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Mefenamic Acid Shows Neuroprotective Effects and Improves Cognitive Impairment in in Vitro and in Vivo Alzheimer's Disease Models

Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, Medical Research Council, Seoul National University, Seoul, South Korea (Y.J., H.-S.K., R.-S.W., C.H.P., K.-Y.S., K.-A.C., S.K., Y.-H.S.); and Department of Pediatrics, School of Medicine, University of California at San Diego, La Jolla, California (J.-P.L.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert anti-inflammatory, analgesic, and antipyretic activities and suppress prostaglandin synthesis by inhibiting cyclooxygenase, an enzyme that catalyzes the formation of prostaglandin precursors from arachidonic acid. Epidemiological observations indicate that the long-term treatment of patients suffering from rheumatoid arthritis with NSAIDs results in reduced risk and delayed onset of Alzheimer's disease. In this study, we investigated the therapeutic potential for Alzheimer's disease of mefenamic acid, a commonly used NSAID that is a cyclooxygenase-1 and 2 inhibitor with only moderate anti-inflammatory properties. We found that mefenamic acid attenuates the neurotoxicities induced by amyloid peptide (A)_1–42 treatment and the expression of a Swedish double mutation (KM595/596NL) of amyloid precursor protein (Swe-APP) or the C-terminal fragments of APP (APP-CTs) in neuronal cells. We also show that mefenamic acid decreases the production of the free radical nitric oxide and reduces cytochrome c release from mitochondria induced by A_1–42, Swe-APP, or APP-CTs in neuronal cells. In addition, mefenamic acid up-regulates expression of the antiapoptotic protein Bcl-X_L. Moreover, our study demonstrates for the first time that mefenamic acid improves learning and memory impairment in an A_1–42-infused Alzheimer's disease rat model. Taking these in vitro and in vivo results together, our study suggests that mefenamic acid could be used as a therapeutic agent in Alzheimer's disease.

Address correspondence to: Yoo-Hun Suh, Department of Pharmacology, College of Medicine National Creative Research Initiative Center for Alzheimer's Dementia Seoul National University Seoul, 110-799, South Korea. E-mail: yhsuh{at}plaza.snu.ac.kr