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Brain ischemia is one of the major causes of chronic disability and death worldwide. It is related to insufficient blood supply to cerebral tissue, which induces irreversible or reversible intracellular effects depending on the time and intensity of the ischemic event. Indeed, neuronal function may be restored in some conditions, such as transient ischemic attack (TIA), which may be responsible for protecting against a subsequent lethal ischemic insult. It is well known that the brain requires high levels of oxygen and glucose to ensure cellular metabolism and energy production and that damage caused by oxygen impairment is tightly related to the brain's low antioxidant capacity. Oxygen is a key player in mitochondrial oxidative phosphorylation (OXPHOS), during which reactive oxygen species (ROS) synthesis can occur as a physiological side-product of the process. Indeed, besides producing adenosine triphosphate (ATP) under normal physiological conditions, mitochondria are the primary source of ROS within the cell. This is because, in 0.2–2% of cases, the escape of electrons from complex I (NADPH-dehydrogenase) and III of the electron transport chain occurring in mitochondria during ATP synthesis leads to the production of the superoxide radical anion (O2•−), which exerts detrimental intracellular effects owing to its high molecular instability. Along with ROS, reactive nitrosative species (RNS) also contribute to the production of free radicals. When the accumulation of ROS and RNS occurs, it can cause membrane lipid peroxidation and DNA damage. Here, we describe the intracellular pathways activated in brain tissue after a lethal/sub lethal ischemic event like stroke or ischemic tolerance, respectively, highlighting the important role played by oxidative stress and mitochondrial dysfunction in the onset of the two different ischemic conditions. [ABSTRACT FROM AUTHOR]

Introduction: Addressing the formidable therapeutic hurdles posed by Alzheimer's disease (AD), our study delves into the central role of amyloid β 1-42 (Aβ1-42) protein aggregation in its onset. Aim: Our investigation aims to assess the therapeutic potential of the isoindolinone derivative 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) against the Aβ1-42-induced toxicity. Material and methods: Employing a combination of thioflavin T fluorescence assay and biological and cellular approaches, alongside other experimental methods, we explored ISOAC1's ability to mitigate Aβ1-42 aggregation and toxicity. Results and conclusions: Our study unveils ISOAC1's capacity to disrupt Aβ1-42 aggregation and impede its transition towards β-sheet structures. Furthermore, our findings shed light on ISOAC1's binding mechanisms with Aβ1-42, indicating its promise as a therapeutic agent. ISOAC1 emerges as a compelling neuroprotective compound, offering novel avenues for AD treatment. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) presents significant therapeutic challenges, with amyloid β1-42 (Aβ1-42) protein aggregation playing a central role in its pathogenesis. Aim: Our study investigates the potential therapeutic efficacy of the isoindolinone derivative 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) against Aβ1-42-induced toxicity. Material and methods: We employed spectroscopic and computational approaches to explore ISOAC1's ability to mitigate Aβ1-42 aggregation and its consequent toxicity. Other experimental analyses included Thioflavin T fluorescence assay, and Western blotting. Results: Our findings reveal ISOAC1's capacity to disrupt Aβ1-42 aggregation and hinder its transition towards β-sheet structures. Computational investigations elucidate ISOAC1's binding mechanisms with Aβ1-42, highlighting its potential as a therapeutic agent. Conclusions: ISOAC1 emerges as a promising neuroprotective compound, offering insights into novel therapeutic strategies for AD treatment. The combined spectroscopic and computational approach herein presented provides a comprehensive understanding of ISOAC1's mechanism of action against Aβ1-42-induced toxicity. [ABSTRACT FROM AUTHOR]

Excessive calcium (Ca 2+ ) release from the endoplasmic reticulum (ER) represents an important hallmark of several neurodegenerative diseases. ER is recharged from Ca 2+ through the so-called Store-Operated Calcium Entry (SOCE) thus providing Ca 2+ signals to regulate critical cell functions. Single transmembrane-spanning domain protein stromal interacting molecule 1 (STIM1), mainly residing in the ER, and plasmalemmal channel Orai1 represent the SOCE key components at neuronal level. However, many other proteins participate to ER Ca 2+ refilling including the Na + /Ca 2+ exchanger isoform 1 (NCX1), whose regulation by ER remains unknown. In this study, we tested the possibility that neuronal NCX1 may take part to SOCE through the interaction with STIM1. In rat primary cortical neurons and in nerve growth factor (NGF)-differentiated PC12 cells NCX1 knocking down by siRNA strategy significantly prevented SOCE as well as SOCE pharmacological inhibition by SKF-96365 and 2-APB. A significant reduction of SOCE was recorded also in synaptosomes from ncx1 - / - mice brain compared with ncx1 + / + mice. Double labeling confocal experiments showed a large co-localization between NCX1 and STIM1 in rat primary cortical neurons. Accordingly, NCX1 and STIM1 co-immunoprecipitated and functionally interacted each other during ischemic preconditioning, a phenomenon inducing ischemic tolerance. However, STIM1 knocking down reduced NCX1 activity recorded by either patch-clamp electrophysiology or Fura-2 single-cell microfluorimetry. Furthermore, canonical transient receptor potential channel 6 (TRPC6) was identified as the mechanism mediating local increase of sodium (Na + ) useful to drive NCX1 reverse mode and, therefore, NCX1-mediated Ca 2+ refilling. In fact, TRPC6 not only interacted with STIM1, as shown by the co-localization and co-immunoprecipitation with the ER Ca 2+ sensor, but it also mediated 1,3-Benzenedicarboxylic acid, 4,4'-[1,4,10-trioxa-7,13-diazacyclopentadecane-7,13-diylbis(5-methoxy-6,12-benzofurandiyl)]bis-, tetrakis[(acetyloxy)methyl] ester (SBFI)-monitored Na + increase elicited by thapsigargin in primary cortical neurons. Accordingly, efficient TRPC6 knockdown prevented thapsigargin-induced intracellular Na + elevation and SOCE. Collectively, we identify NCX1 as a new partner of STIM1 in mediating SOCE, whose activation in the reverse mode may be facilitated by the local increase of Na + concentration due to the interaction between STIM1 and TRPC6 in primary cortical neurons., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)