SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

Melatonin exerts direct neuroprotection against cerebral hypoxic damage, but the mechanisms of its action on microglia have been less characterized. Using both in vitro and in vivo models of hypoxia, we here focused on the role played by silent mating type information regulation 2 homolog 1 (SIRT1) in melatonin’s effects on microglia. Viability of rat primary microglia or microglial BV2 cells and SH-SY5Y neurons was significantly reduced after chemical hypoxia with CoCl2 (250 µM for 24 h). Melatonin (1 µM) significantly attenuated CoCl2 toxicity on microglia, an effect prevented by selective SIRT1 inhibitor EX527 (5 µM) and AMP-activated protein kinase (AMPK) inhibitor BML-275 (2 µM). CoCl2 did not modify SIRT1 expression, but prevented nuclear localization, while melatonin appeared to restore it. CoCl2 induced nuclear localization of hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-kB), an effect contrasted by melatonin in an EX527-dependent fashion. Treatment of microglia with melatonin attenuated potentiation of neurotoxicity. Common carotid occlusion was performed in p7 rats, followed by intraperitoneal injection of melatonin (10 mg/kg). After 24 h, the number of Iba1+ microglia in the hippocampus of hypoxic rats was significantly increased, an effect not prevented by melatonin. At this time, SIRT1 was only detectable in the amoeboid, Iba1+ microglial population selectively localized in the corpus callosum. In these cells, nuclear localization of SIRT1 was significantly lower in hypoxic animals, an effect prevented by melatonin. NF-kB showed an opposite expression pattern, where nuclear localization in Iba1+ cells was significantly higher in hypoxic, but not in melatonin-treated animals. Our findings provide new evidence for a direct effect of melatonin on hypoxic microglia through SIRT1, which appears as a potential pharmacological target against hypoxic-derived neuronal damage.Fil: Merlo, Sara. Universidad de Catania; ItaliaFil: Luaces, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Spampinato, Simona Federica. Universidad de Catania; ItaliaFil: Toro Urrego, Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Caruso, Grazia Ilaria. Universidad de Catania; ItaliaFil: D´Amico, Fabio. Universidad de Catania; ItaliaFil: Capani, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Sortino, Maria Angela. Universidad de Catania; Itali

Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases. Metabotropic glutamate (mGlu) receptors belong to a large family of G protein-coupled receptors largely expressed in neurons as well as in glial cells. They often appear overexpressed in areas involved in neurodegeneration, where they can modulate glutamatergic transmission. Of note, mGlu receptor upregulation may involve microglia or, even more frequently, astrocytes, where their activation causes release of factors potentially able to influence neuronal death. The expression of mGlu receptors has been also reported on oligodendrocytes, a glial cell type specifically involved in the development of multiple sclerosis. Here we will provide a general overview on the possible involvement of mGlu receptors expressed on glial cells in the pathogenesis of different neurodegenerative disorders and the potential use of subtype-selective mGlu receptor ligands as candidate drugs for the treatment of neurodegenerative disorders. Negative allosteric modulators (NAM) of mGlu5 receptors might represent a relevant pharmacological tool to develop new neuroprotective strategies in these diseases. Recent evidence suggests that targeting astrocytes and microglia with positive allosteric modulators (PAM) of mGlu3 receptor or oligodendrocytes with mGlu4 PAMS might represent novel pharmacological approaches for the treatment of neurodegenerative disorders

Shedding light on typical species : implications for habitat monitoring

Habitat monitoring in Europe is regulated by Article 17 of the Habitats Directive, which suggests the use of typical species to assess habitat conservation status. Yet, the Directive uses the term “typical” species but does not provide a definition, either for its use in reporting or for its use in impact assessments. To address the issue, an online workshop was organized by the Italian Society for Vegetation Science (SISV) to shed light on the diversity of perspectives regarding the different concepts of typical species, and to discuss the possible implications for habitat monitoring. To this aim, we inquired 73 people with a very different degree of expertise in the field of vegetation science by means of a tailored survey composed of six questions. We analysed the data using Pearson's Chi-squared test to verify that the answers diverged from a random distribution and checked the effect of the degree of experience of the surveyees on the results. We found that most of the surveyees agreed on the use of the phytosociological method for habitat monitoring and of the diagnostic and characteristic species to evaluate the structural and functional conservation status of habitats. With this contribution, we shed light on the meaning of “typical” species in the context of habitat monitoring

Notulae to the Italian alien vascular flora: 11

In this contribution, new data concerning the distribution of vascular flora alien to Italy are presented. It includes new records, confirmations, exclusions, and status changes for Italy or for Italian administrative regions. Nomenclatural and distribution updates published elsewhere are provided as Suppl. material 1

Molecular Aspects of Cellular Dysfunction in Alzheimer’s Disease: The Need for a Holistic View of the Early Pathogenesis

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, a socio-economic burden destined to worsen with increased population aging [...

Early β-Amyloid-induced Synaptic Dysfunction Is Counteracted by Estrogen in Organotypic Hippocampal Cultures

In the present study we set up a model of slow progression of neuronal injury by exposing organotypic hippocampal cultures to a low concentration of Amyloid β (25-35) peptide (Aβ, 2 μM) to analyze the time-related effects of 17-β estradiol (17β-E2, 10 nM). Neuronal death occurs after 7 d and is prevented by addition of 17β-E2 24 h prior to, together with or 48 h after exposure to Aβ. This effect is mimicked by selective ERα agonist PPT (100 nM). Treatment with Aβ leads to early and transient (16-72 h) increase of pre- and post-synaptic proteins synaptophysin and PSD95, followed by a decrease coincident with neuronal death (7d), all prevented by 17β-E2. At 72 h of Aβ exposure, synaptic activity is increased, as by higher levels of glutamate and increased loading and unloading of FM 1-43-labeled synaptic vesicles. All these effects are also prevented by 17β-E2. These data point out beneficial effects of estrogen on early Aβ-induced synaptic disruption.Fil: Merlo, Sara. Università degli Studi di Catania; ItaliaFil: Spampinato, Simona Federica. Università degli Studi di Catania; ItaliaFil: Capani, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Sortino, Maria Angela. Università degli Studi di Catania; Itali