Inefficient central nervous system delivery limits the use of ibuprofen in neurodegenerative diseases

Mannila, Anne; Rautio, Jarkko; Lehtonen, Marko; Järvinen, Tomi; Savolainen, Jouko

doi:10.1016/j.ejps.2004.10.004

Cited by 32 publications

(25 citation statements)

References 23 publications

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“…In addition, recent in vitro studies demonstrate a novel non-COX-dependent activity of selected NSAIDs, which, at high concentrations, can directly alter ␥-secretase activity and reduce the ratio of A␤ 42/38 peptides in cultured cells (Weggen et al, 2001). These interesting findings have identified lead compounds acting directly on ␥-secretase to favor shorter forms of A␤ peptide; however, studies have differed on whether this mechanism occurs in vivo (Eriksen et al, 2003;Lanz et al, 2005), particularly at the lower therapeutic doses that result in reduced risk of developing AD and the low penetration of NSAIDs across the bloodbrain barrier (Mannila et al, 2005).…”

Section: Discussionmentioning

confidence: 91%

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Liang¹,

Wang²,

Hand³

et al. 2005

J. Neurosci.

221

202

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Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E 2 (PGE 2 ) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE 2 EP2 receptor in the APPSwe-PS1⌬E9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid-␤ (A␤) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1⌬E9 mice lacking the EP2 receptor harbor lower levels of ␤ C-terminal fragments, the product of ␤-site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE 2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased A␤ peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.

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Section: Discussionmentioning

confidence: 91%

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Liang¹,

Wang²,

Hand³

et al. 2005

J. Neurosci.

221

202

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“…The pharmacokinetic studies of ibuprofen and flurbiprofen in rats provide plasma levels in the 100-150 μM range and concentrations in brain tissue about 5 μM (Aldini et al 2002;Mannila et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Lack of enantiomeric influence on the brain cytoprotective effect of ibuprofen and flurbiprofen

López-Villodres

Cruz

Muñoz‐Marín

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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R(-) enantiomers of the 2-arylpropionic acid derivatives ibuprofen and flurbiprofen weakly inhibit cyclooxygenase (COX) activity. However, a possible cytoprotective effect has been proposed. The aim of the study is to investigate the possible mechanism of this effect. An in vitro hypoxia-reoxygenation model in rat brain slices was used (n=6 rats per group). After reoxygenation, we measured LDH efflux (neuronal death), brain prostaglandin E(2) (PGE(2)) concentration, interleukins (IL)-1β and 10, oxidative and nitrosative stress (lipid peroxides, glutathione, 3-nitrotyrosine, and nitrites/nitrates). Anti-COX activity was measured in human whole blood. Racemic, R(-), and S(+) enantiomers of ibuprofen and flurbiprofen were tested. All compounds had a cytoprotective effect with IC(50) values in the range of 10(-5) M. R(-) enantiomers did not significantly inhibit brain PGE(2). The concentration of IL-1β was reduced by 53.1% by the racemic form, 30.6% by the S(+) and 43.2% by the R(-) enantiomer of ibuprofen. The IL-10 concentration increased significantly only with S(+)-flurbiprofen (33.1%) and R(-)-flurbiprofen (26.1%). Lipid peroxidation was significantly reduced by all three forms of flurbiprofen. Nitrite + nitrate concentrations were reduced by racemic, S(+), and R(-)-flurbiprofen. Peroxynitrite formation (3-nitrotyrosine) was significantly reduced by racemic and S(+)-ibuprofen. COX inhibition is not the main mechanism of cytoprotection for these compounds. Their influence on inflammatory mediators and oxidative and nitrosative stress could account for the potential cytoprotective effect of R(-) enantiomers.

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“…Additionally, it has been reported that anionic drugs, such as b-lactam antibiotics, the 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pravastatin, centrally acting anionic NSAIDs, and baclofen, have poor brain distributions (10)(11)(12)(13)(14). However, little is known about whether MRP4 is involved in the renal tubular secretion and/or the restricted distribution in the CNS of these various anionic drugs.…”

Section: Introductionmentioning

confidence: 99%

Multichannel Liquid Chromatography–Tandem Mass Spectrometry Cocktail Method for Comprehensive Substrate Characterization of Multidrug Resistance-Associated Protein 4 Transporter

et al. 2007

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Inefficient central nervous system delivery limits the use of ibuprofen in neurodegenerative diseases

Cited by 32 publications

References 23 publications

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Lack of enantiomeric influence on the brain cytoprotective effect of ibuprofen and flurbiprofen

Multichannel Liquid Chromatography–Tandem Mass Spectrometry Cocktail Method for Comprehensive Substrate Characterization of Multidrug Resistance-Associated Protein 4 Transporter

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Inefficient central nervous system delivery limits the use of ibuprofen in neurodegenerative diseases

Cited by 32 publications

References 23 publications

Deletion of the Prostaglandin E2EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Deletion of the Prostaglandin E2EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Lack of enantiomeric influence on the brain cytoprotective effect of ibuprofen and flurbiprofen

Multichannel Liquid Chromatography–Tandem Mass Spectrometry Cocktail Method for Comprehensive Substrate Characterization of Multidrug Resistance-Associated Protein 4 Transporter

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Product

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Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease