Neuropeptide PACAP Modulators for Neurogenic Rosacea

Written by on February 10, 2011 in neurogenic rosacea, patents with 4 Comments

The recently published paper that called for the creation of Neurogenic Rosacea subtype contained an interesting disclosure.

We are told that one of the paper’s authors, Professor Martin Steinhoff MD PhD , holds a related patent and research grant from Galderma.

Related Rosacea Grant

Dr. Steinhoff, along with Dr. Feramisco, received a $25,000 grant in 2010 from the National Rosacea Society.

Perhaps this below is the grant that the paper refers to. Galderma is a major sponsor of the National Rosacea Society, so indirectly this could be the related grant.

Cellular and molecular analysis of transient receptor potential (TRP) ion channels and neurovascular regulation in rosacea patients.

Dr. Jamison Feramisco, molecular medicine fellow in dermatology, and Dr. Martin Steinhoff, professor of dermatology, University of California-San Francisco.

Dr. Feramisco and Dr. Steinhoff were awarded $25,000 for their study. The researchers hypothesize that, based on earlier studies, the flushing, bumps and pimples of rosacea may be the result of a dysfunctional regulation in the neurovascular system, with subsequent vascular and chronic inflammatory reactions.

Their study has four aims, they noted: to establish a relationship between certain sensory nerves and immune cells in different subtypes of rosacea; to genetically characterize crucial components of the neurovascular network with regard to disease stage, gender, age and the presence or absence of Demodex mites; to investigate the role of specific temperature and irritant receptors as neurovascular regulators in mice; and to identify families suffering rom rosacea with prominent trigger factor-induced flushing/redness and isolate their DNA for analysis.

Related Patent Application

Digging further, I went and had a look to see what I could find. This looks like the patent that the paper refers to.

It is always good to see new discoveries about the way that nerves and skin work leading to something that could be called in inventions. A patent is surely a long way from a product, but it can only be a good thing to see more inventions related to the problems faced by sufferers of rosacea.

A further reason to be encouraged is that the patent is attributed to Galderma, one of the few R&D companies that could have the resources to see novel inventions such as this all the way through to a real product.

Some Extra Comments

Before continuing on a thoughtful related comment from Colin Dahl from Australian Sciences.

Re: Warm Room Flush: PDF released from Australian Science

Australian Sciences has done tests to block individual neuropeptides (Substance P, CGRP, VIP, etc) to see what effect that has on reducing flushing

There are many neuropeptides to stop, and many other kinds of inflammatory chemicals to stop – you can’t block them all, especially when you are producing more because of your excessive skin infrastructure.

However, a few years ago I felt (and still do) that this kind of approach is attractive to a pharmaceutical company but not to someone who wants to reverse rosacea.

PACAP Modulation Patent

PACAP stands for Pituitary adenylate cyclase activating polypeptide. Ready for some heavy reading?

PACAP SIGNALING PATHWAY MODULATORS FOR TREATING INFLAMMATORY SKIN DISEASES WITH A NEUROGENIC COMPONENT, AND MORE PARTICULARLY ROSACEA AND COMPOSITION CONTAINING THEM

WIPO Patent Application WO/2010/007175

The invention relates to the use of modulators of specific PACAP receptors for treating inflammatory skin diseases with a neurogenic component, and more particularly rosacea and/or facial erythema, composition containing them and screening methods for identifying PACAP signalling pathway modulators.

GALDERMA RESEARCH & DEVELOPMENT

VOEGEL, Johannes
RIVIER, Michel
AUBERT, Jérôme
STEINHOFF, Martin

A method for treating an inflammatory skin disease with a neurogenic component in a patient in need thereof comprising topically administering to the patient a composition containing an effective amount of a compound that modulates the activity of VPAC1 -R or VPAC2-R.

The neuropeptide PACAP affects the human cutaneous vascular system and causes a marked vasodilatation and flush phenomenon as well as hyperthermia. Therefore, skin sensory nerves contribute to vascular regulation in humans and PACAP may be an essential mediator of neurovascular interactions during health and disease. Thus, modulation and /or inhibition of this potent neuropeptide and its receptors may be a novel target for the treatment of inflammatory skin diseases with a neurogenic component like those mentioned above.

..

The invention is directed towards offering a novel method for treating acne vulgaris, atopic dermatitis, urticaria, keloids, hypertrophic scars and particularly rosacea, which consists in administering to an individual suffering from this pathology an effective amount of a modulator of the PACAP signalling pathway.

The invention relates more particularly to the use of a modulator of at least one VPAC1 -R or VPAC2-R modulator, for the preparation of a pharmaceutical composition for treating acne vulgaris, atopic dermatitis, urticaria, keloids, hypertrophic scars and particularly rosacea.

For more reading, see also this related article from Experimental Dermatology:

The neuropeptide PACAP upregulates expression and release of cytokines and cell adhesion molecules in human microvascular endothelial cells via VPAC type 1 receptor

Experimental Dermatology, Volume 13, Issue 9, page 586, September 2004, A. Steinhoff, A. Grevelhörster, W. E. Schmidt,  T. A. Luger, M. Steinhoff.

Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) belong to the same superfamily of neuropeptides which exert their effects by activating G-protein-coupled receptors defined as PACAP. So far, three receptor subtypes exist (PAC1R, VPACR-1 and VPACR-2).

Because, PACAP appears to play a crucial role in cutaneous inflammation and vasoregulation, we examined the expression and biological effects of this peptide in primary human dermal microvascular endothelial cells (HDMECs).

We detected the expression of PACAP and VPAC type 1 receptor at RNA and protein level by RT-PCR and immunohistochemistry, indicating an autocrine regulatory mechanism. cAMP assays revealed VPAC1R to be functional in these cells. RT-PCR showed upregulation of IL-8 in a time- and dose-dependent manner. ELISA experiments confirmed release of IL-8 by HDMEC cells.

We also investigated cell adhesion molecule expression after stimulation with PACAP. ICAM-1 mRNA was upregulated at 3 and 6 h after treatment with PACAP, while VCAM was only upregulated maximally at 6 h after PACAP stimulation, indicating the regulation of cell adhesion molecule expression in human dermal endothelial cells via VPAC1R.

Immunoreactivity for VPAC-1R was enhanced in microvascular endothelial cells of patients with atopic dermatitis and urticaria, indicating upregulation of this receptor in endothelial cells during cutaneous inflammation. In summary, VIP and PACAP may play an important role in cutaneous neurogenic inflammation by activating VPAC-1R on dermal microvascular endothelial cells.

More Related Research Papers

The patent application lists the following papers as background to their invention.

Evidence is accumulating that neuropeptides play an essential role in skin-nervous system interactions

PACAP has been suggested to play an anti inflammatory role during chronic inflammation in experimentally-induced arthritis

Sensory fibers have been elucidated to be involved in inflammatory skin diseases such as urticaria, rosacea or atopic dermatitis

Related Articles

Read more about: neurogenic rosacea, patents

About the Author

About the Author: David Pascoe started the Rosacea Support Group in October 1998. .

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4 Reader Comments

  1. Brady Barrows says:

    Another excellent article you have written Dave. Your investigative intuition is quite impressive. Thanks again for all your hard work on this article.

  2. Matthew says:

    Dave, you are the man, this is without a doubt the most informative website where Rosacea is concerned. Any idea if Signum Biosciences have made any progress? nothing on their website etc.

  3. David Pascoe says:

    Thanks Brady and Matthew, always nice to get positive feedback.

    Sorry but I don’t have any extra information about Signum. Once I do, you know where you can read about it …. (here!)

  4. Jasmine 215 says:

    Hi,

    Why do we ALWAYS have to administer Rosacea medications in Topical form?
    Why can’t they device oral pills and/or injections?

    Just a thought

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