Paclitaxel, but Not Cisplatin, Affects Satellite Glial Cells in Dorsal Root Ganglia of Rats with Chemotherapy-Induced Peripheral Neurotoxicity.

Chemotherapy-induced peripheral neurotoxicity is one of the most common dose-limiting toxicities of several widely used anticancer drugs such as platinum derivatives (cisplatin) and taxanes (paclitaxel). Several molecular mechanisms related to the onset of neurotoxicity have already been proposed, most of them having the sensory neurons of the dorsal root ganglia (DRG) and the peripheral nerve fibers as principal targets. In this study we explore chemotherapy-induced peripheral neurotoxicity beyond the neuronocentric view, investigating the changes induced by paclitaxel (PTX) and cisplatin (CDDP) on satellite glial cells (SGC) in the DRG and their crosstalk.

Morpho-Functional Characterisation of the Rat Ventral Caudal Nerve in a Model of Axonal Peripheral Neuropathy.

Peripheral Neuropathies (PN) are common conditions whose treatment is still lacking in most cases. Animal models are crucial, but experimental procedures should be refined in some cases. We performed a detailed characterization of the ventral caudal nerve to contribute to a more effective assessment of axonal damage in future PN studies.

Making Connections: Mesenchymal Stem Cells Manifold Ways to Interact with Neurons.

Mesenchymal Stem Cells (MSCs) are adult multipotent cells able to increase sensory neuron survival: direct co-culture of MSCs with neurons is pivotal to observe a neuronal survival increase. Despite the identification of some mechanisms of action, little is known about how MSCs physically interact with neurons. The aim of this paper was to investigate and characterize the main mechanisms of interaction between MSCs and neurons.

Breast radiotherapy with kilovoltage photons and gold nanoparticles as radiosensitizer: An in vitro study.

Purpose: We investigated the dose enhancement and internalization of gold nanoparticles (AuNPs) used as a radiosensitizer agent for rotational radiotherapy of breast cancer using a kilovoltage (kV) X-ray beam.

Methods: Human breast cancer cells MDA-MB-231 were incubated with or without 100 μg/mL (4.87 nM) or 200 μg/mL (9.

ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine.

Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II.

Establishing sample-preparation protocols for X-ray phase-contrast CT of rodent spinal cords: Aldehyde fixations and osmium impregnation.

Background: Dense and unbiased cellular-resolution representations of extended volumetric central nervous system soft-tissue anatomy are difficult to obtain, even in experimental post-mortem settings. Interestingly, X-ray phase-contrast computed tomography (X-PCI-CT), an emerging soft-tissue-sensitive volumetric imaging technique, can provide multiscale organ- to cellular-level morphological visualizations of neuroanatomical structure.

New Method: Here, we tested different nervous-tissue fixation procedures, conventionally used for transmission electron microscopy, to better establish X-PCI-CT-specific sample-preparation protocols.

Age-related changes in the function and structure of the peripheral sensory pathway in mice.

This study is aimed at describing the changes occurring in the entire peripheral nervous system sensory pathway along a 2-year observation period in a cohort of C57BL/6 mice. The neurophysiological studies evidenced significant differences in the selected time points corresponding to childhood, young adulthood, adulthood, and aging (i.e.

Undifferentiated MSCs are able to myelinate DRG neuron processes through p75.

Over the last few years the therapeutic approach to demyelinating diseases has radically changed, strategies having been developed aimed at partnering the classic symptomatic treatments with the most advanced regenerative medicine tools. At first, the transplantation of myelinogenic cells, Schwann cells or oligodendrocytes was suggested, but the considerable technical difficulties, (poor availability, difficulties in harvesting and culturing, and the problem of rejection in the event of non-autologous sources), shifted attention towards more versatile cellular types, such as Mesenchymal Stem Cells (MSCs). Recent studies have already demonstrate both in vitro and in vivo that glially-primed MSCs (through exposure to chemical cocktails) have myelogenic abilities.

Myelin structure is unaltered in chemotherapy-induced peripheral neuropathy.

Purpose: Alterations in mRNA for myelin proteins are reported in animal models of chemotherapy-induced peripheral neuropathies (CIPN); however, ultrastructural changes in aldehyde-fixed and plastic-embedded myelin are not evident by electron microscopy. Therefore, we used X-ray diffraction (XRD) to investigate more subtle changes in myelin sheath structure from unfixed nerves.

Experimental Design: We used in vivo chronic animal models of CIPN in female Wistar rats, administering cisplatin (CDDP 2mg/kg, i.

Long-term survival of human neural stem cells in the ischemic rat brain upon transient immunosuppression.

Understanding the physiology of human neural stem cells (hNSCs) in the context of cell therapy for neurodegenerative disorders is of paramount importance, yet large-scale studies are hampered by the slow-expansion rate of these cells. To overcome this issue, we previously established immortal, non-transformed, telencephalic-diencephalic hNSCs (IhNSCs) from the fetal brain. Here, we investigated the fate of these IhNSC's immediate progeny (i.

Biological heterogeneity of putative bladder cancer stem-like cell populations from human bladder transitional cell carcinoma samples.

Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells, the cancer stem-like cells (CSCs) or tumor initiating cells. We report on the isolation and biological characterization of putative bladder CSC populations from primary TCCs.

Role of MAPKs in platinum-induced neuronal apoptosis.

An unsolved question is how platinum derivatives used for solid cancer therapy cause peripheral neuropathy in patients and apoptosis in "in vitro" models of chemotherapy-induced peripheral neuropathy. DRG neurons from E15 rat embryos were treated with toxic doses of oxaliplatin or cisplatin. Here, the role of MAPKs in neuronal apoptosis was studied.

Effect of the chronic combined administration of cisplatin and paclitaxel in a rat model of peripheral neurotoxicity.

We have characterised for the first time the general and neurological side effects experienced when using a series of chronic non-lethal cisplatin + paclitaxel schedules in Wistar rats, selected according to our previous experience and the animals' maximum tolerated dose. At the pathological level, the use of combination schedules was definitely more toxic at the kidney and sternal bone marrow level than the single-agent schedules. At the neurophysiological examination based on the assessment of the nerve conduction velocity measurement in the tail nerve, we identified only one combination schedule that was more neurotoxic than the similar schedules based on single-agent administration.

Expression and distribution of 'high affinity' glutamate transporters GLT1, GLAST, EAAC1 and of GCPII in the rat peripheral nervous system.

l-Glutamate is one of the major excitatory neurotransmitters in the mammalian central nervous system, but recently it has been shown to have a role also in the transduction of sensory input at the periphery, and in particular in the nociceptive pathway. An excess of glutamate is implicated in cases of peripheral neuropathies as well. Conventional therapeutic approaches for treating these diseases have focused on blocking glutamate receptors with small molecules or on reducing its synthesis of the receptors through the inhibition of glutamate carboxypeptidase II (GCPII), the enzyme that generates glutamate.

Valproate protective effects on cisplatin-induced peripheral neuropathy: an in vitro and in vivo study.

Background: Antineoplastic drugs, such as cisplatin (CDDP), induce disabling peripheral neuropathies, representing a hindrance to effective cancer treatments. The exact pathogenesis of CDDP-induced neuropathy is not yet understood, and the dysregulation of gene expression has been proposed. Valproate (VPA) is an antiepileptic drug recently discovered to remodel gene expression, with hypothetically putative neuroprotective effects.

Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat.

Bortezomib is a new proteasome inhibitor with a high antitumor activity, but also with a potentially severe peripheral neurotoxicity. To establish a preclinical model and to characterize the changes induced on the peripheral nerves, dorsal root ganglia (DRG) and spinal cord, bortezomib was administered to Wistar rats (0.08, 0.

Paclitaxel toxicity in post-mitotic dorsal root ganglion (DRG) cells.

Paclitaxel is an antineoplastic drug which acts by enhancing tubulin polymerization. The induction of peripheral neuropathy is the main dose-limiting side-effect of paclitaxel treatment. In this study, the neurotoxic effect of this drug in dorsal root ganglion (DRG) explants was analyzed by measuring the neurite length of DRG explants exposed to nerve growth factor (NGF).

Junctional adhesion molecule-A-deficient polymorphonuclear cells show reduced diapedesis in peritonitis and heart ischemia-reperfusion injury.

Junctional Adhesion Molecule-A (JAM-A) is a transmembrane adhesive protein expressed at endothelial junctions and in leukocytes. Here we report that JAM-A is required for the correct infiltration of polymorphonuclear leukocytes (PMN) into an inflamed peritoneum or in the heart upon ischemia-reperfusion injury. The defect was not observed in mice with an endothelium-restricted deficiency of the protein but was still detectable in mice transplanted with bone marrow from JAM-A(-/-) donors.

Multimodal quantal release at individual hippocampal synapses: evidence for no lateral inhibition.

Most CNS synapses investigated thus far contain a large number of vesicles docked at the active zone, possibly forming individual release sites. At the present time, it is unclear whether these vesicles can be discharged independently of one another. To investigate this problem, we recorded miniature excitatory currents by whole-cell and single-synapse recordings from CA3-CA1 hippocampal neurons and analyzed their stochastic properties.