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PGD2 Inhibitor Data

 [test]
 $1.00 - $2.00 

What is PGD2?

New research shows that a lipid called prostaglandin D2 (PGD2) plays a primary role in hair loss.[1]  PGD2 is expressed in the scalp by mast cells.[2]  Inhibition of PGD2 is a novel therapeutic target for male pattern baldness (androgenic alopecia).  Researchers discovered in 2008 that PGD2 was found in bald male scalps in triple the normal concentration, and the newest data (2012) demonstrates a causative role: PGD2 is responsible for baldness.[1] Prostaglandin D2 inhibitors, which will be discussed more in-depth later, are a class of drug that inhibits PGD2 in one of three ways: by inhibiting enzymatic synthesis of PGD2 (PGD2 synthase inhibitors), by binding to PGD2 receptors in an antagonistic fashion (PGD2 antagonists), or in the case of atypical PGD2 inhibitors, by preventing release of PGD2 from mast cells.

 

Prostaglandins (PGs) are cellular signaling lipids formed from arachidonic acid.  Local or external stimuli create a cascade releasing arachidonic acid from cell membranes, and it is enzymatically converted to PGs. The signaling of prostaglandins is a local "autocrine" (meaning: produced within the same cell-type as the receptor-type to which the ligand binds) or "paracrine" (binding to nearby cells without systemic action) event. Prostaglandins are found throughout the body in diverse roles, but nearly always act locally.  Their actions include “early male sexual development and masculinization, development of sexual behavior, induction of labor, inflammatory responses, pain, calcium movement, vasodilation, and hormone regulation.”[3]

 

Roles of PGD2

Prostaglandin D2 is found throughout the body; in adulthood, it acts as a component of the immune system and also plays an important role in the sleep-wake cycle.  In development it plays a role in gender differentiation and other critical processes. The enzyme that generates PGD2 from Prostaglandin H2 is known as “PGD synthase” and is found in both hematopoietic form (meaning “related to blood cells and bone marrow” – found in lymphocyte T-helper2 cells and mast cells) and lipocalin forms, the latter of which primarily occurs in the brain and central nervous system[2].  H-PGDS and L-PGDS are functionally convergent and appear to have developed in parallel, with different roles; the outcomes of PGD2 via L-PGDS in specific tissues are essentially totally separate from the actions of PGD2 via H-PGDS. [4]

 

 PGD2 recruits t-helper cells and other white blood cells and is also a mediator of inflammation; it is a key component of chronic allergic rhinitis and asthma.  PGD2 is also the cause of the so-called niacin flush and plays an excitatory and inhibitory role in itching and scratching: PGD2 seems to be a primary mediator of itching, and scratching lowers it, but continued scratching results in dermatitis, a type of inflammation actually mediated by PGD2.[5,6]

 

Mechanism of PGD2 in baldness

Garza and Cotsarelis have demonstrated that not only are PGDS and PGD2 elevated in the scalps of bald men, the levels elevate further in periods of regression.  When PGD2 was applied topically to mice, it was found to interact with the GPR-44 receptor (but not PTGDR1 receptor) to inhibit hair growth.[1]  A transgenic mouse model lacking expression of enzymes that break down PGD2 in the skin developed alopecia (baldness), follicular miniaturization, and hyperplasia of sebaceous glands - all of which are "hallmarks of human [androgenic alopecia]."[1]  The authors concluded that the PGD2-GPR44 pathway was a target for inhibitory drugs designed to slow or even reverse hair-loss.[1]

 

What the media is saying:

“In the answer to millions of men’s prayers, scientists may have got to the root of baldness. They have identified a scalp chemical that stops hair from growing. Excitingly, drugs that block the protein have already been developed for other purposes, meaning a hair restoring lotion or potion could be on the market in under five years. t is thought it would certainly stop balding in its tracks - and may even coax the growth of new hair.” (The Daily Mail http://www.dailymail.co.uk/sciencetech/article-2118277/Cure-baldness-sale-years.html)

 

Researchers have identified a biological pathway previously unknown to have a role in male pattern hair loss.... The study “is likely to lead to new hair growth products based on prostaglandin biology,” says Anthony Oro, an epithelial biologist at Stanford University in California, who was not involved in the study.... It's also not known whether a treatment that inhibits PGD2 could restore hair to skin that's already bald, Cotsarelis says, but he hopes that it might. In 2011, he and his team showed that hair-follicle stem cells are still intact in balding skin, but that their proliferation is inhibited5. If PGD2 is the inhibitor, then blocking it may allow stem cells to proliferate and give rise to new follicles. (Nature: News www.nature.com/news/clues-to-the-cause-of-male-pattern-baldness-1.10277)

 

Researchers took an unbiased approach when scanning for potential biological causes of baldness, looking in scalp tissue from balding and non-bald spots from men with male pattern baldness and then corroborating findings in mouse models. They found that levels of PGD2 were elevated in bald scalp tissue at levels 3 times greater than what was found in comparative haired scalp of men with androgenetic alopecia. When PGD2 was added to cultured hair follicles, PGD2-treated hair was significantly shortened, while PGD2's derivative, 15-dPGJ2, completely inhibited hair growth. (Penn Medicine http://www.uphs.upenn.edu/news/News_Releases/2012/03/hair/)

 

What are PGD2 inhibitors? How do they work?

To be continued…

 

[1] L. A. Garza, Y. Liu, Z. Yang, B. Alagesan, J. A. Lawson, S. M. Norberg, D. E. Loy, T. Zhao, H. B. Blatt, D. C. Stanton, L. Carrasco, G. Ahluwalia, S. M. Fischer, G. A. FitzGerald, G. Cotsarelis, Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia. Sci. Transl. Med. 4, 126ra34 (2012).

[2]Benyon RC, et al. Prostaglandin D2 release from human skin mast cells in response to ionophore A23187. Br J Pharmacol. 1987 November; 92(3): 635–638.

[3] Kristensen DM, et al. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis. Environ Health Perspec. 119(4). April, 2011.

[4]Urade Y, Eguchi N, Aritake K, Hayaishi O. [Functional analyses of lipocalin-type and hematopoietic prostaglandin D synthases].  Nihon Yakurigaku Zasshi. 2004 Jan;123(1):5-13.

[5] Morrow JD, Parsons WG 3rd, Roberts LJ 2nd. Release of markedly increased quantities of prostaglandin D2 in vivo in humans following the administration of nicotinic acid. Prostaglandins. 1989 Aug;38(2):263-74.

[6] Okano M, Fujiwara T, Sugata Y, Gotoh D, Masaoka Y, Sogo M, Tanimoto W, Yamamoto M, Matsumoto R, Eguchi N, Kiniwa M, Isik AU, Urade Y, Nishizaki K. Am J Rhinol. 2006 May-Jun;20(3):342-8.

Presence and characterization of prostaglandin D2-related molecules in nasal mucosa of patients with allergic rhinitis.

This product was added to our catalog on Wednesday 20 June, 2012.
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