Mefenamic acid shows neuroprotective effects and improves cognitive impairment in in vitro and in vivo Alzheimer's disease models.
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 beta peptide (Abeta)(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 Abeta(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 Abeta(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.
Joo
Yuyoung
Y
Department of Pharmacology, College of Medicine National Creative Research Initiative Center for Alzheimer's Dementia Seoul National University Seoul, 110-799, South Korea.
Kim
Hye-Sun
HS
Woo
Ran-Sook
RS
Park
Cheol Hyoung
CH
Shin
Ki-Young
KY
Lee
Jean-Pyo
JP
Chang
Keun-A
KA
Kim
Seonghan
S
Suh
Yoo-Hun
YH
D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy*; D004789:Enzyme Activation; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D020932:Nerve Growth Factor / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D008528:Mefenamic Acid; D020932:Nerve Growth Factor; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases