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.
- SourceAvailable from: europepmc.org[Show abstract] [Hide abstract]
ABSTRACT: Indomethacin and ibuprofen are potent inhibitors of prostaglandin synthesis. Neonates have been exposed to these compounds for more than 3 decades. Indomethacin is commonly used to prevent intraventricular hemorrhage (IVH), and both drugs are prescribed for the treatment or prevention of patent ductus arteriosus (PDA). This review examines the basis for indomethacin and ibuprofen use in the neonatal intensive care population. Despite the call for restrained use of each drug, the most immature infants are likely to need pharmacologic approaches to reduce high-grade IVH, avoid the need for PDA ligation, and preserve the opportunity for an optimal outcome.Clinics in perinatology 03/2012; 39(1):111-36. · 1.54 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer's disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Ab peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.DNA research: an international journal for rapid publication of reports on genes and genomes 12/2011; 9(4):598-622. · 1.73 Impact Factor
- [Show abstract] [Hide abstract]
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. · 4.01 Impact Factor