Inhibition of NHE1 transport activity and gene transcription in DRG neurons in oxaliplatin-induced painful peripheral neurotoxicity.

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN), one of the major dose-limiting side effects of colorectal cancer treatment, is characterized by both acute and chronic syndromes. Acute exposure to low dose OHP on dorsal root ganglion (DRG) neurons is able to induce an increase in intracellular calcium and proton concentration, thus influencing ion channels activity and neuronal excitability. The Na/H exchanger isoform-1 (NHE1) is a plasma membrane protein that plays a pivotal role in intracellular pH (pH) homeostasis in many cell types, including nociceptors.

P2X Purinergic Receptors Are Multisensory Detectors for Micro-Environmental Stimuli That Control Migration of Tumoral Endothelium.

The tumoral microenvironment often displays peculiar features, including accumulation of extracellular ATP, hypoxia, low pH-acidosis, as well as an imbalance in zinc (Zn) and calcium (Ca). We previously reported the ability of some purinergic agonists to exert an anti-migratory activity on tumor-derived human endothelial cells (TEC) only when applied at a high concentration. They also trigger calcium signals associated with release from intracellular stores and calcium entry from the external medium.

Deletion of calcineurin from astrocytes reproduces proteome signature of Alzheimer's disease and epilepsy and predisposes to seizures.

Calcineurin (CaN), acting downstream of intracellular calcium signals, orchestrates cellular remodeling in many cellular types. In astrocytes, major homeostatic players in the central nervous system (CNS), CaN is involved in neuroinflammation and gliosis, while its role in healthy CNS or in early neuro-pathogenesis is poorly understood. Here we report that in mice with conditional deletion of CaN in GFAP-expressing astrocytes (astroglial calcineurin KO, ACN-KO), at 1 month of age, transcription was largely unchanged, while the proteome was deranged in the hippocampus and cerebellum.

Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification.

Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons.

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice.

The pathogenesis of Alzheimer's disease (AD), a slowly-developing age-related neurodegenerative disorder, is a result of the action of multiple factors including deregulation of Ca homeostasis, mitochondrial dysfunction, and dysproteostasis. Interaction of these factors in astrocytes, principal homeostatic cells in the central nervous system, is still poorly understood. Here we report that in immortalized hippocampal astrocytes from 3xTg-AD mice (3Tg-iAstro cells) bioenergetics is impaired, including reduced glycolysis and mitochondrial oxygen consumption, and increased production of reactive oxygen species.

Assessment of a Silicon-Photomultiplier-Based Platform for the Measurement of Intracellular Calcium Dynamics with Targeted Aequorin.

Ca is among the most important intracellular second messengers participating in a plethora of biological processes, and the measurement of Ca fluctuations is significant in the phenomenology of the underlying processes. Aequorin-based Ca probes represent an invaluable tool for reliable measurement of Ca concentrations and dynamics in different subcellular compartments. However, their use is limited due to the lack on the market of ready-to-use, cost-effective, and portable devices for the detection and readout of the low-intensity bioluminescence signal produced by these probes.

Deletion of calcineurin from GFAP-expressing astrocytes impairs excitability of cerebellar and hippocampal neurons through astroglial Na /K ATPase.

Astrocytes perform important housekeeping functions in the nervous system including maintenance of adequate neuronal excitability, although the regulatory mechanisms are currently poorly understood. The astrocytic Ca /calmodulin-activated phosphatase calcineurin (CaN) is implicated in the development of reactive gliosis and neuroinflammation, but its roles, including the control of neuronal excitability, in healthy brain is unknown. We have generated a mouse line with conditional knockout (KO) of CaN B1 (CaNB1) in glial fibrillary acidic protein-expressing astrocytes (astroglial calcineurin KO [ACN-KO]).

The interaction of SiO nanoparticles with the neuronal cell membrane: activation of ionic channels and calcium influx.

Aim: To clarify the mechanisms of interaction between SiO nanoparticles (NPs) and the plasma membrane of GT1-7 neuroendocrine cells, with focus on the activation of calcium-permeable channels, responsible for the long lasting calcium influx and modulation of the electrical activity in these cells.

Materials & Methods: Nontoxic doses of SiO NPs were administered to the cells. Calcium imaging and patch clamp techniques were combined with a pharmacological approach.

Oxaliplatin induces pH acidification in dorsal root ganglia neurons.

Oxaliplatin induced peripheral neurotoxicity is characterized by an acute cold-induced syndrome characterized by cramps, paresthesias/dysesthesias in the distal limbs and perioral region, that develops rapidly and lasts up to one week affecting nearly all the patients as well as by long-lasting symptoms. It has been previously shown that pharmacological or genetic ablation of TRPA1 responses reduces oxaliplatin-induced peripheral neurotoxicity in mouse models. In the present report, we show that treatment with concentrations of oxaliplatin similar to those found in plasma of treated patients leads to an acidification of the cytosol of mouse dorsal root ganglia neurons in culture and this in turn is responsible for sensitization of TRPA1 channels, thereby providing a mechanistic explanation to toxicity of oxaliplatin.

Susceptibility of different mouse strains to oxaliplatin peripheral neurotoxicity: Phenotypic and genotypic insights.

Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity.

Nanosized TiO2 is internalized by dorsal root ganglion cells and causes damage via apoptosis.

Unlabelled: Titanium dioxide (TiO2) is widely used as ingredient in several products in the nanoform. TiO2-nanoparticles (NPs) are also currently studied for different medical applications. A large debate exists on possible adverse health effects related to their exposure.

Activation of TRPV4 channels reduces migration of immortalized neuroendocrine cells.

Calcium is a universal signal, and its capacity to encode intracellular messages via spatial, temporal and amplitude characteristics allows it to participate in most cellular events. In a specific context, calcium plays a pivotal role in migration, although its role has not been elucidated fully. By using immortalized gonadotropin-releasing hormone-secreting neurons (GN11), we have now investigated the role of TRPV4, a member of the vanilloid family of Ca(2+) channels, in neuronal migration.

Novel adenosine and cAMP signalling pathways in migrating glial cells.

This study was aimed at characterizing the effect of purinergic transmission on migration of embryonic ciliary ganglion satellite glial cells. Application of adenosine significantly decreased the rate of migration of glial cells whereas no differences were observed in the presence of ATP. The A(2B) receptor antagonist reverted this action, but application of an A(2A) receptor antagonist or a cAMP-protein kinase inhibitor had no effect on the agonist's stimulation.

Calcium signals activated by ghrelin and D-Lys(3)-GHRP-6 ghrelin antagonist in developing dorsal root ganglion glial cells.

Ghrelin is a hormone regulating energy homeostasis via interaction with its receptor, GHSR-1a. Ghrelin activities in dorsal root ganglia (DRG) cells are unknown. Herein we show that ghrelin induces a change of cytosolic calcium concentration in both glia and neurons of embryonic chick DRG.

Calcium signals and the in vitro migration of chick ciliary ganglion cells.

We have studied calcium signals and their role in the migration of neuronal and nonneuronal cells of embryonic chick ciliary ganglion (CG). In vitro, neurons migrate in association with nonneuronal cells to form cellular aggregates. Changes in the modulus of the velocity of the neuron-nonneuronal cell complex were observed in response to treatments that increased or decreased intracellular calcium concentration.

Calcium signals activated by arachidonic acid in embryonic chick ciliary ganglion neurons.

Arachidonic acid (AA, 20:4) has been reported to modulate a variety of calcium-permeable ionic channels, both in the plasma membrane and in the endoplasmic reticulum. We have studied the effects of AA on calcium signaling in a well-characterized model of developing peripheral neurons, embryonic chick ciliary ganglion neurons in culture. When given at low non-micellar concentrations (5 microM), in the majority of cells AA directly activated a delayed and long-lasting increase in [Ca2+]i, involving both the cytoplasm and the nucleoplasm, that was completely reversed by abolition of extracellular calcium.

GDNF and bFGF are differentially involved in glial cell differentiation and neurite bundle formation in cultures from chick embryonic ciliary ganglia.

We have shown that the neurotrophic factors glial cell line-derived neurotrophic factor (GDNF) and basic fibroblast growth factor (bFGF) exert different effects on glial cells in cultures from chick embryo ciliary ganglia. bFGF acts as a mitogen on glial cells, and induces their aggregation to neuronal bodies; after 48 h of culture no glial cells could be observed along neurites. GDNF has no proliferative role; in contrast, it promotes the expression of the differentiative marker O4 and the association of glial cell bodies to neurites to form robust bundles.

A K(+) channel activated by cholinergic muscarinic receptors in chick ciliary ganglion neurons at early developmental stage.

Embryonic chick ciliary ganglion (CG) neurons obtained from E7-E8 ganglia maintained in serum-free medium were stimulated with 50 microM muscarine. A fast hyperpolarization of the membrane potential was observed in 25% of the cells tested, that in some cases was associated with a slower depolarization. Accordingly, in voltage clamp experiments, either an outward current or a biphasic current response could be observed.

A calcium-permeable channel activated by muscarinic acetylcholine receptors and InsP3 in developing chick ciliary ganglion neurons.

The electrical responses elicited by the muscarinic cholinergic pathway have been studied in cultured embryonic chick ciliary ganglion (CG) neurons. Neurons obtained from E7-E8 ganglia were maintained in serum-free medium for 1 to 3 days. Stimulation with 50 microM muscarine induced depolarizing responses in about 30% of the cells tested.

In vitro analysis of neuron-glial cell interactions during cellular migration.

We used time-lapse microscopy to study the in vitro migration of neuronal cells from developing chick ciliary ganglion. These cells, when dissociated and cultured in a chemically defined medium, are able to migrate and to associate into clusters. We focused our attention on the study of the distribution of neuronal velocity components.