moongazer
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It's common across both com and org to be using topical solutions of compounds like Minoxidil (oral as well) and Bimatoprost (Latisse) as a lash growth agent. In this thread I'm going to cover a compound that I haven’t been seeing talked about enough in the community that is a superior option to both: Topical Cyclosporine
TLDR: Topical Cyclosporine mogs both Minoxidil and Latisse to death because it works through a cascade of pathways ( that they don't ) and extends the hair growth phase. You can use a 5% formulation of cyclosporine on your hair or lashes 1-2x a day. Make sure to cycle it, such as growth and maintenance phases.
BTW : thanks to @mohito for formatting the whole thread.
How does it actually induce lash/hair growth?
1- Firstly, cyclosporine forms a complex within cyclophilin A; an intracellular protein which then binds to and inhibits calcineurin resulting in the prevention of the dephosphorylation of target proteins, which include ion channels, receptors, and transcription factors. Calcineurin then won’t be able to dephosphorylate NFATc1 which means it can’t enter the nucleus and mediate stem cells into a dormant state. What this means is that the stem cells are released from dormancy generating new hair matrixes. Relevant to the prior point, NFATc1 is activated in murine epithelial HF stem cells (HFSCs) where it maintains HF quiescence. NFATc2 also inhibits the proliferation of murine hair matrix keratinocytes through cyclin G2 and p21waf/cip1.
2- Cyclosporine acts as a disinhibitor of WNT, through down regulating SFRP1 expression in the dermal papilla. As we know, one of the primary factors in hair and eyelash synthesis is the Wnt beta catenin pathway. However, SFRP1; a naturally secreted protein which binds to wnt ligands and inhibits hair follicle development.
3- We first need to understand that in hair loss and thinning disorders, AGA for example; hair follicles miniaturize due to Dermal Papilla fibroblasts slowly migrating away from the hair bulb and escaping into the surrounding dermal sheath. In result it reduces the structural volume and efficiency of the hair follicle in terms of output.In studies we can see that cyclosporine actively prevents this migration. By locking the fibroblasts firmly within the core of the hair bulb, cyclosporine maintains the structural integrity and physical volume of the follicle preventing the decrease in hair and lash density.
4- When a growth phase ends,the follicle undergoes programmed cell death (apoptosis) during the catagen phase. Cyclosporine was found to decrease caspase-3 mRNA expression, one of the primary enzymes involved in cell apoptosis. This results in an immunization effect in cells against signals mediating shedding.
5- One of the regulators of cell death is apoptosis-inducing factor. During catagen regression, AIF escapes from the mitochondria and enters the nucleus, essentially dismantling cellular DNA. As cyclosporine downregulates Cyclophilin A within the mitochondria it also prevents AIF from escaping.
6- Cyclosporine downregulates TGF beta. TGF beta is a cytokine that signals follicles to shrink and stop growing. Cyclosporine downstream has an opposing effect on the cytokine by again inhibiting Cyclophilin A in follicular keratinocytes. Alongside this Cyclosporine upregulates anti cell death factors like Bcl-2 while decreasing apoptotic proteins like p53 and Bax.
7- Cyclosporine through the inhibition of calcineurin/NFAT1 signalling halts the expression of p21 and p27 which are proteins secreted to stop matrix cells from multiplying after a growth cycle ends. In short, this extends the growth phase.
And lastly, cyclosporine increases VEGF expression locally to open up blood vessels. The mechanism is similar to one induced by Minoxidil, matching and possibly exceeding the localized nutrient and oxygen delivery.
Simple logical comparisan; why cyclosporine is superior than minoxidil and Latisse
Firstly, the hair follicle cycle is governed by hair follicle stem cells (HFSCs) residing in the bulge niche. In normal or thinning states stem cells are held in a state of dormancy also known as quiescence by the transcription factor NFATC1. To my knowledge neither Latisse or Minoxidil interacts with this stem cell dormancy mechanism. Minoxidil stimulates secondary cell types by opening adenosine triphosphate-sensitive potassium kATP channels and pumping blood to existing active matrices. Latisse stimulates prostaglandin receptors on active follicles to lengthen their current cycle, but it does not induce the wake up of resting cells to initiate another cycle.
Secondly, one of the most important pathways in lash/hair growth is the wnt beta catenin pathway. As we've covered before cyclosporine downregulates an inhibitor of wnt: SFRP1. While both minoxidil and latisse can promote growth factors downstream, they don’t modulate the limitations of SFRP1 . If the local tissue has high levels of SFRP1 which are prominent in thinning hair and lashes, the Wnt pathway remains suppressed regardless of how much blood flow Minoxidil delivers.
Thirdly, In both androgenetic alopecia and severe lash hypotrichosis, follicles undergo "miniaturization" in which they physically shrink over time. This shrinking occurs because mesenchymal cells, known as Dermal Papilla (DP) fibroblasts, slowly leave the hair bulb matrix and migrate up into the surrounding dermal sheath, resulting in shrinkage. Like prior topics, both latisse and minoxidil leave this issue untouched unlike cyclosporine.
In conclusion, cyclosporine works through a variety of pathways. I could mention even more pathways that latisse and minoxidil don’t modulate but, it's the same story over and over again.
BTW Again thanks to @mohito for formatting.
Works cited
Cyclosporine A increases hair follicle growth by suppressing apoptosis‐inducing factor nuclear translocation: a new mechanism - Lan - 2015 - Fundamental & Clinical Pharmacology - Wiley Online Library
Cyclosporine A increases hair follicle growth by suppressing AIF nuclear translocation: A new mechanism | Request PDF
Re-Evaluating Cyclosporine A as a Hair Growth–Promoting Agent in Human Scalp Hair Follicles
Treatment options for alopecia areata
Identifying novel strategies for treating human hair loss disorders: Cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla of human scalp hair follicles
Cyclosporine-induced childhood generalized hypertrichosis - PMC
Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes | American Journal of Physiology-Cell Physiology | American Physiological Society
Cyclosporine A-induced Hair Repigmentation in a Patient with Dermatitis: A Case Report - PMC
TLDR: Topical Cyclosporine mogs both Minoxidil and Latisse to death because it works through a cascade of pathways ( that they don't ) and extends the hair growth phase. You can use a 5% formulation of cyclosporine on your hair or lashes 1-2x a day. Make sure to cycle it, such as growth and maintenance phases.
BTW : thanks to @mohito for formatting the whole thread.
How does it actually induce lash/hair growth?
1- Firstly, cyclosporine forms a complex within cyclophilin A; an intracellular protein which then binds to and inhibits calcineurin resulting in the prevention of the dephosphorylation of target proteins, which include ion channels, receptors, and transcription factors. Calcineurin then won’t be able to dephosphorylate NFATc1 which means it can’t enter the nucleus and mediate stem cells into a dormant state. What this means is that the stem cells are released from dormancy generating new hair matrixes. Relevant to the prior point, NFATc1 is activated in murine epithelial HF stem cells (HFSCs) where it maintains HF quiescence. NFATc2 also inhibits the proliferation of murine hair matrix keratinocytes through cyclin G2 and p21waf/cip1.
2- Cyclosporine acts as a disinhibitor of WNT, through down regulating SFRP1 expression in the dermal papilla. As we know, one of the primary factors in hair and eyelash synthesis is the Wnt beta catenin pathway. However, SFRP1; a naturally secreted protein which binds to wnt ligands and inhibits hair follicle development.
3- We first need to understand that in hair loss and thinning disorders, AGA for example; hair follicles miniaturize due to Dermal Papilla fibroblasts slowly migrating away from the hair bulb and escaping into the surrounding dermal sheath. In result it reduces the structural volume and efficiency of the hair follicle in terms of output.In studies we can see that cyclosporine actively prevents this migration. By locking the fibroblasts firmly within the core of the hair bulb, cyclosporine maintains the structural integrity and physical volume of the follicle preventing the decrease in hair and lash density.
4- When a growth phase ends,the follicle undergoes programmed cell death (apoptosis) during the catagen phase. Cyclosporine was found to decrease caspase-3 mRNA expression, one of the primary enzymes involved in cell apoptosis. This results in an immunization effect in cells against signals mediating shedding.
5- One of the regulators of cell death is apoptosis-inducing factor. During catagen regression, AIF escapes from the mitochondria and enters the nucleus, essentially dismantling cellular DNA. As cyclosporine downregulates Cyclophilin A within the mitochondria it also prevents AIF from escaping.
6- Cyclosporine downregulates TGF beta. TGF beta is a cytokine that signals follicles to shrink and stop growing. Cyclosporine downstream has an opposing effect on the cytokine by again inhibiting Cyclophilin A in follicular keratinocytes. Alongside this Cyclosporine upregulates anti cell death factors like Bcl-2 while decreasing apoptotic proteins like p53 and Bax.
7- Cyclosporine through the inhibition of calcineurin/NFAT1 signalling halts the expression of p21 and p27 which are proteins secreted to stop matrix cells from multiplying after a growth cycle ends. In short, this extends the growth phase.
And lastly, cyclosporine increases VEGF expression locally to open up blood vessels. The mechanism is similar to one induced by Minoxidil, matching and possibly exceeding the localized nutrient and oxygen delivery.
Simple logical comparisan; why cyclosporine is superior than minoxidil and Latisse
Firstly, the hair follicle cycle is governed by hair follicle stem cells (HFSCs) residing in the bulge niche. In normal or thinning states stem cells are held in a state of dormancy also known as quiescence by the transcription factor NFATC1. To my knowledge neither Latisse or Minoxidil interacts with this stem cell dormancy mechanism. Minoxidil stimulates secondary cell types by opening adenosine triphosphate-sensitive potassium kATP channels and pumping blood to existing active matrices. Latisse stimulates prostaglandin receptors on active follicles to lengthen their current cycle, but it does not induce the wake up of resting cells to initiate another cycle.
Secondly, one of the most important pathways in lash/hair growth is the wnt beta catenin pathway. As we've covered before cyclosporine downregulates an inhibitor of wnt: SFRP1. While both minoxidil and latisse can promote growth factors downstream, they don’t modulate the limitations of SFRP1 . If the local tissue has high levels of SFRP1 which are prominent in thinning hair and lashes, the Wnt pathway remains suppressed regardless of how much blood flow Minoxidil delivers.
Thirdly, In both androgenetic alopecia and severe lash hypotrichosis, follicles undergo "miniaturization" in which they physically shrink over time. This shrinking occurs because mesenchymal cells, known as Dermal Papilla (DP) fibroblasts, slowly leave the hair bulb matrix and migrate up into the surrounding dermal sheath, resulting in shrinkage. Like prior topics, both latisse and minoxidil leave this issue untouched unlike cyclosporine.
In conclusion, cyclosporine works through a variety of pathways. I could mention even more pathways that latisse and minoxidil don’t modulate but, it's the same story over and over again.
BTW Again thanks to @mohito for formatting.
Works cited
Cyclosporine A increases hair follicle growth by suppressing apoptosis‐inducing factor nuclear translocation: a new mechanism - Lan - 2015 - Fundamental & Clinical Pharmacology - Wiley Online Library
Cyclosporine A increases hair follicle growth by suppressing AIF nuclear translocation: A new mechanism | Request PDF
Re-Evaluating Cyclosporine A as a Hair Growth–Promoting Agent in Human Scalp Hair Follicles
Treatment options for alopecia areata
Identifying novel strategies for treating human hair loss disorders: Cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla of human scalp hair follicles
Cyclosporine-induced childhood generalized hypertrichosis - PMC
Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes | American Journal of Physiology-Cell Physiology | American Physiological Society
Cyclosporine A-induced Hair Repigmentation in a Patient with Dermatitis: A Case Report - PMC
