Article

Secretase-Independent and RhoGTPase/PAK/ERK-Dependent Regulation of Cytoskeleton Dynamics in Astrocytes by NSAIDs and Derivatives

Institut de Neurociènces, Universitat Autònoma de Barcelona, Spain.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 10/2010; 22(4):1135-55. DOI: 10.3233/JAD-2010-101332
Source: PubMed

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 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 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 Alzheimer's disease instead of AD by modulating astrocyte reactivity through Rho-GTPase/PAK/ERK-dependent signaling.

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    • "Several in vitro and in vivo studies suggest that CHF5074 is able to inhibit brain plaque deposition and intra neuronal A␤, rescue long-term potentiation (LTP) and dendritic spine density alterations, reduce the level of microglial activation and attenuate contextual and spatial memory deficit in different transgenic mouse models of AD [2] [3] [4] [5]. In addition, recent work demonstrated that CHF5074 facilitates axon growth and astrocyte plasticity through the modulation of Rho-GTPase-dependent signaling pathway [6], thus highlighting a multi-modal mechanism of action of this compound. Importantly, CHF5074 appeared to be well tolerated by both wild-type and AD mice, even after prolonged use. "
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    ABSTRACT: CHF5074 is a non-steroidal anti-inflammatory derivative holding disease-modifying potential for the treatment of Alzheimer's disease. The aim of the present study was to characterize the electrophysiological and metabolic profile of CHF5074 in the hippocampus. Electrophysiological recordings show that CHF5074 inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a dose-dependent reduction of field excitatory post-synaptic potentials with no effect on the paired-pulse ratio. The effects of CHF5074 were not mediated by AMPA or NMDA receptors, since the inward currents induced by local applications of AMPA and NMDA remained constant in the presence of this compound. We also suggest a possible activity of CHF5074 on ASIC1a receptor since ASIC1a-mediated current, evoked by application of a pH 5.5 solution, is reduced by pretreatment with this compound. Moreover, we demonstrate that CHF5074 treatment is able to counteract in hippocampal slices the OGD-induced increase in alanine, lactate and acetate levels. Finally, CHF5074 significantly reduced the apoptosis in hippocampal neurons exposed to OGD, as revealed by cleaved-caspase-3 immunoreactivity and TUNEL staining. Overall, the present work identifies novel mechanisms for CHF5074 in reducing metabolic acidosis, rendering this compound potentially useful also in conditions of brain ischemia.
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    • "Furthermore, Lau et al. [59] [60] described that Fasudil, a Rho kinase (ROCK) (a major downstream effector of RhoA) inhibitor that has been explored as a possible treatment in various neuropathologies [61]. Moreover, non-steroidal anti-inflammatory drugs, that are being considered for the treatment of Alzheimer's disease, regulate the dynamics of GFAP and actin filaments in astrocytes via Rho-GTPases [62]. "
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    • "The possible multifunctional nature of NSAIDs is supported by cumulative evidence showing that the drugs, other than COX, can target γ-secretase (Weggen et al., 2003), Rho-GTPases (Fu et al., 2007), and peroxisome proliferator-activated receptors (PPAR) (Nicolakakis et al., 2008). The γ-secretase mediates production of Aβ, while Rho-GTPases regulate several phenomena relevant to AD including axon growth (Fu et al., 2007), tau phosphorylation (Sayas et al., 1999), and astrocyte motility (Lichtenstein et al., 2010). "
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