The non-cyclooxygenase targets of non-steroidal anti-inflammatory drugs, lipoxygenases, peroxisome proliferator-activated receptor, inhibitor of kappa B kinase, and NF kappa B, do not reduce amyloid beta 42 production.
ABSTRACT Epidemiological evidence suggests that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of Alzheimer's disease. Recently, NSAIDs have been shown to decrease amyloid pathology in a transgenic mouse model of Alzheimer's disease. This benefit may be partially attributable to the ability of NSAIDs to selectively reduce production of the amyloidogenic A beta 42 peptide in both cultured cells and transgenic mice. Although this activity does not appear to require the action of cyclooxygenases in cultured cells, it is not known whether other NSAID-sensitive targets contribute to this A beta 42 effect. In this study, we have used both pharmacological and genetic means to determine if other known cellular targets of NSAIDs could mediate the reduction in A beta 42 secretion from cultured cells. We find that altered arachidonic acid metabolism via NSAID action on cyclooxygenases and lipoxygenases does not alter A beta 42 production. Furthermore, we demonstrate that alterations in activity of peroxisome proliferator-activated receptors, I kappa B kinase beta or nuclear factor kappa B do not affect A beta 42 production. Thus, NSAIDs do not appear to alter A beta 42 production indirectly through previously identified cellular targets and may interact directly with the gamma-secretase complex itself to affect amyloid production.
- Current Topics in Medicinal Chemistry 01/2008; 8(1):47-53. · 3.45 Impact Factor
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ABSTRACT: BACKGROUND: A hallmark of Alzheimer's disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Abeta42 and Abeta40. Many drug discovery efforts have focused on decreasing the production of Abeta42 through gamma-secretase inhibition. However, identification of gamma-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of gamma-secretase to shift Abeta production to favor shorter, less amyloidogenic peptides than Abeta42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called gamma-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer's disease. RESULTS: Here we describe EVP-0015962, a novel small molecule gamma-secretase modulator. EVP-0015962 decreased Abeta42 in H4 cells (IC50 = 67 nM) and increased the shorter Abeta38 by 1.7 fold at the IC50 for lowering of Abeta42. AbetaTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other gamma-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a gamma-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased Abeta42 and did not alter AbetaTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Abeta deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced Abeta aggregates, amyloid plaques, inflammatory markers, and cognitive deficits. CONCLUSIONS: EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective gamma-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Abeta42, attenuated memory deficits, and reduced Abeta plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that gamma-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer's disease.Molecular Neurodegeneration 12/2012; 7(1):61. · 5.29 Impact Factor
- Psychogeriatrics 03/2006; 6(1):1-3. · 1.22 Impact Factor