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

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

doi:10.1177/17562864231156674

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

Ther Adv Neurol Disord. 2023 Feb 27:16:17562864231156674. doi: 10.1177/17562864231156674. eCollection 2023.

Authors

Barbara E Stopschinski^{1

2}, Rick A Weideman³, Danni McMahan³, David A Jacob⁴, Bertis B Little⁵, Hsueh-Sheng Chiang¹, Nil Saez Calveras¹, Olaf Stuve^{1

6

7}

Affiliations

¹ Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
² Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³ Pharmacy Service, Dallas VA Medical Center, Dallas, TX, USA.
⁴ Veterans Integrated Service Network 17, Arlington, TX, USA.
⁵ School of Public Health and Information Sciences, University of Louisville, Louisville, KY, USA.
⁶ Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁷ Neurology Section, Dallas VA Medical Center, 4500 South Lancaster Road, Dallas, TX 75216, USA.

Abstract

Alzheimer's disease (AD) is an untreatable cause of dementia, and new therapeutic approaches are urgently needed. AD pathology is defined by extracellular amyloid plaques and intracellular neurofibrillary tangles. Research of the past decades has suggested that neuroinflammation plays a critical role in the pathophysiology of AD. This has led to the idea that anti-inflammatory treatments might be beneficial. Early studies investigated non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin, celecoxib, ibuprofen, and naproxen, which had no benefit. More recently, protective effects of diclofenac and NSAIDs in the fenamate group have been reported. Diclofenac decreased the frequency of AD significantly compared to other NSAIDs in a large retrospective cohort study. Diclofenac and fenamates share similar chemical structures, and evidence from cell and mouse models suggests that they inhibit the release of pro-inflammatory mediators from microglia with leads to the reduction of AD pathology. Here, we review the potential role of diclofenac and NSAIDs in the fenamate group for targeting AD pathology with a focus on its potential effects on microglia.

Keywords: Alzheimer’s disease; NLRP3 inflammasome; NSAID; diclofenac; microglia; neuroinflammation.

Publication types

Review