Activation of the ROS/TXNIP/NLRP3 pathway disrupts insulin-dependent glucose uptake in skeletal muscle of insulin-resistant obese mice.

Oxidative stress and the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome have been linked to insulin resistance in skeletal muscle. In immune cells, the exacerbated generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome, by facilitating the interaction between thioredoxin interacting protein (TXNIP) and NLRP3. However, the precise role of ROS/TXNIP-dependent NLRP3 inflammasome activation in skeletal muscle during obesity-induced insulin resistance remains undefined.

IPR-Mediated Calcium Release Promotes Ferroptotic Death in SH-SY5Y Neuroblastoma Cells.

Ferroptosis is an iron-dependent cell death pathway that involves the depletion of intracellular glutathione (GSH) levels and iron-mediated lipid peroxidation. Ferroptosis is experimentally caused by the inhibition of the cystine/glutamate antiporter xCT, which depletes cells of GSH, or by inhibition of glutathione peroxidase 4 (GPx4), a key regulator of lipid peroxidation. The events that occur between GPx4 inhibition and the execution of ferroptotic cell death are currently a matter of active research.

Amyloid β-Oligomers Inhibit the Nuclear Ca Signals and the Neuroprotective Gene Expression Induced by Gabazine in Hippocampal Neurons.

Hippocampal neuronal activity generates dendritic and somatic Ca signals, which, depending on stimulus intensity, rapidly propagate to the nucleus and induce the expression of transcription factors and genes with crucial roles in cognitive functions. Soluble amyloid-beta oligomers (AβOs), the main synaptotoxins engaged in the pathogenesis of Alzheimer's disease, generate aberrant Ca signals in primary hippocampal neurons, increase their oxidative tone and disrupt structural plasticity. Here, we explored the effects of sub-lethal AβOs concentrations on activity-generated nuclear Ca signals and on the Ca-dependent expression of neuroprotective genes.

RyR-mediated calcium release in hippocampal health and disease.

Hippocampal synaptic plasticity is widely considered the cellular basis of learning and spatial memory processes. This article highlights the central role of Ca release from the endoplasmic reticulum (ER) in hippocampal synaptic plasticity and hippocampus-dependent memory in health and disease. The key participation of ryanodine receptor (RyR) channels, which are the principal Ca release channels expressed in the hippocampus, in these processes is emphasized.

Subcellular localization and transcriptional regulation of brain ryanodine receptors. Functional implications.

Ryanodine receptors (RyR) are intracellular Ca channels localized in the endoplasmic reticulum, where they act as critical mediators of Ca-induced Ca calcium release (CICR). In the brain, mammals express in both neurons, and non-neuronal cells, a combination of the three RyR-isoforms (RyR1-3). Pharmacological approaches, which do not distinguish between isoforms, have indicated that RyR-isoforms contribute to brain function.

Long-term potentiation and spatial memory training stimulate the hippocampal expression of RyR2 calcium release channels.

Neuronal Ca signals generated through the activation of Ca-induced Ca release in response to activity-generated Ca influx play a significant role in hippocampal synaptic plasticity, spatial learning, and memory. We and others have previously reported that diverse stimulation protocols, or different memory-inducing procedures, enhance the expression of endoplasmic reticulum-resident Ca release channels in rat primary hippocampal neuronal cells or hippocampal tissue. Here, we report that induction of long-term potentiation (LTP) by Theta burst stimulation protocols of the CA3-CA1 hippocampal synapse increased the mRNA and protein levels of type-2 Ryanodine Receptor (RyR2) Ca release channels in rat hippocampal slices.

Ryanodine Receptor Mediated Calcium Release Contributes to Ferroptosis Induced in Primary Hippocampal Neurons by GPX4 Inhibition.

Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant regulator, promotes ferroptosis in different cell types. Scant information is available on GPX4-induced ferroptosis in hippocampal neurons.

Hippocampal dendritic spines express the RyR3 but not the RyR2 ryanodine receptor isoform.

The hippocampus is a brain region implicated in synaptic plasticity and memory formation; both processes require neuronal Ca signals generated by Ca entry via plasma membrane Ca channels and Ca release from the endoplasmic reticulum (ER). Through Ca-induced Ca release, the ER-resident ryanodine receptor (RyR) Ca channels amplify and propagate Ca entry signals, leading to activation of cytoplasmic and nuclear Ca-dependent signaling pathways required for synaptic plasticity and memory processes. Earlier reports have shown that mice and rat hippocampus expresses mainly the RyR2 isoform, with lower expression levels of the RyR3 isoform and almost undetectable levels of the RyR1 isoform; both the RyR2 and RyR3 isoforms have central roles in synaptic plasticity and hippocampal-dependent memory processes.

The calcium-iron connection in ferroptosis-mediated neuronal death.

Iron, through its participation in oxidation/reduction processes, is essential for the physiological function of biological systems. In the brain, iron is involved in the development of normal cognitive functions, and its lack during development causes irreversible cognitive damage. Yet, deregulation of iron homeostasis provokes neuronal damage and death.

RyR-mediated Ca release elicited by neuronal activity induces nuclear Ca signals, CREB phosphorylation, and Npas4/RyR2 expression.

The expression of several hippocampal genes implicated in learning and memory processes requires that Ca signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca signals to the nucleus. Here, we present evidence showing that Ca release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca signals induced by gabazine (GBZ) addition, glutamate uncaging in the dendrites, or high-frequency field stimulation of primary hippocampal neurons.

Ryanodine receptor-mediated Ca release and atlastin-2 GTPase activity contribute to IP-induced dendritic Ca signals in primary hippocampal neurons.

Neuronal Ca signals are fundamental for synaptic transmission and activity-dependent changes in gene expression. Voltage-gated Ca channels and N-methyl-d-aspartate receptors play major roles in mediating external Ca entry during action potential firing and glutamatergic activity. Additionally, the inositol-1,4,5-trisphosphate receptor (IPR) and the ryanodine receptor (RyR) channels expressed in the endoplasmic reticulum (ER) also contribute to the generation of Ca signals in response to neuronal activity.

Astaxanthin Counteracts Excitotoxicity and Reduces the Ensuing Increases in Calcium Levels and Mitochondrial Reactive Oxygen Species Generation.

Astaxanthin (ASX) is a carotenoid pigment with strong antioxidant properties. We have reported previously that ASX protects neurons from the noxious effects of amyloid-β peptide oligomers, which promote excessive mitochondrial reactive oxygen species (mROS) production and induce a sustained increase in cytoplasmic Ca concentration. These properties make ASX a promising therapeutic agent against pathological conditions that entail oxidative and Ca dysregulation.

-Methyl-d-Aspartate Receptor Modulation by Nicotinamide Adenine Dinucleotide Phosphate Oxidase Type 2 Drives Synaptic Plasticity and Spatial Memory Impairments in Rats Exposed Pre- and Postnatally to Ethanol.

Pre- and/or early postnatal ethanol exposure (prenatal alcohol exposure [PAE]) impairs synaptic plasticity as well as memory formation, but the mechanisms underlying these effects remain unclear. Both long-term potentiation (LTP) and spatial memory formation in the hippocampus involve the nicotinamide adenine dinucleotide phosphate oxidase type 2 (NOX2) enzyme. Previous studies have reported that -methyl-d-aspartate receptor (NMDAR) activation increases NOX2-mediated superoxide generation, resulting in inhibition of NMDAR function, but whether NOX2 impacts NMDAR function in PAE animals leading to impaired LTP and memory formation remains unknown.

Noxious Iron-Calcium Connections in Neurodegeneration.

Iron and calcium share the common feature of being essential for normal neuronal function. Iron is required for mitochondrial function, synaptic plasticity, and the development of cognitive functions whereas cellular calcium signals mediate neurotransmitter exocytosis, axonal growth and synaptic plasticity, and control the expression of genes involved in learning and memory processes. Recent studies have revealed that cellular iron stimulates calcium signaling, leading to downstream activation of kinase cascades engaged in synaptic plasticity.

N-Acetylcysteine Prevents the Spatial Memory Deficits and the Redox-Dependent RyR2 Decrease Displayed by an Alzheimer's Disease Rat Model.

We have previously reported that primary hippocampal neurons exposed to synaptotoxic amyloid beta oligomers (AβOs), which are likely causative agents of Alzheimer's disease (AD), exhibit abnormal Ca signals, mitochondrial dysfunction and defective structural plasticity. Additionally, AβOs-exposed neurons exhibit a decrease in the protein content of type-2 ryanodine receptor (RyR2) Ca channels, which exert critical roles in hippocampal synaptic plasticity and spatial memory processes. The antioxidant N-acetylcysteine (NAC) prevents these deleterious effects of AβOs .

Triclosan Impairs Hippocampal Synaptic Plasticity and Spatial Memory in Male Rats.

Triclosan, a widely used industrial and household agent, is present as an antiseptic ingredient in numerous products of everyday use, such as toothpaste, cosmetics, kitchenware, and toys. Previous studies have shown that human brain and animal tissues contain triclosan, which has been found also as a contaminant of water and soil. Triclosan disrupts heart and skeletal muscle Ca signaling, damages liver function, alters gut microbiota, causes colonic inflammation, and promotes apoptosis in cultured neocortical neurons and neural stem cells.

Ryanodine Receptor-Mediated Calcium Release Has a Key Role in Hippocampal LTD Induction.

The induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission entails pre- and postsynaptic Ca signals, which represent transient increments in cytoplasmic free Ca concentration. In diverse synapse types, Ca release from intracellular stores contributes to amplify the Ca signals initially generated by activation of neuronal Ca entry pathways. Here, we used hippocampal slices from young male rats to evaluate whether pharmacological activation or inhibition of Ca release from the endoplasmic reticulum (ER) mediated by ryanodine receptor (RyR) channels modifies LTD induction at Schaffer collateral-CA1 synapses.

The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca signals, ERK and PI3K.

The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) induces complex neuronal signaling cascades that are critical for the cellular changes underlying synaptic plasticity. These pathways include activation of Ca entry via N-methyl-D-aspartate receptors and sequential activation of nitric oxide synthase and NADPH oxidase, which via generation of reactive nitrogen/oxygen species stimulate Ca-induced Ca release mediated by Ryanodine Receptor (RyR) channels. These sequential events underlie BDNF-induced spine remodeling and type-2 RyR up-regulation.

Contextual Fear Memory Formation and Destabilization Induce Hippocampal RyR2 Calcium Channel Upregulation.

Hippocampus-dependent spatial and aversive memory processes entail Ca signals generated by ryanodine receptor (RyR) Ca channels residing in the endoplasmic reticulum membrane. Rodents exposed to different spatial memory tasks exhibit significant hippocampal RyR upregulation. Contextual fear conditioning generates robust hippocampal memories through an associative learning process, but the effects of contextual fear memory acquisition, consolidation, or extinction on hippocampal RyR protein levels remain unreported.

Calcium Release Mediated by Redox-Sensitive RyR2 Channels Has a Central Role in Hippocampal Structural Plasticity and Spatial Memory.

Aims: Previous studies indicate that hippocampal synaptic plasticity and spatial memory processes entail calcium release from intracellular stores mediated by ryanodine receptor (RyR) channels. In particular, RyR-mediated Ca release is central for the dendritic spine remodeling induced by brain-derived neurotrophic factor (BDNF), a neurotrophin that stimulates complex signaling pathways leading to memory-associated protein synthesis and structural plasticity. To examine if upregulation of ryanodine receptor type-2 (RyR2) channels and the spine remodeling induced by BDNF entail reactive oxygen species (ROS) generation, and to test if RyR2 downregulation affects BDNF-induced spine remodeling and spatial memory.

Development of an iron-selective antioxidant probe with protective effects on neuronal function.

Iron accumulation, oxidative stress and calcium signaling dysregulation are common pathognomonic signs of several neurodegenerative diseases, including Parkinson´s and Alzheimer's diseases, Friedreich ataxia and Huntington's disease. Given their therapeutic potential, the identification of multifunctional compounds that suppress these damaging features is highly desirable. Here, we report the synthesis and characterization of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide, named CT51, which exhibited potent free radical neutralizing activity both in vitro and in cells.