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

Abstract

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.

Characterization of the interaction between fenamates and hippocampal neuron GABAA receptors

“…MFA has also been reported to reduce neuronal damage induced by intraventricular amyloid beta peptide (Aβ ) and improve learning in rats treated with Aβ 1-42 (Joo et al, 2006).…”

Microglial NLRP3 Activity in Alzheimer's Disease

“…In addition, this treatment prevents memory deficit and neuroinflammation, besides decreasing NLRP3 activation in microglia from treated animals [52]. In another study, the treatment with mefenamic acid, another NSAID drug, reduced neural cell toxicity and protected rats from memory deficits [53]. Furthermore, ibuprofen specifically reduced pro-amyloidogenic α1 antichymotrypsin in vitro and in vivo by suppressing IL-1β [54].…”

The Discovery of Pyridone and Pyridazone Heterocycles as γ-Secretase Modulators

“…When the biaryl aniline was moved from the C4 to the C5 position, we saw more than a 10-fold decrease of activity (15). When an oxygen linker was introduced (16), the activity was 4-fold less potent as compared to its amino analogue (11).…”

“…To further improve the activity, we next turned our attention to modification of the C6 position. As summarized in Table 1, introduction of alkyl ethers at C6 was tolerated and gave reasonably good in vitro activity (11)(12)(13). Bulky substituents did not affect the activity too much and gave comparable Aβ42 inhibition and Aβtotal/42 selectivity (14).…”

“…There are two major classes of γ-secretase modulators in clinical trials. One is structure-related to nonsteroidal anti-inflammatory acids (NSAIDs), 11,12 such as 1 from Myriad. The other is the non-NSAIDs class, such as 2 from Eisai.…”