Secretase-independent and RhoGTPase/PAK/ERK-dependent regulation of cytoskeleton dynamics in astrocytes by NSAIDs and derivatives

Lichtenstein, Mathieu P., Carriba, Paulina, Baltrons, Maria Antonia, Wojciak-Stothard, Beata, Peterson, Jeffrey R., Garcia, Agustina and Galea, Elena 2010. Secretase-independent and RhoGTPase/PAK/ERK-dependent regulation of cytoskeleton dynamics in astrocytes by NSAIDs and derivatives. Journal of Alzheimer's Disease 22 (4) , pp. 1135-1155. 10.3233/JAD-2010-101332

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Abstract

Profens like ibuprofen, R-flurbiprofen, or CHF5074 are being considered for the treatment of Alzheimer’s disease because epidemiological data indicates that non-steroidal anti-inflammatory drugs protective against neurodegeneration. Rho-GTPases are small G proteins, including RhoA, Cdc42, and Rac1, which control cytoskeleton dynamics. Because ibuprofen promotes axon growth via RhoA in neurons, we examined whether profens modulate astrocyte plasticity via Rho-GTPases. We report that ibuprofen (100-500 µM), R-flurbiprofen (100-500 µM), and CHF5074 (10-30 µM) caused a concentration-dependent stellation of astrocytes in primary cultures, associated with the reorganization of GFAP and actin filaments. The stellation was independent of COX2, α-, β- or γ-secretase as judged by the lack of effect of inhibitors of these enzymes. RhoA, PAK, and Cdc42, but not Rac1, accounted for the profen-mediated stellation, as concluded from the joint analyses of activities and reversal experiments with adenoviral or pharmacological manipulations. Ibuprofen accelerated migration in a scratch-wound assay, while R-flurbiprofen had no effect and CHF5074 caused deceleration. Cell polarity regulation by Cdc42 and ERK1/2 may underlie the paradoxical effects of profens on migration. We conclude that profens regulate cytoskeleton dynamics in astrocytes via Rho-GTPases, PAK, and ERK1/2. Since migration is a hallmark of astrocyte response during inflammation we propose that, in addition to (or instead of) lowering amyloid-β42 via secretases, ibuprofen and its derivatives may prevent AD by modulating astrocyte reactivity through Rho-GTPase/PAK/ERK-dependent signaling.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Subjects:	R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	Actin, Alzheimer's disease, astrocytes, Cdc42, CHF5074, ibuprofen, IPA3, NSAIDs, Rac1, RhoA, R-Flurbiprofen
Publisher:	IOS Press
ISSN:	1387-2877
Last Modified:	17 Mar 2021 02:42
URI:	https://orca.cardiff.ac.uk/id/eprint/66915

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