GABA RECEPTORS AND PAIN REGULATION

Pain is an adaptive sensation that normally appears as a warning, activated in response to a damage of the organism. Pain serves to protect the organism to further tissue injuries. The International Association for the Study of Pain (IASP) defined pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (see definition on the IASP homepage at www.iasp-pain.org). Pain can be generally divided into two categories, acute and chronic pain: acute pain is properly a sudden warning pain which signals that something is wrong in the body. If the cause is not removed acute pain may develop in chronic pain, which is persistent and debilitating

Neuroactive steroids influence peripheral myelination: A promising opportunity for preventing or treating age-dependent dysfunctions of peripheral nerves

The process of aging deeply influences morphological and functional parameters of peripheral nerves. The observations summarized here indicate that the deterioration of myelin occurring in the peripheral nerves during aging may be explained by the fall of the levels of the major peripheral myelin proteins [e.g., glycoprotein Po (Po) and peripheral myelin protein 22 (PMP22)]. Neuroactive steroids, such as progesterone (PROG), dihydroprogesterone (5α-DH PROG), and tetrahydroprogesterone (3α,5α-TH PROG), are able to stimulate the low expression of these two myelin proteins present in the sciatic nerve of aged male rats. Since Po and PMP22 play an important physiological role in the maintenance of the multilamellar structure of PNS myelin, we have evaluated the effect of PROG and its neuroactive derivatives, 5α-DH PROG and 3α,5α-TH PROG, on the morphological alterations of myelinated fibers in the sciatic nerve of 22-24-month-old male rats. Data obtained clearly indicate that neuroactive steroids are able to reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in the sciatic nerve. © 2003 Elsevier Ltd. All rights reserved.Peer Reviewe

Peripheral nerve regeneration following injury is altered in mice lacking P2X7 receptor

From Wiley via Jisc Publications RouterHistory: received 2020-04-09, rev-recd 2020-08-27, accepted 2020-09-23, pub-electronic 2020-10-22, pub-print 2021-09Article version: VoRPublication status: PublishedFunder: The Rosetrees Trust and the Stoneygate Trust; Grant(s): M746Funder: Academy of Medical Sciences; Id: http://dx.doi.org/10.13039/501100000691; Grant(s): AMS‐SGCL7Abstract: Peripheral nerve injuries are debilitating, and current clinical management is limited to surgical intervention, which often leads to poor functional outcomes. Development of pharmacological interventions aimed at enhancing regeneration may improve this. One potential pharmacological target is the P2X purinergic receptor 7 (P2X7R) expressed in Schwann cells, which is known to play a role during the development of the peripheral nerves. Herein, we analysed differences in regeneration between genetically engineered P2X7 knockout mice and wild‐type controls, using in vivo and ex vivo models of peripheral nerve regeneration. We have found that the speed of axonal regeneration is unaltered in P2X7 knockout mice, nevertheless regenerated P2X7 knockout nerves are morphologically different to wild‐type nerves following transection and immediate repair. Indeed, the detailed morphometric analysis at 4 and 8 weeks after injury showed evidence of delayed remyelination in P2X7 knockout mice, compared to the wild‐type controls. Furthermore, the Wallerian degeneration phase was unaltered between the two experimental groups. We also analysed gene expression changes in the dorsal root ganglia neurones as a result of the peripheral nerve injury, and found changes in pathways related to pain, inflammation and cell death. We conclude that P2X7 receptors in Schwann cells may be a putative pharmacological target to control cell fate following injury, thus enhancing nerve re‐myelination

In vivo morphological evaluation of the efficacy of an hydrogel conduit as scaffold for peripheral nerve regeneration

Autologous nerve grafting is considered the gold standard for bridging nerve lesion, although in several cases the use of artificial tubular guides is needed. Nowadays, the research is addressed to identify the ideal treatment able to support complete nerve regeneration and functional recovery. Therefore, the use of artificial synthetic or natural guides is required but, despite numerous studies on several kinds of conduits, the clinicians are still waiting for an alternative scaffolds giving the best regenerative properties. In this light, we evaluated in vivo the efficacy of a polyamidoamine-based hydrogel, shaped as small tubing for nerve regeneration. Studies were done on 3 experimental groups consisting of injured guide-implanted, sham operated and autograft rats (in which sciatic nerve was excised, inverted and re-implanted). In the implanted rats the sciatic nerve was transected and 5 mm gap between proximal and distal stumps was left in the middle of the conduit. Animals were then analyzed at 1, 3, 6, months post-surgery. The gait analysis and the thermal sensitivity analysis demonstrated movement improvement and sensitive recovery. The repaired, control and autograft nerves from all groups analyzed (implanted, sham and autograft) were processed for light microscopy and morphometric analysis. The axon size, myelin thickness and fiber density showed a complete nerve regeneration covering the gap in the central part of the conduit. In particular, the medial segment of the nerve tended to turn similar to sham operated (control) animals, while the autograft rats showed a less extensive regenerative process. Moreover, immunofluorescence analysis of longitudinal sections of the conduits were performed by labeling the axonal neurofilaments. The immunopositivity observed further confirmed that the regenerative process was complete, being the fibres present through the entire conduit between the proximal and the distal stumps. Overall, our data demonstrate that polyamidoamine-based hydrogel conduits are an implantable material providing a good support for the peripheral nerve regeneration. These conduits are biocompatible and biodegradable over the time to non toxic product metabolites. Finally our findings are promising for the achievement of implantable poliamidoamine- based hydrogel conduits functionalized for drug delivery with growth factors. This work has been supported by Fondazione CARIPLO under the Project “Functional Polymeric Hydrogels for Tissue Regeneration” (no. 2010-0501), call for the Scientific Research on Advanced Materials, 2010

Peripheral nerve regeneration following injury is altered in mice lacking P2X7 receptor

Peripheral nerve injuries are debilitating, and current clinical management is limited to surgical intervention, which often leads to poor functional outcomes. Development of pharmacological interventions aimed at enhancing regeneration may improve this. One potential pharmacological target is the P2X purinergic receptor 7 (P2X7R) expressed in Schwann cells, which is known to play a role during the development of the peripheral nerves. Herein, we analysed differences in regeneration between genetically engineered P2X7 knockout mice and wild‐type controls, using in vivo and ex vivo models of peripheral nerve regeneration. We have found that the speed of axonal regeneration is unaltered in P2X7 knockout mice, nevertheless regenerated P2X7 knockout nerves are morphologically different to wild‐type nerves following transection and immediate repair. Indeed, the detailed morphometric analysis at 4 and 8 weeks after injury showed evidence of delayed remyelination in P2X7 knockout mice, compared to the wild‐type controls. Furthermore, the Wallerian degeneration phase was unaltered between the two experimental groups. We also analysed gene expression changes in the dorsal root ganglia neurones as a result of the peripheral nerve injury, and found changes in pathways related to pain, inflammation and cell death. We conclude that P2X7 receptors in Schwann cells may be a putative pharmacological target to control cell fate following injury, thus enhancing nerve re‐myelination

Transcriptomic Profile Reveals Deregulation of Hearing-Loss Related Genes in Vestibular Schwannoma Cells Following Electromagnetic Field Exposure

From MDPI via Jisc Publications RouterHistory: accepted 2021-07-18, pub-electronic 2021-07-20Publication status: PublishedFunder: Capita Foundation; Grant(s): grant 2019 to V.M.Funder: Università degli Studi di Milano; Grant(s): grant PSR_VMAGN_2019 to V.MFunder: MIUR Italian Ministry of Research; Grant(s): Progetto di EccellenzaHearing loss (HL) is the most common sensory disorder in the world population. One common cause of HL is the presence of vestibular schwannoma (VS), a benign tumor of the VIII cranial nerve, arising from Schwann cell (SC) transformation. In the last decade, the increasing incidence of VS has been correlated to electromagnetic field (EMF) exposure, which might be considered a pathogenic cause of VS development and HL. Here, we explore the molecular mechanisms underlying the biologic changes of human SCs and/or their oncogenic transformation following EMF exposure. Through NGS technology and RNA-Seq transcriptomic analysis, we investigated the genomic profile and the differential display of HL-related genes after chronic EMF. We found that chronic EMF exposure modified the cell proliferation, in parallel with intracellular signaling and metabolic pathways changes, mostly related to translation and mitochondrial activities. Importantly, the expression of HL-related genes such as NEFL, TPRN, OTOGL, GJB2, and REST appeared to be deregulated in chronic EMF exposure. In conclusion, we suggest that, at a preclinical stage, EMF exposure might promote the transformation of VS cells and contribute to HL

Transmembrane protein TMEM230, regulator of metalloproteins and motor proteins in gliomas and gliosis

Glial cells provide physical and chemical support and protection for neurons and for the extracellular compartments of neural tissue through secretion of soluble factors, insoluble scaffolds, and vesicles. Additionally, glial cells have regenerative capacity by remodeling their physical microenvironment and changing physiological properties of diverse cell types in their proximity. Various types of aberrant glial and macrophage cells are associated with human diseases, disorders, and malignancy. We previously demonstrated that transmembrane protein, TMEM230 has tissue revascularization and regenerating capacity by its ability to secrete pro-angiogenic factors and metalloproteinases, inducing endothelial cell sprouting and channel formation. In healthy normal neural tissue, TMEM230 is predominantly expressed in glial and marcophate cells, suggesting a prominent role in neural tissue homeostasis. TMEM230 regulation of the endomembrane system was supported by co-expression with RNASET2 (lysosome, mitochondria, and vesicles) and STEAP family members (Golgi complex). Intracellular trafficking and extracellular secretion of glial cellular components are associated with endocytosis, exocytosis and phagocytosis mediated by motor proteins. Trafficked components include metalloproteins, metalloproteinases, glycans, and glycoconjugate processing and digesting enzymes that function in phagosomes and vesicles to regulate normal neural tissue microenvironment, homeostasis, stress response, and repair following neural tissue injury or degeneration. Aberrantly high sustained levels TMEM230 promotes metalloprotein expression, trafficking and secretion which contribute to tumor associated infiltration and hypervascularization of high tumor grade gliomas. Following injury of the central nervous or peripheral systems, transcient regulated upregulation of TMEM230 promotes tissue wound healing, remodeling and revascularization by activating glial and macrophage generated microchannels/microtubules (referred to as vascular mimicry) and blood vessel sprouting and branching. Our results support that TMEM230 may act as a master regulator of motor protein mediated trafficking and compartmentalization of a large class of metalloproteins in gliomas and gliosis

GABA and Neuroactive Steroid Interactions in Glia: New Roles for Old Players?

In recent years it has becoming clear that glial cells of the central and peripheral nervous system play a crucial role from the earliest stages of development throughout adult life. Glial cells are important for neuronal plasticity, axonal conduction and synaptic transmission. In this respect, glial cells are able to produce, uptake and metabolize many factors that are essential for neuronal physiology, including classic neurotransmitters and neuroactive steroids. In particular, neuroactive steroids, which are mainly synthesized by glial cells, are able to modulate some neurotransmitter receptors affecting both glia and neurons. Among the signaling systems that are specialized for neuron-glial communication, we can include neurotransmitter GABA

Effetti di alcuni steroidi ormonali sulle cellule gliali e sulle proteine specifiche della mielina

Dottorato di ricerca in scienze endocrinologiche e metaboliche. 11. ciclo. Coordinatore Luciano MartiniConsiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7, Rome; Biblioteca Nazionale Centrale - P.za Cavalleggeri, 1, Florence / CNR - Consiglio Nazionale delle RichercheSIGLEITItal