This is lengthy, from ID. Another pathway to save your hair?
Introduction: PGD2 Revisited
Over the past two years, prostaglandin D2 (PGD2) inhibitors have taken center-stage ever since the influential study from Garza & Cotsarelis in 2012[1] entitled Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia revealed that a cure for baldness might not be far off. Two of Iron Dragons best-selling PGD2 research products have generated enormous interest: a specially formulated proprietary high purity high-concentration indomethacin-chromoglycate solution and a proprietary solution of 99% pure ramatroban. Due to popular demand from customers to learn more about these PGD2 products and their potential for research, we have decidedin Part 1 of the April newsletter to provide an updated look at the PGD2 pathway, including the numerous therapeutic targets, and in the April newsletter, Part 2 to take a closer look at the various PGD2 inhibitor candidates that have emerged and been discussed or promoted since 2012. That is not to say that PGD2 inhibitors are the only promising candidate in the development pipeline for androgenic alopecia: researchers have been providing very positive preliminary feedback about another product that works through a separate pathway, cortexolone 17-alpha propionate, also carried by Iron Dragon. A future newsletter will focus on cortexolone.
Primer: Basic PGD2 Terminology
So everyone is on the same page, it will help our understanding to take a close look together at the PGD2 pathway with a brief review of the terminology, the components, the mechanisms, and of course the hypothesis/theory behind the claim that PGD2 is a key player in baldness.
A pathway refers to a series of events that take place in a replicable way in the body, usually at the microscopic and molecular level, in the body, with a known outcome. When scientists say PGD2 is a baldness pathway, they mean that when PGD2 interacts in certain ways in the body, it may majorly contribute to, or cause, baldness. We will look into the reasons for this more soon, but first lets take a closer look at the other terminology. The term pathway can be used to describe a distinctive aspect of a healthy physiological process, or to describe a method by which an unhealthy or disease process occurs.
Prostaglandin D2, PGD2 for short, is a found in many organisms. It is evolutionarily conserved, meaning that it is found in many different types of life-forms on Earth but that while it is commonly found it often serves different purposes in different species. Its as if each species that inherited the PGD2 compound from their ancestors decided to do something slightly different with it; with evolution, as long as it works and the species survives, thats fine.
PGD2: Creation, Origins, Functions
Prostaglandins are enzymatically created from fats and other prostaglandin compounds. PGD2 is itself a lipid, meaning it has a similar structure to other fatty acids. Enzymes remove molecules from fats and prostaglandins to create other prostaglandins. If a chemical ends in -ase it is usually an enzyme: aromatASE, cellulASE, lactASE are all enzymes that create one compound from another compound. We will come back to the enzyme that creates PGD2 soon. Just remember: if it ends in -ase, chances are its an enzyme!
PGD2 is found all throughout the human body and it has more than one important, well-known role, which explains why it took so long for researchers to discover that it may be a key player in male pattern baldness. The two best known roles are a) it helps control the sleep-wake cycle in the central nervous system, and b) it is involved in inflammation, especially allergy responses and asthma. These two roles or functions are very different; in fact, the only thing they have in common is that they both involve PGD2! PGD2 is a jack of all trades: it behaves differently depending on where it is found. The term for one compound playing two very different roles in the same species is functional convergence.
There are actually two different enzymes that create PGD2 from fats: lipocalin PTGDS and hemopoietic PTGDS. PTGDS stands for prostaglandin D-synthase. We can tell its an enzyme since it ends in -ase. Whats amazing is that hPTGDS is actually totally different from lPTGDs. The L type creates PGD2 in nervous system tissues, while the H type creates it in skin cells and especially mast cells. Even though PGD2 is found in both these places, it plays totally different roles in both. The PGD2 for mast cells is important for balding, but the nervous system PGD2 may be less so, although (as covered in our next installment) Garza actually states they are both important. Again this is due to functional convergence. Researchers think, but do not know for sure, that PGD2 may have evolved independently for each role, which would be pretty amazing: thats like one person inventing a pry-bar for pulling up nails, and another person inventing the same identical pry-bar for opening beer bottles, and the pry-bars being 100% identical despite being invented by two different people for different purposes. The people who created the tools are different (just like H vs L synthase) and the purposes are different (just like
mast cell vs nervous system roles for PGD2) but the tool turns out to be the same.
The latest perspectives are that both lipocalin and hematopoetic PGD2 generation are important in hair loss for different reasons. Many different healthy physiological processes involve PGD2 directly or indirectly. The pathway is very important for the body to function in a healthy way, but like any pathway it can also be involved in unhealthy or undesirable states. PGD2 is involved in asthma (an unhealthy state) and baldness (an undesirable state). This means it is a mechanism that is behind these states. That does not mean PGD2 is all bad - it just means that PGD2 is partially responsible for some types of asthma and baldness.
Relevant to Researchers: PGD2s Functional Relevance to Baldness and Pipeline Development
The good news is that when a pathway and/or mechanism are identified, scientists and researchers can look for something called therapeutic targets. Knowing the underlying physiology of a disease state or undesirable physiological occurrence is the very first step to designing proper treatments.
The second step in creating a good treatment is to understand the components in the pathway in order to determine proper therapeutic targets. For a safe and effective drug to work, it must affect physiology in a way that is both powerful enough to change the underlying pathways and thus change the final outcome, but specific enough to not affect the body so much it creates undesirable side-effects.
Development and Innovation: From Pathways to Therapeutic Targets
By definition a pathway contains several different components. In the example of prostaglandin D2, it must be created from fats, arachidonic and other prostaglandins by various hormones, including PTGDS (prostaglandin D-synthase). Once it is created, usually it is stored in mast cells. When it is released from mast cells, usually in a process called degranulation, it circulates and binds to receptors on cells.
A receptor on a cell is like a key-hole, and PGD2 is like the key: sometimes the key opens a door for something to go in or out, and other times it starts a process (like igniting the engine of an automobile).
Two key receptors for PGD2 are identified that may play a role in baldness[2]: PTGDR (prostaglandin-D receptor) and the GPR-44 receptor, which is sometimes called the PGD2 receptor or CRTH-2 receptor (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells)[3].
In the above paragraphs we have identified individual components that comprise the PGD2 pathway. Scientists and researchers understand the pathway well enough that not only is it possible to design compounds that target each of those components, such potential treatments actually already exist and are being investigated currently!
Key Takeaways: The Promise of the PGD2 Pathway
We will go into more detail about these possible candidates for developing treatments in our next installment, but for now we will finish by learning how each of those components, or therapeutic targets, might work.
Inhibiting PTGDSs enzymatic activity would prevent creation of PGD2, just like inhibiting 5-alpha-aromatase prevents creation of di-hydrogen-testosterone, or inhibiting aromatase prevents creation of estrogens.
Another component in the pathway, mast cells that release stored PGD2 after it is created, can also be targeted; if a compound prevents mast cells from releasing their stored PGD2, it will prevent PGD2 from having any effect.
Once PGD2 is circulating, another therapeutic target is to destroy or change PGD2 so that it cant bind to receptors and create cellular effects (such as baldness or inflammation) - this would be called a true PGD2 inhibitor.
The final possible mechanism is to block the PGD2 receptor on each cell (ideally, in both cells that may be involved with baldness) with a compound that has a similar structure, except the compound has a different or even opposite effect! To give an example, this would be similar to the way that SERMs like tamoxifen bind to estrogen receptors but block estrogen from working (and in many cases, actually have an opposite effect from estrogen).
Compounds that block receptors from working properly and prevent activation are called antagonists; other compounds that can actually have the opposite effect (such as regrowing hair instead of causing baldness) are called inverse agonists.
Introduction: PGD2 Revisited
Over the past two years, prostaglandin D2 (PGD2) inhibitors have taken center-stage ever since the influential study from Garza & Cotsarelis in 2012[1] entitled Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia revealed that a cure for baldness might not be far off. Two of Iron Dragons best-selling PGD2 research products have generated enormous interest: a specially formulated proprietary high purity high-concentration indomethacin-chromoglycate solution and a proprietary solution of 99% pure ramatroban. Due to popular demand from customers to learn more about these PGD2 products and their potential for research, we have decidedin Part 1 of the April newsletter to provide an updated look at the PGD2 pathway, including the numerous therapeutic targets, and in the April newsletter, Part 2 to take a closer look at the various PGD2 inhibitor candidates that have emerged and been discussed or promoted since 2012. That is not to say that PGD2 inhibitors are the only promising candidate in the development pipeline for androgenic alopecia: researchers have been providing very positive preliminary feedback about another product that works through a separate pathway, cortexolone 17-alpha propionate, also carried by Iron Dragon. A future newsletter will focus on cortexolone.
Primer: Basic PGD2 Terminology
So everyone is on the same page, it will help our understanding to take a close look together at the PGD2 pathway with a brief review of the terminology, the components, the mechanisms, and of course the hypothesis/theory behind the claim that PGD2 is a key player in baldness.
A pathway refers to a series of events that take place in a replicable way in the body, usually at the microscopic and molecular level, in the body, with a known outcome. When scientists say PGD2 is a baldness pathway, they mean that when PGD2 interacts in certain ways in the body, it may majorly contribute to, or cause, baldness. We will look into the reasons for this more soon, but first lets take a closer look at the other terminology. The term pathway can be used to describe a distinctive aspect of a healthy physiological process, or to describe a method by which an unhealthy or disease process occurs.
Prostaglandin D2, PGD2 for short, is a found in many organisms. It is evolutionarily conserved, meaning that it is found in many different types of life-forms on Earth but that while it is commonly found it often serves different purposes in different species. Its as if each species that inherited the PGD2 compound from their ancestors decided to do something slightly different with it; with evolution, as long as it works and the species survives, thats fine.
PGD2: Creation, Origins, Functions
Prostaglandins are enzymatically created from fats and other prostaglandin compounds. PGD2 is itself a lipid, meaning it has a similar structure to other fatty acids. Enzymes remove molecules from fats and prostaglandins to create other prostaglandins. If a chemical ends in -ase it is usually an enzyme: aromatASE, cellulASE, lactASE are all enzymes that create one compound from another compound. We will come back to the enzyme that creates PGD2 soon. Just remember: if it ends in -ase, chances are its an enzyme!
PGD2 is found all throughout the human body and it has more than one important, well-known role, which explains why it took so long for researchers to discover that it may be a key player in male pattern baldness. The two best known roles are a) it helps control the sleep-wake cycle in the central nervous system, and b) it is involved in inflammation, especially allergy responses and asthma. These two roles or functions are very different; in fact, the only thing they have in common is that they both involve PGD2! PGD2 is a jack of all trades: it behaves differently depending on where it is found. The term for one compound playing two very different roles in the same species is functional convergence.
There are actually two different enzymes that create PGD2 from fats: lipocalin PTGDS and hemopoietic PTGDS. PTGDS stands for prostaglandin D-synthase. We can tell its an enzyme since it ends in -ase. Whats amazing is that hPTGDS is actually totally different from lPTGDs. The L type creates PGD2 in nervous system tissues, while the H type creates it in skin cells and especially mast cells. Even though PGD2 is found in both these places, it plays totally different roles in both. The PGD2 for mast cells is important for balding, but the nervous system PGD2 may be less so, although (as covered in our next installment) Garza actually states they are both important. Again this is due to functional convergence. Researchers think, but do not know for sure, that PGD2 may have evolved independently for each role, which would be pretty amazing: thats like one person inventing a pry-bar for pulling up nails, and another person inventing the same identical pry-bar for opening beer bottles, and the pry-bars being 100% identical despite being invented by two different people for different purposes. The people who created the tools are different (just like H vs L synthase) and the purposes are different (just like
mast cell vs nervous system roles for PGD2) but the tool turns out to be the same.
The latest perspectives are that both lipocalin and hematopoetic PGD2 generation are important in hair loss for different reasons. Many different healthy physiological processes involve PGD2 directly or indirectly. The pathway is very important for the body to function in a healthy way, but like any pathway it can also be involved in unhealthy or undesirable states. PGD2 is involved in asthma (an unhealthy state) and baldness (an undesirable state). This means it is a mechanism that is behind these states. That does not mean PGD2 is all bad - it just means that PGD2 is partially responsible for some types of asthma and baldness.
Relevant to Researchers: PGD2s Functional Relevance to Baldness and Pipeline Development
The good news is that when a pathway and/or mechanism are identified, scientists and researchers can look for something called therapeutic targets. Knowing the underlying physiology of a disease state or undesirable physiological occurrence is the very first step to designing proper treatments.
The second step in creating a good treatment is to understand the components in the pathway in order to determine proper therapeutic targets. For a safe and effective drug to work, it must affect physiology in a way that is both powerful enough to change the underlying pathways and thus change the final outcome, but specific enough to not affect the body so much it creates undesirable side-effects.
Development and Innovation: From Pathways to Therapeutic Targets
By definition a pathway contains several different components. In the example of prostaglandin D2, it must be created from fats, arachidonic and other prostaglandins by various hormones, including PTGDS (prostaglandin D-synthase). Once it is created, usually it is stored in mast cells. When it is released from mast cells, usually in a process called degranulation, it circulates and binds to receptors on cells.
A receptor on a cell is like a key-hole, and PGD2 is like the key: sometimes the key opens a door for something to go in or out, and other times it starts a process (like igniting the engine of an automobile).
Two key receptors for PGD2 are identified that may play a role in baldness[2]: PTGDR (prostaglandin-D receptor) and the GPR-44 receptor, which is sometimes called the PGD2 receptor or CRTH-2 receptor (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells)[3].
In the above paragraphs we have identified individual components that comprise the PGD2 pathway. Scientists and researchers understand the pathway well enough that not only is it possible to design compounds that target each of those components, such potential treatments actually already exist and are being investigated currently!
Key Takeaways: The Promise of the PGD2 Pathway
We will go into more detail about these possible candidates for developing treatments in our next installment, but for now we will finish by learning how each of those components, or therapeutic targets, might work.
Inhibiting PTGDSs enzymatic activity would prevent creation of PGD2, just like inhibiting 5-alpha-aromatase prevents creation of di-hydrogen-testosterone, or inhibiting aromatase prevents creation of estrogens.
Another component in the pathway, mast cells that release stored PGD2 after it is created, can also be targeted; if a compound prevents mast cells from releasing their stored PGD2, it will prevent PGD2 from having any effect.
Once PGD2 is circulating, another therapeutic target is to destroy or change PGD2 so that it cant bind to receptors and create cellular effects (such as baldness or inflammation) - this would be called a true PGD2 inhibitor.
The final possible mechanism is to block the PGD2 receptor on each cell (ideally, in both cells that may be involved with baldness) with a compound that has a similar structure, except the compound has a different or even opposite effect! To give an example, this would be similar to the way that SERMs like tamoxifen bind to estrogen receptors but block estrogen from working (and in many cases, actually have an opposite effect from estrogen).
Compounds that block receptors from working properly and prevent activation are called antagonists; other compounds that can actually have the opposite effect (such as regrowing hair instead of causing baldness) are called inverse agonists.
