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  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Blackwell Publishing Ltd/Inc.
    Experimental dermatology 13 (2004), S. 0 
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: POMC processing in human melanocytes has been widely documented, and the α-MSH/MC1R/cAMP cascade has been implicated in the control of pigmentation. Only very recently, a role of β-endorphin, one cleavage product of β-LPH, has been demonstrated to influence melanocyte growth, dendricity and melanin biosynthesis via the µ-opiate receptor. However, much earlier, it was shown that β-MSH, the other cleavage product of β-LPH, controls melanogenesis and melanin transfer in amphibians. To date, a specific receptor for β-MSH has not been identified. Earlier POMC processing has been found in melanosomes. Therefore, an MC1R-independent role of α-MSH was postulated and demonstrated in control of 6-tetrahydrobiopterin (6BH4)-inhibited tyrosinase. Utilizing the depigmentation disorder vitiligo, we were now able to follow the fate of epidermal POMC processing in the presence of mM levels of hydrogen peroxide (H2O2). In vitiligo epidermal PC2 and 7B2 protein expression is increased, whereas α-MSH, β-MSH and β-endorphin are significantly decreased. Analysis of the peptide sequences revealed in all three cases H2O2 oxidation targets such as methionine and tryptophan yielding significant structural alterations. Moreover, we have identified a new function of β-MSH due to its capacity to bind the important cofactor 6BH4 as well as its isomer 7BH4. Hence, we propose for the first time that β-MSH can control both the supply of l-tyrosine from l-phenylalanine via phenylalanine hydroxylase and l-Dopa synthesis via tyrosinase hydroxylase in melanocytes and keratinocytes. Therefore, both melanogenesis and catecholamine synthesis could be regulated by this peptide.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Stress is said to induce itchiness of the skin and exacerbate inflammatory skin diseases such as atopic dermatitis. In this context, stress mediators such as the neuropeptide substance P play a role as immunmodulators and in a wider sense growth factors. For example, we were recently able to show that stress or treatment of mice with substance P is associated with mast cell degranulation, increased cutaneous inflammation and increased apoptosis in the hair follicle. However, local interactions between the nervous and immune systems, especially under perceived stress, have rarely been reported. Here, we show for the first time, that 24 and 48 h after sonic stress exposure, the number of SP-immunoreactive nerve fibres in the back skin of C57BL/6 mice with all there hair follicles in the resting phase of the hair cycle (telogen, low numbers of cutaneous nerve fibres) increased significantly over non-stressed mice with the strongest increase after 24 h. Such substance P immunoreactive nerve fibres contacted mast cells more frequently, which became significant after 48 h. At the same time, the percentage of degranulated mast cells increased significantly after 24 and 48 h with the strongest increase after 48 h when apoptotic cells also became significantly upregulated. The same stressor increased dermal infiltration, e.g. by eosinophils in C57BL/6 mice with experimentally induced allergic dermatitis over mice that were either stressed or had allergic dermatitis as well as over untreated controls. Increased infiltration was associated with increased epidermal thickness in stressed mice with allergic dermatitis and with an increased number of VCAM-immunoreactive blood vessels. At the same time, the percentage of degranulated mast cells increased significantly, and the number of substance P-immunoreactive peptidergic sensory nerve fibres decreased in the acute allergic dermatitis lesions. By semiquantitative RT-PCR, allergic dermatitis increased cutaneous IL-4 and to a lesser degree IFN-γ production, but this was not affected by stress. Ultrastructural investigation showed unmyelinated peptidergic nerve fibres in a state of deterioration close to degranulating mast cells and eosinophils in the skin of stressed mice with allergic dermatitis, suggesting a decreased number of substance P-immunoreactive nerve fibres due to active release of SP. This may lead to an upregulation of endothelial adhesion molecules and increased infiltration by immunocytes to the skin but at mRNA level does not alter the production of classical atopy-related cytokines in skin. These data provide first evidence for stress-induced exacerbation of cutaneous allergic diseases such as atopic dermatitis by local interaction of the peripheral nervous system with substance P.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK; Malden, USA : Blackwell Publishing Ltd/Inc
    Experimental dermatology 13 (2004), S. 0 
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Recently, we have pointed to the existence of a brain-hair follicle axis (BFA), with neuropeptide substance P (SP) as one candidate mediator, to which stress-triggered hair loss is imputable. Based on findings indicating that levels of nerve growth factor (NGF) increase upon exposure to stressful events, which is particularly striking within the context of the BFA, because NGF is known to increase the release of SP, we then aimed at dissecting the role of NGF in stress-triggered hair loss. We observed increased expression of NGF, analyzed by real time PCR and immunohistochemistry, in stress-exposed mice with a depilation-induced hair cycle. Expression of NGF receptor p75 was also upregulated with stress, and TrkA receptor was moderately downregulated. Upon neutralization of NGF by antibody injection, stress-triggered premature onset of catagen, which was accompanied by apoptosis and increased number/activation of perifollicular mast cells and macrophages, was significantly inhibited. Interestingly, subcutaneous injection of recombinant NGF to mimick stress effects resulted in an increased percentage of SP-positive neurons in dorsal root ganglia. Taken together, our data indicate that an interactive communication network between sensory nerves and immune cells in the skin is promoted by stress-triggered release of NGF and results in mast cell activation and migration of macrophages, the release of proinflammatory neuropeptides, i.e. SP. Such disequilibrium, which may be referred to as neurogenic inflammation, constitutes the prerequisite of increased hair loss.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Recently, we introduced a mouse model launching experimental evidence for stress-induced hair growth inhibition (HGI), pointing to the existence of a brain-hair follicle axis (BFA). We suggested that nerve growth factor (NGF), besides neuropeptide substance P (SP), is a candidate mediator along the BFA. Published data further indicate that stress-related neuropeptides, e.g. calcitonin gene-related peptide (CGRP) and SP may be involved in HGI. SP and CGRP are synthesized in dorsal root ganglia (DRG) and released after axonal transport in the skin. Thus, aim of the present study was to investigate the effect of stress or subcutaneous injection of NGF, which mimics stress and regulates neuropeptide genes in sensory neurons, on the expression of SP and CGRP in DRG. Anagen was induced in C57BL/6 mice by depilation and retrograde tracing was employed on day 9 post-depilation (PD). On day 14 PD, mice were either exposed to sound stress (n = 4) injected subcutaneously with NGF (n = 4) or served as control (n = 4). On day 16 PD, DRG (mean of 30/mouse) were harvested and SP and CGRP in skin-specific sensory neurons, as identified by the tracer dye, were labelled by immunohistochemistry and counted. Stress exposure as well as NGF injection leads to a significant induction of SP and CGRP in retrograde-labelled neurons. This allows us to conclude that sensitive dermal nerve fibres are likely to originate from the presently identified neuropeptide-positive neurons. Peripheral activation of SP-expressing afferent nerve fibres via NGF-dependent pathways may cause neurogenic inflammation, eventually resulting in HGI.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Experimental dermatology 8 (1999), S. 0 
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Since we have recently shown that the β2-adrenoreceptor (β2-AR) expression of selected regions of the hair follicle (HF) epithelium as well as the number of adrenergic nerve fibers in murine skin change in a hair cycle-dependent manner, this has raised the possibility that adrenergic nerves may exert “trophic” functions during HF cycling. To further explore this concept, we have investigated the effect of neuro-pharmacological manipulations on hair growth (anagen) induction in quiescent telogen mouse skin in vivo. Here, we demonstrate that subcutaneous injections of the noradrenaline (NA)-depleting agent guanethidine, or of the neurotoxin 6-hydroxydopaine, but not of the β2-AR agonist isoproterenol induce a premature onset of anagen in the lower back skin of C57BL/6 mice. On day 20 after the start of treatment, more than 80% of the guanethidine-treated mice and ca. 65% of the 6-hydroxydopamine-treated (6-OHDA) mice exhibited premature skin darkening and hair growth at the site of drug application, whereas less than one-third of all control animals showed macroscopic signs of anagen developent. This was confirmed by histology, demonstrating mature anagen VI HFs only at the immediate site of treatment with guanethidine of 6-OHDA as opposed to resting telogen HFs in the neighboring untreated skin area. This observation further supports the concept that sympathetic nerves are intimately involved in hair growth control and invites one to explore the neuro-pharmacological manipulation of piloneural interactions as a novel therapeutic strategy for the management of hair growth disorders.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-069X
    Keywords: Key words Mast cell ; Nerve fibers ; Avidin ; Neuropeptides ; Skin ; Hair cycle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Close contacts between mast cells (MC) and nerve fibers have previously been demonstrated in normal and inflamed skin by light and electron microscopy. A key step for any study in MC-nerve interactions in situ is to simultaneously visualize both communication partners, preferably with the option of double labelling the nerve fibers. For this purpose, we developed the following triple-staining technique. After paraformaldehyde-picric acid perfusion fixation, cryostat sections of back skin from C57BL/6 mice were incubated with a primary rat monoclonal antibody to substance P (SP), followed by incubation with a secondary goat-anti-rat TRITC-conjugated IgG. A rabbit antiserum to CGRP was then applied, followed by a secondary goat-anti-rabbit FITC-conjugated IgG. MCs were visualized by incubation with AMCA-labelled avidin, or (for a more convenient quantification of close MC-nerve fiber contacts) with a mixture of TRITC- and FITC-labelled avidins. Using this simple, novel covisualization method, we were able to show that MC-nerve associations in mouse skin are, contrary to previous suggestions, highly selective for nerve fiber types, and that these interactions are regulated in a hair cycle-dependent manner: in telogen and early anagen skin, MCs preferentially contacted CGRP-immunoreactive (IR) or SP/CGRP-IR double-labelled nerve fibers. Compared with telogen values, there was a significant increase in the number of close contacts between MCs and tyrosine hydroxylase-IR fibers during late anagen, and between MCs and peptide histidine-methionine-IR and choline acetyl transferase-IR fibers during catagen.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Archives of dermatological research 290 (1998), S. 574-578 
    ISSN: 1432-069X
    Keywords: Key words Hair growth ; C57BL/6 mice ; Denervation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Neuropeptides produced, stored and secreted by the unusually dense sensory and autonomic innervation of hair follicles (HFs) can induce hair growth (anagen) and may be involved in hair growth control. To test the role of follicle innervation of HF cycling in vivo, we generated innervation-deficient HFs by unilateral surgical denervation of a defined region of back skin in C57BL/6 mice and assessed its effect on spontaneous and induced anagen development. Successful denervation was demonstrated by the absence of PGP 9.5+ or tyrosine hydroxylase+ nerves and nerve-associated neuropeptides (substance P, CGRP). By quantitative histomorphometry, no significant difference in spontaneous or cyclosporin A-induced anagen development could be detected between sham-operated control skin and denervated skin. Only after hair growth induction by depilation, a discrete, marginally significant retardation of anagen development was apparent in denervated HFs. Thus, even though cutaneous nerves may exert a minor modulatory role in depilation-induced hair growth, they are not essential for normal murine anagen development.
    Type of Medium: Electronic Resource
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