AGA is the most prevalent form of hair loss in men, characterized by the progressive miniaturisation or shrinking of hair follicles. This condition is primarily driven by dihydrotestosterone (DHT), a derivative of testosterone that interferes with the natural hair growth cycle. Elevated levels of PGD2, a lipid mediator, further suppress hair follicle growth by promoting the transition of follicles into the catagen (regression) phase.
A key player in this transformation is the enzyme 5-alpha reductase, which converts testosterone into DHT in dermal papilla cells. DHT binds strongly to androgen receptors, triggering pathways that inhibit hair growth and cause hair follicles to shrink. Despite significant research, the precise mechanisms underlying AGA remain unclear.
While AGA’s specific underlying mechanisms have yet to be determined, researchers know that human follicle dermal papilla cells (HFDPCs) — which connect to capillaries beneath hair follicles — are central to studying hair loss and growth improvement. These mesenchymal cells exhibit stem cell properties and are critical for stimulating hair growth by promoting cell division and migration around the dermal papilla.
Past studies have shown that PGD2 interacts with the DP2 receptor to inhibit hair growth, blocking follicle regeneration during wound-healing and accelerating hair follicle shrinkage. The link between androgens and PGD2 is also noteworthy. Androgens stimulate prostaglandin D2 synthase (PTGDS), increasing PGD2 production. This highlights the interplay between hormonal activity and prostaglandins in hair follicle shrinkage, emphasising the role of PGD2 in AGA progression.
These findings highlight the importance of targeting PGD2 pathways and androgen-related mechanisms for developing effective treatments for AGA.
Anti-AGA antagonism
Using the AI-based DeepZema drug development programme, researchers at Konkuk University, Innovo Therapeutics, Dankook University and Dankook University Hospital discovered that the DP2A could effectively target the DP2 receptor of PGD2 (the lipid mediator linked to hair loss).
This breakthrough represents a promising avenue for addressing hair loss, particularly for individuals seeking alternatives to current treatments like minoxidil and finasteride.
The study also revealed several promising outcomes from DP2A treatment in DHT-damaged HFDPCs, which are pivotal for hair follicle health and regeneration. These included enhanced cell viability and proliferation, wherein DP2A not only avoided cytotoxic effects but actively stimulated cellular growth and survival in HFDPCs damaged by DHT.
The researchers also observed improved migration and repair in wound-healing assays, in which DP2A was found to have accelerated the migration of HFDPCs. This pointed to its potential as an aid in follicle regeneration in damaged tissue.
The use of the compound also resulted in reduced oxidative stressed. It achieved this by significantly decreasing levels of reactive oxygen species (ROS), which are known to exacerbate hair loss and follicular damage.
Finally, the researchers reported that they observed restored mitochondrial function following the application of the DP2A. By recovering mitochondrial membrane potential, DP2A improved cellular energy balance, a critical factor for healthy follicle function.
Activating pathways essential for hair growth
At the molecular level, DP2A was found to stimulate the phosphorylation of key proteins (including Akt and ERK) and increase the expression of β-catenin, a protein essential for initiating hair growth through the Wnt signalling pathway. These findings suggested that DP2A could not only prevent hair loss but also actively promote the regeneration of hair follicles.
The researchers also noted promising results in advanced models — the DP2A’s efficacy was further validated in advanced three-dimensional spheroid cultures, which mimicked the natural environment of hair follicles. Treatment with DP2A resulted in larger spheroid sizes, indicative of improved follicular health.
Additionally, in ex vivo human hair follicle organ cultures, DP2A significantly enhanced hair shaft elongation by up to 15%, compared to untreated controls.
A step forward in hair loss treatment innovation
Current hair loss treatments often come with significant side effects and limited efficacy. By targeting the underlying molecular mechanisms of hair loss, the DP2A represents a novel, targeted approach. Its low molecular weight also suggests potential advantages in scalp penetration, making it a strong candidate for topical formulations in both therapeutic and cosmetic applications.
As demand for effective hair loss solutions continues to grow, the DP2A could fill a critical gap in the market, offering a safer, more targeted alternative for millions of individuals affected by AGA. Further research and clinical trials are anticipated to bring this innovative compound closer to commercial availability.
Source: Cosmetics
“Anti-Hair Loss Effects of the DP2 Antagonist in Human Follicle Dermal Papilla Cells”
https://doi.org/10.3390/cosmetics11050177
Authors: Hye Won Lim, et al.