Long-Term Efficacy and Safety of Celecoxib in Alzheimer’s Disease

Soininen, Hilkka; West, Christine R.; Robbins, Jeffery; Niculescu, Liviu

doi:10.1159/000096588

Cited by 123 publications

(72 citation statements)

References 88 publications

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“…Therefore, COX-2 has been considered a pharmacologic target for selective therapies for neuroinflammation. However, several trials with COX-2-selective inhibitors such as celecoxib and rofecoxib have failed to ameliorate AD, whereas COX-1-selective or nonselective NSAIDs such as indomethacin and ibuprofen show Ab-lowering properties in both AD transgenic mice and cell cultures (16)(17)(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

“…4A). To identify the cellular origin of (S)-11 C-KTP-Me accumulation in APP-Tg mice, we performed triple immunostaining for COX-1 or COX-2 with microglial markers Iba-1 or CD11b and Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] . Ab plaques were age-dependently increased in size and number, and COX-1 immunopositive microglia were also found in association with areas of abundant Ab (Fig.…”

Section: Changes In Coxs During Pathologic Process In App-tg Micementioning

confidence: 99%

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Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

Shukuri

Mawatari²,

Ohno³

et al. 2015

J Nucl Med

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Cyclooxygenase (COX), a prostanoid-synthesizing enzyme, is considered to be involved in the neuroinflammatory process of neurodegenerative diseases. However, the role of COX in the progression of neurodegeneration is not well understood. We hypothesized that in vivo imaging of COX by PET will contribute to elucidation of the function of COX during the neurodegenerative process in Alzheimer's disease (AD). 11 C-labeled ketoprofen methyl ester (racemic (RS)-11 C-KTP-Me) developed recently by our group is a useful PET probe for in vivo imaging of COX-1 during neuroinflammation. The (S)-enantiomer of ketoprofen is known to be pharmacologically more active than the (R)-enantiomer. We thus synthesized 11 C-labeled (S)-ketoprofen methyl ester ((S)-11 C-KTP-Me) as an improved PET probe specific for COX-1 and applied it for investigation of the changes in COX-1 during the progression of AD in a mouse model. Methods: The specificity of (S)-11 C-KTP-Me for COXs was examined in PET studies with rats that had intrastriatal injection of lipopolysaccharide. To determine the details of changes in COX-1 during progression of amyloid-β (Aβ) plaque formation in amyloid precursor protein transgenic (APP-Tg) mice, we performed immunohistochemical studies and ex vivo autoradiography with (S)-11 C-KTP-Me. Results: PET studies using hemispheric lipopolysaccharide injection into rats revealed that the sensitivity of (S)-11 C-KTP-Me in neuroinflammation was much higher than that of (RS)-11 C-KTP-Me and (R)-11 C-KTP-Me; these results closely corresponded to the inhibitory activities of each enantiomer against COX-1 estimated by an in vitro assay. In APP-Tg mice, (S)-11 C-KTP-Me administration resulted in progressive and significant increases in accumulation of radioactivity in the brain from 16 to 24 mo old in accordance with the histopathologic appearance of abundant Aβ plaques and activated microglia, whereas few changes in radioactivity accumulation and few Aβ plaques were seen in age-matched wild-type control mice. High-radioactivity accumulation by (S)-11 C-KTP-Me was markedly observed in the frontal cortex and hippocampus in which COX-1-expressing activated microglia tightly surrounded and enclosed large and more intensely stained Aβ plaques, indicating neuroinflammation that originated with Aβ. Conclusion: (S)-11 C-KTP-Me is a potent PET probe that is highly selective for COX-1. Studies using APP-Tg mice demonstrated that (S)-11 C-KTP-Me could detect activated microglia that are associated with amyloid plaque progression, suggesting the involvement of COX-1 in the neuroinflammatory process in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Changes In Coxs During Pathologic Process In App-tg Micementioning

confidence: 99%

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

Shukuri

Mawatari²,

Ohno³

et al. 2015

J Nucl Med

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“…However, the outcomes from those trials were disappointing (Table 1). Clinical trials with NSAIDs in patients with established dementia did not significantly attenuate progression of dementia (Soininen et al 2007;Thal et al 2005). In a study with rofecoxib and naproxen, the drugs were not able to halt or slow the progression of AD (Aisen et al 2003).…”

Section: Anti-inflammatory Agents and Their Therapeutic Potentials Fomentioning

confidence: 92%

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

et al. 2015

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Alzheimer's disease (AD) is the most common form of dementia. It is characterized by beta-amyloid (Aβ) peptide fibrils, which are extracellular depositions of a specific protein, and is accompanied by extensive neuroinflammation. Various studies have demonstrated risk factors that can affect AD pathogenesis, and they include accumulation of Aβ, hyperphosphorylation of tau protein, and neuroinflammation. Among these detrimental factors, neuroinflammation has been highlighted by epidemiologic studies suggesting that use of anti-inflammatory drugs could significantly reduce the incidence of AD. Evidence suggests that astrocytes, microglia, and infiltrating immune cells from periphery might contribute to or modify the process of neuroinflammation and neurodegeneration in AD brains. In addition, recent data indicate that microRNAs may affect neuroinflammatory responses in the brain. This article focuses on supportive evidence that neuroinflammation plays a critical role in AD development. In addition, we depict putative therapeutic capacity of anti-inflammatory drugs for AD prevention or treatment. We also discuss pathogenic mechanisms by which astrocytes, microglia, T cells and microRNA participate in AD and the neuroprotective mechanisms of anti-inflammatory drugs.

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“…Despite this premise, in prospective studies, rofecoxib [62], naproxen [63], diclofenac [64], celecoxib [65], dapsone [66], hydroxychloroquine [67] and nimesulide [68] failed to slow progression of cognitive decline in patients with mild to moderate AD. In contrast, indomethacin may delay cognitive decline in this subset of patients, but gastrointestinal toxicity is treatment limiting [69].…”

Section: Anti-inflammatory Drugsmentioning

confidence: 99%

Progress in Alzheimer’s disease

2011

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After more than one century from Alois Alzheimer and Gaetano Perusini's first report, progress has been made in understanding the pathogenic steps of Alzheimer's disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.

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Long-Term Efficacy and Safety of Celecoxib in Alzheimer’s Disease

Cited by 123 publications

References 88 publications

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer’s Disease Model Mice

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

Progress in Alzheimer’s disease

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