Chou VP, Holman TR, Manning-Bog AB. Differential contribution of lipoxygenase isozymes to nigrostriatal vulnerability[J]. Neuroscience, 2013, 228: 73-82.
[55] Ikonomovic MD, Abrahamson EE, Uz T, et al. Increased 5-lipoxygenase immunoreactivity in the hippocampus of patients with Alzheimer's disease[J]. J Histochem Cytochem, 2008, 56: 1065-1073.
[56] Chu J, Pratico D. 5-Lipoxygenase pharmacological blockade decreases tau phosphorylation in vivo: involvement of the cyclin-dependent kinase-5[J]. Neurobiol Aging, 2013, 34: 1549-1554.
[57] Chu J, Giannopoulos PF, Ceballos-Diaz C, et al. 5-Lipoxy­genase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease[J]. Ann Neurol, 2012, 72: 442-454.
[58] Joshi YB, Chu J, Pratico D. Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice[J]. Aging Cell, 2013, 12: 706-711.
[59] Chinnici CM, Yao Y, Praticò D. The 5-lipoxygenase enzymatic pathway in the mouse brain: young versus old[J]. Neurobiol Aging, 2007, 28: 1457-1462.
[60] Chu J, Pratico D. 5-Lipoxygenase as an endogenous modulator of amyloid beta formation in vivo[J]. Ann Neurol, 2011, 69: 34-46.
[61] Wang ZJ, Zhou B, Mao WW, et al. Overexpression of 5-lipoxygenase increases the neuronal vulnerability of PC12 cells to A beta42[J]. Yakugaku Zasshi, 2011, 131: 1843-1853.
[62] Dzitoyeva S, Imbesi M, Ng LW, et al. 5-Lipoxygenase DNA methylation and mRNA content in the brain and heart of young and old mice[J]. Neural Plast, 2009, 2009: 209596.
[63] Chu J, Zhuo JM, Pratico D. Transcriptional regulation of beta-secretase-1 by 12/15-lipoxygenase results in enhanced amyloidogenesis and cognitive impairments[J]. Ann Neurol, 2012, 71: 57-67.
[64] Lebeau A, Terro F, Rostene W, et al. Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by beta-amyloid peptide[J]. Cell Death Differ, 2004, 11: 875-884.
[65] Lukiw WJ, Bazan NG. Survival signalling in Alzheimer's disease[J]. Biochem Soc Trans, 2006, 34: 1277-1282.
[66] Okubo M, Yamanaka H, Kobayashi K, et al. Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal cord contribute to the generation of neuropathic pain[J]. Glia, 2010, 58: 599-610.
[67] Wada K, Arita M, Nakajima A, et al. Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation[J]. FASEB J, 2006, 20: 1785-1792.
[68] Daniele S, Lecca D, Trincavelli ML, et al. Regulation of PC12 cell survival and differentiation by the new P2Y-like receptor GPR17[J]. Cell Signal, 2010, 22: 697-706.
[69] Sobrado M, Pereira MP, Ballesteros I, et al. Synthesis of lipoxin A4 by 5-lipoxygenase mediates PPARgamma-dependent, neuroprotective effects of rosiglitazone in experimental stroke[J]. J Neurosci, 2009, 29: 3875-3884.
[70] Tu XK, Yang WZ, Wang CH, et al. Zileuton reduces inflammatory reaction and brain damage following permanent cerebral ischemia in rats[J]. Inflammation, 2010, 33: 344-352.
[71] Ye Y, Lin Y, Perez-Polo JR, et al. Phosphorylation of 5-lipoxygenase at ser523 by protein kinase A determines whether pioglitazone and atorvastatin induce proinflammatory leukotriene B4 or anti-inflammatory 15-epi-lipoxin a4 production[J]. J Immunol, 2008, 181: 3515-3523.
[72] Singh RK, Gupta S, Dastidar S, et al. Cysteinyl leukotrienes and their receptors: molecular and functional characteristics[J]. Pharmacology, 2010, 85: 336-349.
[73] Back M, Dahlen SE, Drazen JM, et al. International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions[J]. Pharmacol Rev, 2011, 63: 539-584.
[74] Ding Q, Fang SH, Zhou Y, et al. Cysteinyl leukotriene receptor 1 partially mediates brain cryoinjury in mice[J]. Acta Pharmacol Sin, 2007, 28: 945-952.
[75] Khan M, Singh J, Gilg AG, et al. Very long-chain fatty acid accumulation causes lipotoxic response via 5-lipoxygenase in cerebral adrenoleukodystrophy[J]. J Lipid Res, 2010, 51: 1685-1695.
[76] Wang XY, Tang SS, Hu M, et al. Leukotriene D4 induces amyloid-beta generation via CysLT(1)R-mediated NF-kappaB pathways in primary neurons[J]. Neurochem Int, 2013, 62: 340-347.
[77] Pallast S, Arai K, Wang XY, et al. 12/15-Lipoxygenase targets neuronal mitochondria under oxidative stress[J]. J Neurochem, 2009, 111: 882-889.
[78] Loscalzo J. Membrane redox state and apoptosis: death by peroxide[J]. Cell Metab, 2008, 8: 182-183.
[79] Serhan CN, Krishnamoorthy S, Recchiuti A, et al. Novel anti-inflammatory-pro-resolving mediators and their receptors[J]. Curr Top Med Chem, 2011, 11: 629-647.
[80] Serhan CN. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways[J]. Annu Rev Immunol, 2007, 25: 101-137.
[81] Das UN. Is multiple sclerosis a proresolution deficiency disorder?[J]. Nutrition, 2012, 28: 951-958.
[82] Wu L, Miao S, Zou LB, et al. Lipoxin A4 inhibits 5-lipoxygenase translocation and leukotrienes biosynthesis to exert a neuroprotective effect in cerebral ischemia/reperfusion injury[J]. J Mol Neurosci, 2012, 48: 185-200.
[83] Manev H, Chen H, Dzitoyeva S, et al. Cyclooxygenases and 5-lipoxygenase in Alzheimer's disease[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2011, 35: 315-319.
[84] Ge QF, Hu X, Ma ZQ, et al. Baicalin attenuates oxygen-glucose deprivation-induced injury via inhibiting NMDA receptor-mediated 5-lipoxygenase activation in rat cortical neurons[J]. Pharmacol Res, 2007, 55: 148-157.
[85] Li CT, Zhang WP, Fang SH, et al. Baicalin attenuates oxygen-glucose deprivation-induced injury by inhibiting oxidative stress-mediated 5-lipoxygenase activation in PC12 cells[J]. Acta Pharmacol Sin, 2010, 31: 137-144.
[86] Zhang Y, Feng TJ, Zhang ZJ, et al. Progress in research of baicalein affecting Alzheimer's disease and improving learning and memory of brain[J]. Chin Pharmacol Bull (中国药理学通报), 2010, 26: 20-23.
[87] Yin F, Liu JH, Ji XH, et al. Baicalin prevents the production of hydrogen peroxide and oxidative stress induced by Abeta aggregation in SH-SY5Y cells[J]. Neurosci Lett, 2011, 492: 76-79.
[88] Xu YW, Sun L, Liang H, et al. 12/15-Lipoxygenase inhibitor baicalein suppresses PPAR gamma expression and nuclear translocation induced by cerebral ischemia/reperfusion[J]. Brain Res, 2010, 1307: 149-157.
[89] Sul D, Kim HS, Lee D, et al. Protective effect of caffeic acid against beta-amyloid-induced neurotoxicity by the inhibition of calcium influx and tau phosphorylation[J]. Life Sci, 2009, 84: 257-262.
[90] Pan YQ, Zhang P, Yang JQ, et al. 5-Lipoxygenase expression in a brain damage model induced by chronic oral administration of aluminum[J]. Neural Regen Res, 2010, 5: 1634-1638.
[91] Liu Y, Wang H, Zhu YM, et al. The protective effect of nordihydroguaiaretic acid on cerebral ischemia/reperfusion injury is mediated by the JNK pathway[J]. Brain Res, 2012, 1445: 73-81.
[92] Li L, Zeng HW, Liu F, et al. Target identification and validation of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate, an anti-inflammatory natural product[J]. Eur J Inflamm, 2012, 10: 297-309.
[93] Cuello AC, Ferretti MT, Leon WC, et al. Early-stage inflammation and experimental therapy in transgenic models of the Alzheimer-like amyloid pathology[J]. Neurodegener Dis, 2010, 7: 96-98.
[94] Chu LS, Fang SH, Zhou Y, et al. Minocycline inhibits 5-lipoxygenase expression and accelerates functional recovery in chronic phase of focal cerebral ischemia in rats[J]. Life Sci, 2010, 86: 170-177.
[95] Kumar A, Prakash A, Pahwa D, et al. Montelukast potentiates the protective effect of rofecoxib against kainic acid-induced cognitive dysfunction in rats[J]. Pharmacol Biochem Behav, 2012, 103: 43-52.
[96] Chu J, Praticò D. Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer's disease mouse model[J]. J Neuroinflammation, 2012, 9: 127.
[97] Bishnoi M, Patil CS, Kumar A, et al. Protective effects of nimesulide (COX inhibitor), AKBA (5-LOX inhibitor), and their combination in aging-associated abnormalities in mice[J]. Methods Find Exp Clin Pharmacol, 2005, 27: 465-470.