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.
|Data di pubblicazione:||2016|
|Titolo:||Fluoxetine prevents Aβ1-42-induced toxicity via a paracrine signaling mediated by transforming-growth-factor-β1|
|Autore/i:||Caraci, Filippo; Tascedda, Fabio; Merlo, Sara; Benatti, Cristina; Spampinato, Simona F.; Munafò, Antonio; Leggio, Gian Marco; Nicoletti, Ferdinando; Brunello, Nicoletta; Drago, Filippo; Sortino, Maria Angela; Copani, Agata|
|Digital Object Identifier (DOI):||10.3389/fphar.2016.00389|
|Codice identificativo ISI:||WOS:000386167400001|
|Codice identificativo Scopus:||2-s2.0-84995394907|
|Codice identificativo Pubmed:||27826242|
|Citazione:||Fluoxetine prevents Aβ1-42-induced toxicity via a paracrine signaling mediated by transforming-growth-factor-β1 / Caraci, Filippo; Tascedda, Fabio; Merlo, Sara; Benatti, Cristina; Spampinato, Simona F.; Munafò, Antonio; Leggio, Gian Marco; Nicoletti, Ferdinando; Brunello, Nicoletta; Drago, Filippo; Sortino, Maria Angela; Copani, Agata. - In: FRONTIERS IN PHARMACOLOGY. - ISSN 1663-9812. - 7:OCT(2016), pp. 389-400.|
|Tipologia||Articolo su rivista|
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