Microglia as a cellular target of diclofenac therapy in Alzheimer’s disease

Stopschinski, Barbara E.; Weideman, Rick; McMahan, Danni; Jacob, David; Little, Bertis B.; Chiang, Hsueh-Sheng; Saez-Calveras, Nil; Stüve, Olaf

doi:10.1177/17562864231156674

Cited by 5 publications

(5 citation statements)

References 122 publications

(221 reference statements)

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“…Aside from their effects on AChE, AChEIs possess other biological activities, including suppression of Aβ plaque formation and brain inflammation [ 61 – 64 ]. Moreover, in this study we chose donepezil as anti-inflammatory control, rather than other typical medicines, such as Ibuprofen, mainly because the data regarding treatment of AD with Ibuprofen from epidemiological studies, clinical trials and meta-analyses in the past is still controversial [ 65 ]. Interestingly, several in vitro and in vivo studies have reported the anti-inflammatory effects of donepezil on various stimulus-induced inflammatory responses [ 66 – 71 ].…”

Section: Discussionmentioning

confidence: 99%

Ginkgolide attenuates memory impairment and neuroinflammation by suppressing the NLRP3/caspase-1 pathway in Alzheimer’s disease

Liu,

Niu,

et al. 2023

Aging

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The NLRP3 inflammasome is involved in the neuroinflammatory pathway of Alzheimer’s disease (AD). The aim of this study is to explore the roles and underlying mechanisms of ginkgolide (Baiyu®) on amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and a murine microglial cell line, BV-2. In the present study, the APP/PS1 mice were administered with ginkgolide, followed by a Morris water maze test. The mice were then euthanized to obtain brain tissue for histological and Aβ analysis. Additionally, BV-2 cells were pretreated with ginkgolide and then incubated with Aβ1–42 peptide. NLRP3, ASC, and caspase-1 mRNA and protein expression in brain tissue of mice and BV-2 cells were quantified by real-time PCR and western blotting, as well as reactive oxygen species (ROS) production, interleukin (IL)-1β and IL-18 levels by lucigenin technique and ELISA. Compared with the APP/PS1 mice, ginkgolide-treated mice demonstrated the shortened escape latency, reduced plaques, less inflammatory cell infiltration and neuron loss in the hippocampi of APP/PS1 mice. The levels of NLRP3, ASC, caspase-1, ROS, IL-1β, and IL-18 were also decreased in the brain tissue of APP/PS1 mice or Aβ1–42-treated BV-2 cells following ginkgolide treatment. Ginkgolide exerted protective effects on AD, at least partly by inactivating the NLRP3/caspase-1 pathway.

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Section: Discussionmentioning

confidence: 99%

Ginkgolide attenuates memory impairment and neuroinflammation by suppressing the NLRP3/caspase-1 pathway in Alzheimer’s disease

Liu,

Niu,

et al. 2023

Aging

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“…Amyloid deposits activate microglia, which then release neurotoxins; amyloid also stimulates an overall immune response [41]. For AD treatment, many nonsteroidal antiinflammatory agents (NSAIDs) have been used with highly variable responses [41,42]. Diclofenac is the only NSAID associated with a significant reduction in cognition.…”

Section: Treatment To Reverse Neuroinflammationmentioning

confidence: 99%

“…Diclofenac is the only NSAID associated with a significant reduction in cognition. A report of a retrospective cohort study of 1431 patients with AD receiving diclofenac showed a reduced incidence of dementia as compared to other NSAIDs; that report discussed the mechanisms whereby diclofenac is effective [42].…”

Section: Treatment To Reverse Neuroinflammationmentioning

confidence: 99%

Personalized, Precision Medicine to Cure Alzheimer’s Dementia: Approach #1

Fessel

2024

IJMS

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The goal of the treatment for Alzheimer’s dementia (AD) is the cure of dementia. A literature review revealed 18 major elements causing AD and 29 separate medications that address them. For any individual with AD, one is unlikely to discern which major causal elements produced dementia. Thus, for personalized, precision medicine, all causal elements must be treated so that each individual patient will have her or his causal elements addressed. Twenty-nine drugs cannot concomitantly be administered, so triple combinations of drugs taken from that list are suggested, and each triple combination can be administered sequentially, in any order. Ten combinations given over 13 weeks require 2.5 years, or if given over 26 weeks, they require 5.0 years. Such sequential treatment addresses all 18 elements and should cure dementia. In addition, any comorbid risk factors for AD whose first presence or worsening was within ±1 year of when AD first appeared should receive appropriate, standard treatment together with the sequential combinations. The article outlines a randomized clinical trial that is necessary to assess the safety and efficacy of the proposed treatments; it includes a triple-drug Rx for equipoise. Clinical trials should have durations of both 2.5 and 5.0 years unless the data safety monitoring board (DSMB) determines earlier success or futility since it is uncertain whether three or six months of treatment will be curative in humans, although studies in animals suggest that the briefer duration of treatment might be effective and restore defective neural tracts.

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“…As in other neurological disorders, the first class of drugs tested in the neuroinflammatory pathway was the non-steroidal anti-inflammatory drugs (NSAIDs) [ 171 ]. NSAIDs were proposed due to the generalized anti-inflammatory effect aiming to suppress activated microglia.…”

Section: Beyond Amyloid: Tau and Neuroinflammationmentioning

confidence: 99%

Novel Therapeutic Strategies in Alzheimer’s Disease: Pitfalls and Challenges of Anti-Amyloid Therapies and Beyond

Tondo,

De Marchi,

Bonardi

et al. 2024

JCM

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Alzheimer’s disease (AD) causes a significant challenge to global healthcare systems, with limited effective treatments available. This review examines the landscape of novel therapeutic strategies for AD, focusing on the shortcomings of traditional therapies against amyloid-beta (Aβ) and exploring emerging alternatives. Despite decades of research emphasizing the role of Aβ accumulation in AD pathogenesis, clinical trials targeting Aβ have obtained disappointing results, highlighting the complexity of AD pathophysiology and the need for investigating other therapeutic approaches. In this manuscript, we first discuss the challenges associated with anti-Aβ therapies, including limited efficacy and potential adverse effects, underscoring the necessity of exploring alternative mechanisms and targets. Thereafter, we review promising non-Aβ-based strategies, such as tau-targeted therapies, neuroinflammation modulation, and gene and stem cell therapy. These approaches offer new avenues for AD treatment by addressing additional pathological hallmarks and downstream effects beyond Aβ deposition.

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Microglia as a cellular target of diclofenac therapy in Alzheimer’s disease

Cited by 5 publications

References 122 publications

Ginkgolide attenuates memory impairment and neuroinflammation by suppressing the NLRP3/caspase-1 pathway in Alzheimer’s disease

Ginkgolide attenuates memory impairment and neuroinflammation by suppressing the NLRP3/caspase-1 pathway in Alzheimer’s disease

Personalized, Precision Medicine to Cure Alzheimer’s Dementia: Approach #1

Novel Therapeutic Strategies in Alzheimer’s Disease: Pitfalls and Challenges of Anti-Amyloid Therapies and Beyond

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