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Curr Alzheimer Res. 2019 Nov 5. doi: 10.2174/1567205016666191106095038. [Epub ahead of print]

Consideration of a Pharmacological Combinatorial Approach to Inhibit Chronic Inflammation in Alzheimer's Disease.

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1
Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, British Columbia. Canada.

Abstract

A combinatorial cocktail approach is suggested as a rationale intervention to attenuate chronic inflammation and confer neuroprotection in Alzheimer's disease (AD). The requirement for an assemblage of pharmacological compounds follows from the host of pro-inflammatory pathways and mechanisms present in activated microglia in the disease process. This article suggests a starting point using four compounds which present some differential in anti-inflammatory targets and actions but a commonality in showing a finite permeability through blood-brain barrier (BBB). A basis for first- choice compounds demonstrated neuroprotection in animal models (thalidomide and minocycline), clinical trial data showing some slowing in the progression of pathology in AD brain (ibuprofen) and indirect evidence for putative efficacy in blocking oxidative damage and chemotactic response mediated by activated microglia (dapsone). It is emphasized that a number of candidate compounds, other than ones suggested here, could be considered as components of the cocktail approach and would be expected to be examined in subsequent work. In this case, systematic testing in AD animal models is required to rigorously examine the efficacy of first-choice compounds and replace ones showing weaker effects. This protocol represents a practical approach to optimize the reduction of microglial-mediated chronic inflammation in AD pathology. Subsequent work would incorporate the anti-inflammatory cocktail de- livery as an adjunctive treatment with ones independent of inflammation as an overall preventive strategy to slow the progression of AD.

KEYWORDS:

Combinatorial pharmacology; chronic inflammation; dapsone; ibuprofen; microglia; minocycline; thalidomide

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