Fluoxetine Prevents Aβ1-42-Induced Toxicity via a Paracrine Signaling Mediated by Transforming-Growth-Factor-β1

Abstract

Selective reuptake inhibitors (SSRIs), such as fluoxetine and sertraline, increase circulating Transforming-Growth-Factor-β1 (TGF-β1) levels in depressed patients, and are currently studied for their neuroprotective properties in Alzheimer’s disease. TGF-β1 is an anti-inflammatory cytokine that exerts neuroprotective effects against β-amyloid (Aβ)-induced neurodegeneration. In the present work, the SSRI, fluoxetine, was tested for the ability to protect cortical neurons against 1 μM oligomeric Aβ1-42-induced toxicity. At therapeutic concentrations (100 nM–1 μM), fluoxetine significantly prevented Aβ-induced toxicity in mixed glia-neuronal cultures, but not in pure neuronal cultures. Though to a lesser extent, also sertraline was neuroprotective in mixed cultures, whereas serotonin (10 nM–10 μM) did not mimick fluoxetine effects. Glia-conditioned medium collected from astrocytes challenged with fluoxetine protected pure cortical neurons against Aβ toxicity. The effect was lost in the presence of a neutralizing antibody against TGF-β1 in the conditioned medium, or when the specific inhibitor of type-1 TGF-β1 receptor, SB431542, was added to pure neuronal cultures. Accordingly, a 24 h treatment of cortical astrocytes with fluoxetine promoted the release of active TGF-β1 in the culture media through the conversion of latent TGF-β1 to mature TGF-β1. Unlike fluoxetine, both serotonin and sertraline did not stimulate the astrocyte release of active TGF-β1. We conclude that fluoxetine is neuroprotective against Aβ toxicity via a paracrine signaling mediated by TGF-β1, which does not result from a simplistic SERT blockade.

Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis

“…Indeed, there are some reports of tau-induced cell cycle entry in neurons (Andorfer et al, 2005;Bonda et al, 2009;Jaworski et al, 2009;Seward et al, 2013a;Hradek et al, 2014), albeit entry mediated by NFT has been contested (Jaworski et al, 2009), and at least in some cases it involves Aβ (Seward et al, 2013a;Hradek et al, 2014). When compared to tau-related models, cell cycle deregulation has been vigorously researched in models of Aβ pathology (Copani et al, 1999(Copani et al, , 2006Giovanni et al, 1999Giovanni et al, , 2000Park et al, 2000;Wu et al, 2000;Kruman et al, 2004;Sortino et al, 2004;Yang et al, 2006;Caraci et al, 2008;Majd et al, 2008;Varvel et al, 2008Varvel et al, , 2009Bhaskar et al, 2009;Lopes et al, 2009Lopes et al, , 2010Li et al, 2011;Modi et al, 2012Modi et al, , 2015Seward et al, 2013b;Hradek et al, 2014;Merlo et al, 2015;Caraci et al, 2016;Leggio et al, 2016; Table 1). Virtually all reports report cell cycle related cell death, which is of relevance for senescence.…”

International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets

“…Interestingly different preclinical and clinical studies have shown that ketamine is endowed with anti-inflammatory activity (De Kock et al, 2013) and reverses inflammation-induced depression in the lipopolysaccharide model by decreasing brain levels of inflammatory cytokines (Yang et al, 2013) or by blocking the effects of quinolinic acid, a downstream product of the kynurenine pathway, on NMDA receptors (Walker et al, 2013b). Furthermore, recent in vitro studies have shown that fluoxetine and venlafaxine increase the release of TGF-b1, an antiinflammatory cytokine that is reduced in nonresponder MDD patients (Vollmar et al, 2008;Caraci et al, 2016).…”

Major Depressive Disorder and Oxidative Stress: In Silico Investigation of Fluoxetine Activity against ROS

“…Fluoxetine effectively acts on a wide spectrum of mood disorders and protects against the adverse effects of different types of stressors by decreasing some effects of stress on the immune system and by protecting against oxidative damage. Different molecular mechanisms have been proposed to explain its neuroprotective effects, including BDNF (Brain-derived Neurotrophic Factor) release, antagonism on NMDA (N-methyl-D-aspartate) receptors, the inhibition of NF-kB (Nuclear Factor Kappa B Subunit 1) activity, and inhibition of the release of pro-inflammatory factors (TNF-α, Tumor Necrosis Factor-Alpha, IL-1β, Interleukin 1 Beta) from microglial cells [12]. However, the underlying mechanisms of its therapeutic efficacy remain unclear, particularly those related to its antioxidant activity.…”