Giorgia Melli

Axonal protective effects of the myelin associated glycoprotein

Progressive axonal degeneration follows demyelination in many neurological diseases, including multiple sclerosis and inherited demyelinating neuropathies, such as Charcot-Marie-Tooth disease. One glial molecule, the myelin-associated glycoprotein (MAG), located in the adaxonal plasmalemma of myelin-producing cells, is known to signal to the axon and to modulate axonal caliber through phosphorylation of axonal neurofilament proteins. This report establishes for the first time that MAG also promotes resistance to axonal injury and prevents axonal degeneration both in cell culture and in vivo. This effect on axonal stability depends on the RGD domain around arginine 118 in the extracellular portion of MAG, but it is independent of Nogo signaling in the axon. Exploiting this pathway may lead to therapeutic strategies for neurological diseases characterized by axonal loss.

Dorsal Root Ganglia Sensory Neuronal Cultures: a tool for drug discovery for peripheral neuropathies.

Background: Peripheral neuropathies affect many people worldwide and are caused by or associated with a wide range of conditions, both genetic and acquired. Current therapies are directed at symptomatic control because no effective regenerative treatment exists. The primary challenge is that mechanisms that lead to distal axonal degeneration, a common feature of all peripheral neuropathies, are largely unknown. Objective/methods: To address the role and specific characteristics of dorsal root ganglia (DRG) derived sensory neuron culture system as a useful model in evaluating the pathogenic mechanisms of peripheral neuropathies and examination and validation of potential therapeutic compounds. A thorough review of the recent literature was conducted and select examples of the use of DRG neurons in different peripheral neuropathy models were chosen to highlight the utility of these cultures. Conclusion: Many useful models of different peripheral neuropathies have been developed using DRG neuronal culture and potential therapeutic targets have been examined, but so far none of the potential therapeutic compounds have succeeded in clinical trials. In recent years, the focus has changed to evaluation of axon degeneration as the primary outcome measure advocating a drug development strategy starting with phenotypic drug screening, followed by validation in primary complex co-cultures and animal models.

Erythropoietin protects sensory axons against paclitaxel-induced distal degeneration

Paclitaxel causes a sensory polyneuropathy with characteristic features of distal axonal degeneration. Although the exact mechanisms underlying distal axonal degeneration are unknown, paclitaxel-induced axonal degeneration has been shown to be associated with an increase in detyrosinated tubulin. Here we show that recombinant human erythropoietin prevents axonal degeneration in sensory neurons in vitro and this effect is associated with downregulation of detyrosinated tubulin. Furthermore, in an animal model of paclitaxel-induced distal sensory polyneuropathy, recombinant human erythropoietin protects against distal axonal degeneration. These findings suggest that recombinant human erythropoietin may be useful as a therapy to prevent paclitaxel-induced sensory polyneuropathy in patients undergoing chemotherapy.

Clinical and genetic description of a family with Charcot-Marie-Tooth disease type 1B from a transmembrane MPZ mutation.

Mutations in the myelin protein zero gene (MPZ) are associated with certain demyelinating neuropathies, and in particular with Charcot–Marie–Tooth disease type 1B (CMT1B), Dejerine–Sottas syndrome, and congenital hypomyelination. MPZ mutations affecting the proteins transmembrane domain are generally associated with more severe phenotypes. We describe a family with mild CMT1B associated with a transmembrane MPZ mutation. Sequence analysis identified a G‐to‐C transversion at nucleotide 1064, predicting a glycine‐to‐arginine substitution in codon 163 (G163R) of MPZ. This report furthers the understanding of the clinical and electrophysiological manifestations of MPZ mutations. Muscle Nerve 29: 867–869, 2004

Canadian Association of Neurosciences review: regulation of myelination by trophic factors and neuron-glial signaling.

Myelination in the nervous system is a tightly regulated process that is mediated by both soluble and non-soluble factors acting on axons and glial cells. This process is bi-directional and involves a variety of neurotrophic and gliotrophic factors acting in paracrine and autocrine manners. Neuron-derived trophic factors play an important role in the control of early proliferation and differentiation of myelinating glial cells. At later stages of development, same molecules may play a different role and act as inducers of myelination rather than cell survival signals for myelinating glial cells. In return, myelinating glial cells provide trophic support for axons and protect them from injury. Chronic demyelination leads to secondary axonal degeneration that is responsible for long-term disability in primary demyelinating diseases such as multiple sclerosis and inherited demyelinating peripheral neuropathies. A better understanding of the molecular mechanisms controlling myelination may yield novel therapeutic targets for demyelinating nervous system disorders.

Perioperative bilateral median neuropathy.

NERVE injuries associated with surgical operations are well recognized and described in literature. 1,2 Ulnar neuropathy, brachial plexus, and lumbosacral roots injuries are the most frequent, as shown by two large reviews on anesthesia-related nerve damage from the American Society of Anesthesiologists closed claims study. 3,4 Several factors such as section, compression, traction, and ischemia, contribute to the nerve injuries but the exact mechanism(s) in an individual case often is unclear. 4,5 We describe a case of perioperative bilateral median neuropathy at the distal forearm, an uncommon site of nerve injury, which we ascribe to demyelinative conduction block secondary to nerve compression.

History and Biology of Erythropoietin in Hematopoietic and Non-Neural Tissues

Erythropoietin (EPO) is a glycoprotein hormone, which is produced in kidney and liver, and is mainly involved in regulating proliferation and maturation of red blood cells. EPO gene expression is induced by hypoxia through the transcription factor hypoxia inducible factor-1, which has been found to be the main regulator of oxygen homeostasis in the body. Suppression of apoptosis is the principle mechanism of action of EPO in maintaining erythropoiesis. It has been recently recognized that EPO is a member of the cytokine type I superfamily and it has multiple effects in organs and tissues different from the hematopoietic system. Recent evidence of EPO as a protective factor in various injury models in the nervous system and heart has raised the possibility that EPO can exert protective effects in many organs in the body. However, whether the mechanism of protective action involves inhibition of apoptosis remains to be seen.