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Lichtenstein Mathieu P , Carriba Paulina , Baltrons Maria Antonia , Wojciak-Stothard Beata , Peterson Jeffrey R , Garcia Agustina , Galea Elena
Secretase-independent and RhoGTPase/PAK/ERK-dependent regulation of cytoskeleton dynamics in astrocytes by NSAIDs and derivatives
Journal of Alzheimer's Disease. 2010 ;22(4) :1135-1155
PMID: Peer Reviewed Journal: 2011-00088-009   
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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 are 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 M), R-flurbiprofen (100-500 M), and CHF5074 (10-30 M) 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, alpha -, beta - or gamma -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-beta 42 via secretases, ibuprofen and its derivatives may prevent Alzheimer's disease by modulating astrocyte reactivity through Rho-GTPase/PAK/ERK-dependent signaling. (PsycINFO Database Record (c) 2010 APA, all rights reserved) (journal abstract).
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