No 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.

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive degeneration and loss of neurons in specific regions of the central nervous system. Chronic activation of the immune cells resident in the brain, peripheral immune cell trafficking across the blood-brain barrier, and release of inflammatory and neurotoxic factors, appear critical contributors of the neuroinflammatory response that drives the progression of neurodegenerative processes in AD. As the neuro-immune network is impaired in course of AD, this review is aimed to point out the essential supportive role of innate and adaptive immune response either in normal brain as well as in brain recovery from injury. Since a fine-tuning of the immune response appears crucial to ensure proper nervous system functioning, we focused on the role of the TNF superfamily member, TNF-related apoptosis-inducing ligand (TRAIL), which modulates both the innate and adaptive immune response in the pathogenesis of several immunological disorders and, in particular, in AD-related neuroinflammation. We here summarized mounting evidence of potential involvement of TRAIL signaling in AD pathogenesis, with the aim to provide clearer insights about potential novel therapeutic approaches in AD.

Alzheimer’s disease (AD) is the most common form of dementia worldwide, with a complex, poorly understood pathogenesis. Cerebral atrophy, amyloid-β (Aβ) plaques, and neurofibrillary tangles represent the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as a prominent feature of the AD brain and substantial evidence suggests that the inflammatory response modulates disease progression. Additionally, dysregulation of calcium (Ca2+) homeostasis represents another early factor involved in the AD pathogenesis, as intracellular Ca2+ concentration is essential to ensure proper cellular and neuronal functions. Although growing evidence supports the involvement of Ca2+ in the mechanisms of neurodegeneration-related inflammatory processes, scant data are available on its contribution in microglia and astrocytes functioning, both in health and throughout the AD continuum. Nevertheless, AD-related aberrant Ca2+ signalling in astrocytes and microglia is crucially involved in the mechanisms underpinning neuroinflammatory processes that, in turn, impact neuronal Ca2+ homeostasis and brain function. In this light, we attempted to provide an overview of the current understanding of the interactions between the glia cells-mediated inflammatory responses and the molecular mechanisms involved in Ca2+ homeostasis dysregulation in AD.

Enterococcus faecalis infective endocarditis (EFIE) continues to represent a potentially fatal infectious disease characterized by elevated morbidity and mortality. Despite advances in antimicrobial therapy, changing demographics and the reduced availability of useful antibiotics combined with the dissemination of multi-drug resistant strains, the mortality rate remained unchanged in the last decades. Nowadays, optimizing the antibiotic regimen is still of paramount importance. Historically, aminoglycosides were considered as a cornerstone for treatment even though their use is associated with a high risk of kidney failure. It is against this background that, in recent years, several studies have been carried in order to assess the validity of alternative therapeutic approaches, including combinations of beta-lactams, that, acting synergistically, have yielded useful results in different clinical settings. In this scenario, we searched and critically report clinical studies assessing the efficacy and safety of double beta-lactam therapy in treating EFIE.