Library

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.

Notes: Although relatively little attention has been paid to the question how acute alcohol withdrawal might affect cognitive functions, this factor remains of particular interest because it influences psychotherapeutic treatment during detoxification. The clinical outcome and neuropsychological state of 37 inpatients with alcohol withdrawal was investigated in a randomized single-blind approach. Two different medical strategies [chlormethiazole (CMZ) vs. carbamazepine (CBZ)] in the treatment of inpatients with alcohol withdrawal syndrome were compared. Among comparable groups (related to gender, age, initial alcohol level, severity of abuses, severity of initial withdrawal symptoms such as tremor, perspiration, psychomotor agitation, hallucinations, orientation, intelligence, patient demographics), CBZ is just as potent as CMZ in therapy of withdrawal symptoms (circulatory function, vegetative function, psychomotor activity). Patients in both groups showed initial impairments in some neuropsychological tests (d2, Zahlen-Verbundings test, Beck Depression Inventory, Anxiety Sensitivity Index) with significant improvement during detoxification. Additionally, CBZ-treated patients showed significantly better verbal memory performance during the first days of treatment. Without any addictive potential, CBZ therapy could be very supportive in alcohol detoxification. In addition a higher verbal memory performance state could be favourable for a psychotherapeutic approach.

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.

Notes: The hair follicle offers an exquisite model for the experimental exploration of key issues of cutaneous neuroimmunology, for example, how local, intracutaneous and systemic stress–response systems are integrated with the skin immune system and with epithelial–mesenchymal interactions (as they occur during hair follicle growth and cycling). Previously, we had shown that skin mast cells, which operate as central switchboards of inflammation and tissue remodelling, also are important regulators of hair growth in mice and that endogenous, immunomodulatory mast cell secretagogues are potent hair growth modulators. This is true both for secretagogues that are generated by the hair follicle epithelium itself (e.g. ACTH) and for mast cell-activating neuropeptides synthesized by the sensory hair follicle innervation (e.g. SP). Also, we had shown that the prototypic stress-associated neuropeptide, SP, plays a crucial role in mediating the hair growth-inhibitory, mast cell-activating, inflammation- and catagen-promoting properties of chronic psychoemotional stress on murine hair follicles. Now, we show that the immunomodulatory and mast cell-activating neurotrophin, NGF, is also crucially involved in mediating the inhibitory effects of stress on murine hair growth. Furthermore, the central, stress-related neurohormone CRH, a recognized mast cell secretagogue which is expressed by the hair follicle epithelium, also is a hair growth inhibitor and activates a fully functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis within organ-cultured human scalp hair follicles, including the synthesis and secretion of cortisol as well as the induction of classical feedback loops. We also demonstrate that one of the melanocortins whose intrafollicular synthesis is stimulated by CRH (α-MSH) is a potent suppressor of MHC class I expression in situ and is thus capable of restoring the collapsed immune privilege of human anagen hair bulbs, while SP upregulates the ectopic expression of MHC class I, thus endangering the hair follicle immune privilege. Finally, we show that vanilloids long exploited as experimental tools for neuroimmunological research in the skin (capsaicin) can, in fact, directly modulate human hair growth via the stimulation of vanilloid receptors (VR1) expressed by the follicle epithelium, in addition to stimulating vanilloid expressed by skin mast cells. Therefore, the hair follicle offers an ideal, highly instructive and clinically most relevant research model for dissecting how nervous system, central and peripheral (neuro-) endocrine signalling loops and the immune system interact in order to adapt skin functions to changing environmental conditions (e.g. in response to external stressors, by alterating, e.g. keratinocyte proliferation/apoptosis, skin immune status, as well as defined cutaneous metabolic and endocrine activities).

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.

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.