Xenia Kodji

Calcitonin Gene-Related Peptide: Physiology and Pathophysiology

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.

TRPA1 is essential for the vascular response to environmental cold exposure

The cold-induced vascular response, consisting of vasoconstriction followed by vasodilatation, is critical for protecting the cutaneous tissues against cold injury. Whilst this physiological reflex response is historic knowledge, the mechanisms involved are unclear. Here by using a murine model of local environmental cold exposure, we show that TRPA1 acts as a primary vascular cold sensor, as determined through TRPA1 pharmacological antagonism or gene deletion. The initial cold-induced vasoconstriction is mediated via TRPA1-dependent superoxide production that stimulates α2C-adrenoceptors and Rho-kinase-mediated MLC phosphorylation, downstream of TRPA1 activation. The subsequent restorative blood flow component is also dependent on TRPA1 activation being mediated by sensory nerve-derived dilator neuropeptides CGRP and substance P, and also nNOS-derived NO. The results allow a new understanding of the importance of TRPA1 in cold exposure and provide impetus for further research into developing therapeutic agents aimed at the local protection of the skin in disease and adverse climates.

TRPA1 activation leads to neurogenic vasodilatation: involvement of reactive oxygen nitrogen species in addition to CGRP and NO

Transient receptor potential ankyrin‐1 (TRPA1) activation is known to mediate neurogenic vasodilatation. We investigated the mechanisms involved in TRPA1‐mediated peripheral vasodilatation in vivo using the TRPA1 agonist cinnamaldehyde.

Evidence for physiological and pathological roles for sensory nerves in the microvasculature and skin

This review highlights the progress from the initial finding of neurogenic inflammation up to the most recent development in the field of sensory nerves research, focusing on their roles in the microvasculature and the skin. Recent discovery of Transient Receptor Potential (TRP) channels highlight their important roles in detecting a range of environmental stimuli, including chemical and temperature. This provides us novel mechanisms for driving neurogenic inflammation upstream of neuropeptide release in addition to promising potential therapeutic targets in various diseases, including pain, itching and skin inflammation.

Sensory nerves mediate spontaneous behaviors in addition to inflammation in a murine model of psoriasis

Psoriasis is characterized by keratinocyte hyperproliferation, erythema, as well as a form of pruritus, involving cutaneous discomfort. There is evidence from both clinical and murine models of psoriasis that chemical or surgical depletion of small‐diameter sensory nerves/nociceptors benefits the condition, but the mechanisms are unclear. Hence, we aimed to understand the involvement of sensory nerve mediators with a murine model of psoriasis and associated spontaneous behaviors, indicative of cutaneous discomfort. We have established an Aldara model of psoriasis in mice and chemically depleted the small‐diameter nociceptors in a selective manner. The spontaneous behaviors, in addition to the erythema and skin pathology, were markedly improved. Attenuated inflammation was associated with reduced dermal macrophage influx and production of reactive oxygen/nitrogen species (peroxynitrite and protein nitrosylation). Subsequently, this directly influenced observed behavioral responses. However, the blockade of common sensory neurogenic mechanisms for transient receptor potential (TRP)V1, TRPA1, and neuropeptides (substance P and calcitonin gene‐related peptide) using genetic and pharmacological approaches inhibited the behaviors but not the inflammation. Thus, a critical role of the established sensory TRP‐neuropeptide pathway in influencing cutaneous discomfort is revealed, indicating the therapeutic potential of agents that block that pathway. The ongoing inflammation is mediated by a distinct sensory pathway involving macrophage activation.—Kodji, X., Arkless, K. L., Kee, Z., Cleary, S. J., Aubdool, A. A., Evans, E., Caton, P., Pitchford, S. C., Brain, S. D. Sensory nerves mediate spontaneous behaviors in addition to inflammation in a murine model of psoriasis. FASEB J. 33, 1578–1594 (2019). www.fasebj.org

The Role of Calcitonin Gene Related Peptide (CGRP) in Neurogenic Vasodilation and Its Cardioprotective Effects

Calcitonin gene-related peptide (CGRP) is a highly potent vasoactive peptide released from sensory nerves, which is now proposed to have protective effects in several cardiovascular diseases. The major α-form is produced from alternate splicing and processing of the calcitonin gene. The CGRP receptor is a complex composed of calcitonin like receptor (CLR) and a single transmembrane protein, RAMP1. CGRP is a potent vasodilator and proposed to have protective effects in several cardiovascular diseases. CGRP has a proven role in migraine and selective antagonists and antibodies are now reaching the clinic for treatment of migraine. These clinical trials with antagonists and antibodies indicate that CGRP does not play an obvious role in the physiological control of human blood pressure. This review discusses the vasodilator and hypotensive effects of CGRP and the role of CGRP in mediating cardioprotective effects in various cardiovascular models and disorders. In models of hypertension, CGRP protects against the onset and progression of hypertensive states by potentially counteracting against the pro-hypertensive systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic system. With regards to its cardioprotective effects in conditions such as heart failure and ischaemia, CGRP-containing nerves innervate throughout cardiac tissue and the vasculature, where evidence shows this peptide alleviates various aspects of their pathophysiology, including cardiac hypertrophy, reperfusion injury, cardiac inflammation, and apoptosis. Hence, CGRP has been suggested as a cardioprotective, endogenous mediator released under stress to help preserve cardiovascular function. With the recent developments of various CGRP-targeted pharmacotherapies, in the form of CGRP antibodies/antagonists as well as a CGRP analog, this review provides a summary and a discussion of the most recent basic science and clinical findings, initiating a discussion on the future of CGRP as a novel target in various cardiovascular diseases.

TRPA1 activation leads to neurogenic vasodilatation

Transient receptor potential ankyrin‐1 (TRPA1) activation is known to mediate neurogenic vasodilatation. We investigated the mechanisms involved in TRPA1‐mediated peripheral vasodilatation in vivo using the TRPA1 agonist cinnamaldehyde.

TRPA1 activation leads to neurogenic vasodilatation: involvement of reactive oxygen nitrogen species in addition to CGRP and NO: Mechanisms underlying TRPA1-induced vasodilatation

Transient receptor potential ankyrin‐1 (TRPA1) activation is known to mediate neurogenic vasodilatation. We investigated the mechanisms involved in TRPA1‐mediated peripheral vasodilatation in vivo using the TRPA1 agonist cinnamaldehyde.

190 THE PARTICIPATION OF REACTIVE OXYGEN SPECIES AND TRPA1 IN CINNAMALDEHYDE-INDUCED VASODILATATION IN THE PERIPHERAL VASCULATURE

The non-selective transient receptor potential ankryrin-1 (TRPA1) channels have been previously reported to be a major chemosensory receptor for reactive oxidants in sensory neurons in both in vivo and in vitro studies, but its importance to the vascular field has yet to be investigated. We have recently shown that cinnamaldehyde can activate TRPA1 and release potent microvascular vasodilators neuropeptide CGRP and nitric oxide (Aubdool et al., 2012a, 2012b) and, causes vasodilatation. We hypothesised that reactive oxygen species (ROS) are involved in the downstream signalling mechanism and this was investigated using the mouse ear model. Using laser Doppler flowmetry, cutaneous blood flow was measured in male CD1 mice (20–25g) under anaesthesia (ketamine-75mg/kg; medetomidine-25mg/kg, i.p.) and following topical application of cinnamaldehyde (10%) and vehicle (10% DMSO in ethanol). Ear samples were collected and hydrogen peroxide (H2O2) levels were assessed using the amplex red assay. All animals were randomly assigned to drug-treated or respective control groups. Results were expressed as mean+S.E.M. in arbitrary flux units and analysed by 2-way ANOVA+Bonferroni’s test. A sustained (30 min) increase in vasodilatation was observed after topical application of cinnamaldehyde and this was significantly attenuated by a treatment of ROS scavenger N-acetylcysteine (NAC, 300mg/kg), (379.0+40.1x103 flux units for control-treated vs 168.4+24.2x103 flux units for NAC-treated, n=5-6, p<0.001). No change in H2O2 levels was observed in cinnamaldehyde-treated ears compared to vehicle. There was no significant change in cinnamaldehyde-induced vasodilatation in vehicle or NADPH oxidase inhibitor apocynin (20mg/kg, i.v.) pre-treated wild-type (WT) mice (n=6, p>0.05). However, TRPA1-mediated vasodilatation was significantly reduced by a co-treatment of superoxide dismutase (SOD) and catalase (25000U/kg, p<0.01, n=6), but not deactivated enzymes, supporting a novel role for ROS generation. This response was also attenuated in WT mice pre-treated with the iron chelator deferoxamine (25mg/kg, p<0.001, n=6) or the permeable SOD mimic TEMPOL (30mg/kg, p<0.001, n=6), suggesting a potential involvement of hydroxyl radicals and oxidative stress. These studies provide novel evidence that ROS are involved in TRPA1-dependent neurogenic vasodilatation in vivo. Aubdool AA et al (2012a). BPS Focused Meeting on Neuropeptides 028P pA2 Online. Aubdool AA et al (2012b). BPS Winter Meeting Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol10Issue4abst156P.pdf This study was supported by a BBSRC-led IMB capacity building award.