Journal of neuropathology and experimental neurology, 2018
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of Charcot-Marie-Tooth diseases... more Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of Charcot-Marie-Tooth diseases, is a demyelinating neuropathy caused by a deletion encompassing the gene coding for PMP22, a myelin protein of the peripheral nervous system. Although myelinated fibers are mostly involved in CMT1A, some patients experience neuropathic pain. We thus investigated whether unmyelinated fibers are lost in CMT1A. Skin biopsies were taken from the distal portion of the leg of 80 patients with CMT1A as part of the PXT30003-01 study and processed for quantification of intraepidermal nerve fiber density (IENFD). Mean IENFD was significantly lower in CMT1A patients than in healthy controls. Although the data were highly dispersed, IENFD tended to decrease with age and was higher overall in female patients and controls than male patients and controls. This study shows that small nerve fibers are affected in CMT1A and that this correlates with pin sensitivity. The density of epidermal Langerhans c...
The skin is a highly sensitive organ. It is densely innervated with different types of sensory ne... more The skin is a highly sensitive organ. It is densely innervated with different types of sensory nerve endings, which discriminate between pain, temperature and touch. Autonomic nerve fibres which completely derive from sympathetic (cholinergic) neurons are also present. During all the phases of skin wound healing (inflammatory, proliferative and remodelling phases), neuromediators are involved. Several clinical observations indicate that damage to the peripheral nervous system influences wound healing, resulting in chronic wounds within the affected area. Patients with cutaneous sensory defects due to lepromatous leprosy, spinal cord injury and diabetic neuropathy develop ulcers that fail to heal. In addition, numerous experimental observations suggest that neurogenic stimuli profoundly affect wound repair after injury and that delayed wound healing is observed in animal models after surgical resection of cutaneous nerves. All these observations clearly suggest that innervation and n...
Since its cloning in 1997, functional and structural studies of TRPV1 have led to an improvement ... more Since its cloning in 1997, functional and structural studies of TRPV1 have led to an improvement in our understanding of the mechanisms that underlie the transduction of noxious thermal and mechanical stimuli by sensory neurons. Because of its role in inflammatory processes and nociceptive pathways, TRPV1 has become an important target for neuropathic pain relief. Models of painful small-fiber sensory neuropathy were developed and several laboratories have progressed in the conception of TRPV1 agonists and antagonists. Patch and cream containing capsaicin, the most famous TRPV1 agonist, are commercialized to relieve neuropathic pain. Others agonists and TRPV1 antagonists are tested in clinical trials and new agents, "TRPV1 modulators", with fewer side effects are currently developed in experimental studies.
The fibroblasts and the myofibroblasts are key players for maintaining skin homeostasis and for o... more The fibroblasts and the myofibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair. The (myo)fibroblasts are embedded in a sophisticated extracellular matrix (ECM) that they secrete, and a complex and interactive dialogue exists between (myo)fibroblasts and their microenvironment. The composition of the ECM around (myo)fibroblasts is variable depending on the situation and, in addition to the secretion of the ECM, the (myo)fibroblasts, by secreting matrix metalloproteinases and tissue inhibitors of metalloproteinases can remodel this ECM. The (myo)fibroblasts and their microenvironment form a changing network with reciprocal actions leading to cell differentiation, proliferation, quiescence or apoptosis, and also acting on growth factor biodisponibility. In pathological situations (such as chronic wounds or excessive scarring), or during ageing, especially due to ultraviolet exposition, this dialogue between the (myo)fibroblasts and their microenvironment is disrupted, leading to repair defects or to skin injuries with unaesthetic alterations such as wrinkles. Knowing the intimate exchanges between the (myo)fibroblasts and their microenvironment represents a fascinating domain important not only for characterizing new targets and drugs able to prevent pathological developments but also for interfering with skin alterations observed during ageing.
Small-fiber neuropathy was induced in young adult mice by intraperitoneal injection of resinifera... more Small-fiber neuropathy was induced in young adult mice by intraperitoneal injection of resiniferatoxin (RTX), a TRPV1 agonist. At day 7, RTX induced significant thermal and mechanical hypoalgesia. At day 28, mechanical and thermal nociception were restored. No nerve degeneration in skin was observed and unmyelinated nerve fiber morphology and density in sciatic nerve were unchanged. At day 7, substance P (SP) was largely depleted in dorsal root ganglia (DRG) neurons, although calcitonin gene-related peptide (CGRP) was only moderately depleted. Three weeks after, SP and CGRP expression was restored in DRG neurons. At the same time, CGRP expression remained low in intraepidermal nerve fibers (IENFs) whereas SP expression had improved. In summary, RTX induced in our model a transient neuropeptide depletion in sensory neurons without nerve degeneration. We think this model is valuable as it brings the opportunity to study functional nerve changes in the very early phase of small fiber neuropathy. Moreover, it may represent a useful tool to study the mechanisms of action of therapeutic strategies to prevent sensory neuropathy of various origins.
Journal of neuropathology and experimental neurology, 2018
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of Charcot-Marie-Tooth diseases... more Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of Charcot-Marie-Tooth diseases, is a demyelinating neuropathy caused by a deletion encompassing the gene coding for PMP22, a myelin protein of the peripheral nervous system. Although myelinated fibers are mostly involved in CMT1A, some patients experience neuropathic pain. We thus investigated whether unmyelinated fibers are lost in CMT1A. Skin biopsies were taken from the distal portion of the leg of 80 patients with CMT1A as part of the PXT30003-01 study and processed for quantification of intraepidermal nerve fiber density (IENFD). Mean IENFD was significantly lower in CMT1A patients than in healthy controls. Although the data were highly dispersed, IENFD tended to decrease with age and was higher overall in female patients and controls than male patients and controls. This study shows that small nerve fibers are affected in CMT1A and that this correlates with pin sensitivity. The density of epidermal Langerhans c...
The skin is a highly sensitive organ. It is densely innervated with different types of sensory ne... more The skin is a highly sensitive organ. It is densely innervated with different types of sensory nerve endings, which discriminate between pain, temperature and touch. Autonomic nerve fibres which completely derive from sympathetic (cholinergic) neurons are also present. During all the phases of skin wound healing (inflammatory, proliferative and remodelling phases), neuromediators are involved. Several clinical observations indicate that damage to the peripheral nervous system influences wound healing, resulting in chronic wounds within the affected area. Patients with cutaneous sensory defects due to lepromatous leprosy, spinal cord injury and diabetic neuropathy develop ulcers that fail to heal. In addition, numerous experimental observations suggest that neurogenic stimuli profoundly affect wound repair after injury and that delayed wound healing is observed in animal models after surgical resection of cutaneous nerves. All these observations clearly suggest that innervation and n...
Since its cloning in 1997, functional and structural studies of TRPV1 have led to an improvement ... more Since its cloning in 1997, functional and structural studies of TRPV1 have led to an improvement in our understanding of the mechanisms that underlie the transduction of noxious thermal and mechanical stimuli by sensory neurons. Because of its role in inflammatory processes and nociceptive pathways, TRPV1 has become an important target for neuropathic pain relief. Models of painful small-fiber sensory neuropathy were developed and several laboratories have progressed in the conception of TRPV1 agonists and antagonists. Patch and cream containing capsaicin, the most famous TRPV1 agonist, are commercialized to relieve neuropathic pain. Others agonists and TRPV1 antagonists are tested in clinical trials and new agents, "TRPV1 modulators", with fewer side effects are currently developed in experimental studies.
The fibroblasts and the myofibroblasts are key players for maintaining skin homeostasis and for o... more The fibroblasts and the myofibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair. The (myo)fibroblasts are embedded in a sophisticated extracellular matrix (ECM) that they secrete, and a complex and interactive dialogue exists between (myo)fibroblasts and their microenvironment. The composition of the ECM around (myo)fibroblasts is variable depending on the situation and, in addition to the secretion of the ECM, the (myo)fibroblasts, by secreting matrix metalloproteinases and tissue inhibitors of metalloproteinases can remodel this ECM. The (myo)fibroblasts and their microenvironment form a changing network with reciprocal actions leading to cell differentiation, proliferation, quiescence or apoptosis, and also acting on growth factor biodisponibility. In pathological situations (such as chronic wounds or excessive scarring), or during ageing, especially due to ultraviolet exposition, this dialogue between the (myo)fibroblasts and their microenvironment is disrupted, leading to repair defects or to skin injuries with unaesthetic alterations such as wrinkles. Knowing the intimate exchanges between the (myo)fibroblasts and their microenvironment represents a fascinating domain important not only for characterizing new targets and drugs able to prevent pathological developments but also for interfering with skin alterations observed during ageing.
Small-fiber neuropathy was induced in young adult mice by intraperitoneal injection of resinifera... more Small-fiber neuropathy was induced in young adult mice by intraperitoneal injection of resiniferatoxin (RTX), a TRPV1 agonist. At day 7, RTX induced significant thermal and mechanical hypoalgesia. At day 28, mechanical and thermal nociception were restored. No nerve degeneration in skin was observed and unmyelinated nerve fiber morphology and density in sciatic nerve were unchanged. At day 7, substance P (SP) was largely depleted in dorsal root ganglia (DRG) neurons, although calcitonin gene-related peptide (CGRP) was only moderately depleted. Three weeks after, SP and CGRP expression was restored in DRG neurons. At the same time, CGRP expression remained low in intraepidermal nerve fibers (IENFs) whereas SP expression had improved. In summary, RTX induced in our model a transient neuropeptide depletion in sensory neurons without nerve degeneration. We think this model is valuable as it brings the opportunity to study functional nerve changes in the very early phase of small fiber neuropathy. Moreover, it may represent a useful tool to study the mechanisms of action of therapeutic strategies to prevent sensory neuropathy of various origins.
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Papers by Aurore Danigo