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Ibuprofen May Protect Against Alzheimer's Disease

Posted by Quintal on August 10, 2007, at 4:34:35

Although ibuprofen has ulcerated my stomach, it does seem to posses some redeeming features. There's also evidence ibuprofen can protect against Parkinson's Disease.

1: J Biol Chem. 2003 Aug 15;278(33):30748-54. Epub 2003 May 31.Click here to read Links
Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain.
Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Golde TE, Koo EH.

Department of Neurosciences, University of California San Diego, La Jolla, California 92093, USA.

Epidemiological studies indicate that long term use of nonsteroidal anti-inflammatory drugs (NSAIDs) confers protection from Alzheimer's disease, and some NSAIDs were shown to specifically decrease production of the amyloidogenic Abeta42 peptide, most likely by direct modulation of gamma-secretase activity. In contrast to gamma-secretase inhibitors, Abeta42-lowering NSAIDs do not impair S3 cleavage in the NOTCH receptor and release of the NOTCH intracellular domain, a finding with conceptual implications for the development of safer drugs targeting Abeta production through gamma-secretase modulation. Intramembrane cleavage and release of an intracellular signaling domain has recently been demonstrated in a number of additional gamma-secretase substrates. We now show in cell-based assays that intramembrane cleavage of APP and ErbB-4 receptor is not impaired by the Abeta42-lowering NSAIDs, sulindac sulfide and ibuprofen. Generation of the APP intracellular domain (AICD) was further not inhibited in a cell-free assay at concentrations far exceeding those effective in reducing Abeta42 production. Closer inspection of AICD signaling showed that stabilization of the AICD peptide by FE65 and AICD-mediated transcription were also retained at Abeta42-lowering concentrations. These results demonstrate that S3-like/intramembrane cleavage is preserved by Abeta42-lowering NSAIDs in at least three substrates of gamma-secretase APP, ErbB-4, and NOTCH and underline the striking specificity by which these drugs target Abeta42 production.

PMID: 12777371 [PubMed - indexed for MEDLINE]

2: Science. 2003 Nov 14;302(5648):1215-7.Click here to read Links
Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho.
Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, Gonzalez-DeWhitt PA, Gelfanova V, Hale JE, May PC, Paul SM, Ni B.

Neuroscience Discovery Research and Bioresearch Technologies and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.

A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-beta peptide Abeta42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Abeta42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Abeta42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Abeta42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Abeta42 through inhibition of Rho activity.

PMID: 14615541 [PubMed - indexed for MEDLINE]

3: J Clin Invest. 2003 Aug;112(3):440-9.Click here to read Click here to read Links

Comment in:
J Clin Invest. 2003 Aug;112(3):321-3.

NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.
Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE.

Department of Neuroscience, Mayo Graduate School, Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA.

Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.

PMID: 12897211 [PubMed - indexed for MEDLINE]

4: J Neurochem. 2004 Nov;91(3):521-36.Click here to read Links
Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease: old and new mechanisms of action.
Gasparini L, Ongini E, Wenk G.

Nicox Research Institute, 20091 Bresso, Milan, Italy.

Alzheimer's disease (AD) is characterized by cerebral deposits of beta-amyloid (A beta) peptides and neurofibrillary tangles (NFT) which are surrounded by inflammatory cells. Epidemiological studies have shown that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. It has been postulated that some NSAIDs target pathological hallmarks of AD by interacting with several pathways, including the inhibition of cyclooxygenases (COX) and activation of the peroxisome proliferator-activated receptor gamma. A variety of experimental studies indicate that a subset of NSAIDs such as ibuprofen, flurbiprofen, indomethacin and sulindac also possess A beta-lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. While COX inhibition occurs at low concentrations in vitro (nM-low microm range), the A beta-lowering activity is observed at high concentrations (< or = 50 microm). Nonetheless, studies with flurbiprofen or ibuprofen in AD transgenic mice show that the effects on A beta levels or deposition are attained at plasma levels similar to those achieved in humans at therapeutic dosage. Still, it remains to be assessed whether adequate concentrations are reached in the brain. This is a crucial aspect that will allow defining the dose-window and the length of treatment in future clinical trials. Here, we will discuss how the combination of anti-amyloidogenic and anti-inflammatory activities of certain NSAIDs may produce a profile potentially relevant to their clinical use as disease-modifying agents for the treatment of AD.

PMID: 15485484 [PubMed - indexed for MEDLINE]

5: Neuropharmacology. 2005 Dec;49(7):1088-99. Epub 2005 Aug 25.Click here to read Links
Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro.
Hirohata M, Ono K, Naiki H, Yamada M.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan.

The pathogenesis of Alzheimer's disease (AD) is characterized by cerebral deposits of amyloid beta-peptides (A beta) and neurofibrillary tangles which are surrounded by inflammatory cells. Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of NSAIDs such as ibuprofen, aspirin, meclofenamic acid sodium salt, diclofenac sodium salt, ketoprofen, flurbiprofen, naproxen, sulindac sulfide and indomethacin on the formation, extension, and destabilization of beta-amyloid fibrils (fA beta) at pH 7.5 at 37 degrees C in vitro. All examined NSAIDs dose-dependently inhibited formation of fA beta from fresh A beta(1-40) and A beta(1-42), as well as their extension. Moreover, these NSAIDs dose-dependently destabilized preformed fA betas. The overall activity of the molecules examined was in the following order: ibuprofen approximately sulindac sulfide >or= meclofenamic acid sodium salt>aspirin approximately ketoprofen >or= flurbiprofen approximately diclofenac sodium salt>naproxen approximately indomethacin. Although the mechanisms by which these NSAIDs inhibit fA beta formation from A beta, and destabilize preformed fA beta in vitro are still unclear, NSAIDs may be promising for the prevention and treatment of AD.

PMID: 16125740 [PubMed - indexed for MEDLINE]

6: Expert Opin Investig Drugs. 2004 Nov;13(11):1469-81.Click here to read Links
The potential role of non-steroidal anti-inflammatory drugs in treating Alzheimer's disease.
Imbimbo BP.

Chiesi Farmaceutici, Research & Development Department, Via Palermo 26/A, 43100 Parma, Italy.

Epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Despite encouraging evidence, all large, long-term, placebo-controlled clinical trials aimed at reducing inflammation in the brain of AD patients produced negative results. More recently it has been shown that some NSAIDs decrease the production of amyloid-beta(1-42) (Abeta42), the major component of senile plaques of the AD brain, and counteract the progression of Abeta42 pathology in transgenic mouse models of AD. The proposed mechanism for this activity is an allosteric modulation of gamma-secretase activity, the enzyme responsible for the formation of amyloid-beta. The inhibition of Abeta42 production is independent from the anti-cyclooxygenase (COX) activity and is related to the chemical structure of the compounds, with some NSAIDs being active (ibuprofen, sulindac, flurbiprofen, indomethacin, diclofenac) and others not (naproxen, aspirin, celecoxib). This could explain the negative results of the large AD trials carried out so far, as they were conducted with compounds (naproxen, hydroxychloroquine, dapsone, prednisone, rofecoxib and celecoxib) that are not able to decrease Abeta42 production. Unfortunately, the use of these NSAIDs in AD is hampered by a significant gastrointestinal toxicity associated with COX inhibition. Thus, new NSAID analogues are being developed with potent and selective inhibitory activity on Abeta42 but with either lack of COX inhibitory activity or reduced gastrointestinal toxicity potential.

PMID: 15500394 [PubMed - indexed for MEDLINE]

7: Neurodegener Dis. 2006;3(4-5):298-304.Click here to read Links
Gamma-secretase modulation with Abeta42-lowering nonsteroidal anti-inflammatory drugs and derived compounds.
Czirr E, Weggen S.

Emmy Noether Research Group, Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, Mainz, Germany.

The amyloid-beta (Abeta) peptides and specifically the highly amyloidogenic isoform Abeta42 appear to be key agents in the pathogenesis of familial and sporadic forms of Alzheimer's disease (AD). The final step in the generation of Abeta from the amyloid precursor protein is catalyzed by the multiprotein complex gamma-secretase, which constitutes a prime drug target for prevention and therapy of the disease. However, highly potent gamma-secretase inhibitors that block formation of all Abeta peptides have provoked troubling side effects in preclinical animal models of AD. This toxicity can be readily explained by the promiscuous substrate specificity of gamma-secretase and its essential role in the NOTCH signaling pathway. For that reason and because of the crucial role of Abeta42 in the pathogenesis of the disease, selective inhibition of Abeta42 production would seem to be a more promising alternative to complete inhibition of gamma-secretase activity. This theoretical concept has edged much closer to clinical reality with the surprising finding that certain nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, and derived compounds display preferential Abeta42-lowering activity. In contrast to gamma-secretase inhibitors, these gamma-secretase modulators effectively suppress Abeta42 production while sparing processing of NOTCH and other gamma-secretase substrates. Although not fully resolved on the molecular level, the mechanism of action of Abeta42-lowering NSAIDs is independent of cyclooxygenase inhibition and most likely involves direct interaction with components of the gamma-secretase complex or its substrates. Current efforts to improve the pharmacological shortcomings of available gamma-secretase modulators will hopefully lead to the development of clinically useful Abeta42-lowering compounds in the near future. Copyright 2006 S. Karger AG, Basel.

PMID: 17047371 [PubMed - indexed for MEDLINE]





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