neuropeptide-y and Skin-Diseases

Neuropeptides (NP) are a heterogeneous group of proteins functioning as neurotransmitters, neuromodulators and neurohormones. More than fifty of these molecules have been described, and some have been detected in human skin through immunochemistry and radioimmunoassay. In this article we attempt to study the role played by some of these substances such as substance P (SP), calcitonin gene related peptide (CGRP), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), somatostatin (S), and neurotensin (N). Several NP induce inflammatory response with edema and erythema. They can also induce the release of histamine by mastocytes, regulate cutaneous blood flow, and participate in sweat regulation and nociception. They also exert their action over several cells that participate in immunity, acting as mitotic, and chemotactic factors, inhibiting or stimulating inflammatory mechanisms. Specific NP have their receptors on epidermal cells. We will also try to study certain diseases in which NP play an important role in inducing or alleviating lesions, such as psoriasis, atopic eczema, alopecia areata, vitiligo, nodular prurigo, aquagenic pruritus, hypertrophic scars and other entities.

Topics: Calcitonin; Humans; Neuropeptide Y; Neuropeptides; Neurotensin; Skin Diseases; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Tissue damage is one of the major etiological factors in the emergence of chronic/persistent pain, although mechanisms remain enigmatic. Using incision of the back skin of adult rats as a model for tissue damage, we observed sensitization in a nociceptive reflex enduring to 28days post-incision (DPI). To determine if the enduring behavioral changes corresponded with a long-term impact of tissue damage on sensory neurons, we examined the temporal expression profile of injury-regulated genes and the electrophysiological properties of traced dorsal root ganglion (DRG) sensory neurons. The mRNA for the injury/stress-hub gene Activating Transcription Factor 3 (ATF3) was upregulated and peaked within 4 DPI, after which levels declined but remained significantly elevated out to 28 DPI, a time when the initial incision appears healed and tissue-inflammation largely resolved. Accordingly, stereological image analysis indicated that some neurons expressed ATF3 only transiently (mostly medium-large neurons), while in others it was sustained (mostly small neurons), suggesting cell-type-specific responses. In retrogradely-traced ATF3-expressing neurons, Calcium/calmodulin-dependent protein kinase type IV (CAMK4) protein levels and isolectin-B4 (IB4)-binding were suppressed whereas Growth Associated Protein-43 (GAP-43) and Neuropeptide Y (NPY) protein levels were enhanced. Electrophysiological recordings from DiI-traced sensory neurons 28 DPI showed a significant sensitization limited to ATF3-expressing neurons. Thus, ATF3 expression is revealed as a strong predictor of single cells displaying enduring pain-related electrophysiological properties. The cellular injury/stress response induced in sensory neurons by tissue damage and indicated by ATF3 expression is positioned to contribute to pain which can occur after tissue damage.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Disease Models, Animal; Female; Functional Laterality; Ganglia, Spinal; GAP-43 Protein; Glycoproteins; Lectins; Neuropeptide Y; Nociception; Nociceptive Pain; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sensory Receptor Cells; Skin Diseases; Transcription Factor 3; Up-Regulation; Versicans

The purpose of this article is to characterize skin lesions in cynomolgus monkeys following vildagliptin (dipeptidyl peptidase-4 inhibitor) treatment. Oral vildagliptin administration caused dose-dependent and reversible blister formation, peeling and flaking skin, erosions, ulcerations, scabs, and sores involving the extremities at ≥5 mg/kg/day and necrosis of the tail and the pinnae at ≥80 mg/kg/day after 3 weeks of treatment. At the affected sites, the media and the endothelium of dermal arterioles showed hypertrophy/hyperplasia. Skin lesion formation was prevented by elevating ambient temperature. Vildagliptin treatment also produced an increase in blood pressure and heart rate likely via increased sympathetic tone. Following treatment with vildagliptin at 80 mg/kg/day, the recovery time after lowering the temperature in the feet of monkeys and inducing cold stress was prolonged. Ex vivo investigations showed that small digital arteries from skin biopsies of vildagliptin-treated monkeys exhibited an increase in neuropeptide Y-induced vasoconstriction. This finding correlated with a specific increase in NPY and in NPY1 receptors observed in the skin of vildagliptin-treated monkeys. Present data provide evidence that skin effects in monkeys are of vascular origin and that the effects on the NPY system in combination with increased peripheral sympathetic tone play an important pathomechanistic role in the pathogenesis of cutaneous toxicity.

Topics: Adamantane; Administration, Oral; Animals; Blood Pressure; Cold Temperature; Dipeptidases; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Macaca fascicularis; Neuropeptide Y; Nitriles; Norepinephrine; Pyrrolidines; Skin; Skin Diseases; Stress, Physiological; Vascular System Injuries; Vasoconstriction; Vildagliptin