Minoxidil

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Minoxidil is a potassium channel opener vasodilator.[1][2][3] Oral minoxidil was FDA-approved for treatment of hypertension in 1979.[4] Off-label low-dose oral minoxidil (≤5-mg/day) has been studied for androgenetic alopecia treatment.[5]

Application for stimulation of elastin expression

Elastin is a long-lived fibrous protein that is abundant in the extracellular matrix where it plays an important role in tissue elasticity.[6][7] In many tissues reduced elasticity, as a result of compromised elastic fibre function, becomes increasingly prevalent with age and contributes significantly to the burden of human morbidity and mortality.[8][9] Elastin gene expression is limited to late embryonic and early postnatal development, so elastin cannot be replaced in aging arteries. At the same time elastin degrades with aging (elastin has a half-life of ∼70 yr), leading to a decrease in the elastin to collagen ratio and increased arterial stiffness.[10] Minoxidil can potentially stimulate elastogenesis in aortic smooth muscle cells,[11][12][13][14][15] and in skin fibroblasts[16] in a dose-dependent manner. In hypertensive rats, minoxidil increases elastin level in the mesenteric, abdominal, and renal arteries by a decrease in "elastase" enzyme activity in these tissues.[17] In rats, potassium channel openers decrease calcium influx which inhibits elastin gene transcription through extracellular signal-regulated kinase ½ (ERK 1/2)-activator protein 1 signaling pathway.[18][19] ERK 1/2 increases, through elastin gene transcription, adequately cross-linked elastic fiber content synthetized by smooth muscle cells, and decreases the number of cells in the aorta.[18][19]

When treating fibrosis and for activation of elastin synthesis, oral doses of minoxidil should be used not exceeding 1.25 - 2.5 mg per day.

Treatment of fibrosis

Lysyl hydroxylase modify and crosslink proteins by converting lysine to hydroxylysine and so make collagen more resistant to degradation.[20] Minoxidil was reported to reduce lysyl hydroxylase activity by decreasing the lysine hydroxylase mRNA level.[21][22] and thus reducing the formation of hydroxyallysine cross-links.[23] Thus minoxidil exert anti-fibrotic properties. However, these reducing effects of minoxidil on the pulmonary fibrosis were at least partly mediated via inhibition of the matrix metalloproteinases and TGF-β1/Smad3 signaling.[23]

Application for hair growth

After minoxidil was was approved and marketed for the treatment of hypertension, clinicians learned that the drug stimulated hair growth.[24][25] [26] The mechanism of action of minoxidil on hair growth is probably not related to its effect on blood pressure in the vessels, since increased hair growth is observed even with very low doses of the drug (<5-mg/day) that do not cause a noticeable decrease in blood pressure.[27] Moreover, oral administration of the drug, even in such small doses, turned out to be a more effective way to stimulate hair growth than applying it to the skin.

In hair follicles (HFs), minoxidil is converted to its active form, minoxidil sulphate, by the SULT1A1 sulfotransferase enzyme found in the outer root sheath (ORS). Individuals with loss-of-function mutations in the SULT1A1 gene have been referred to as non-responders to minoxidil.[28][29]

References

  1. ↑ Nawar, T., Nolin, L., Plante, G. E., Caron, C., & Montambault, P. (1977). Long-term treatment of severe hypertension with minoxidil. Canadian Medical Association Journal, 117(10), 1178. PMID: 603847 PMC1880293
  2. ↑ Campese, V. M. (1981). Minoxidil: a review of its pharmacological properties and therapeutic use. Drugs, 22, 257-278. https://doi.org/10.2165/00003495-198122040-00001
  3. ↑ Gupta, A. K., Talukder, M., Venkataraman, M., & Bamimore, M. A. (2022). Minoxidil: a comprehensive review. Journal of Dermatological Treatment, 33(4), 1896-1906.
  4. ↑ Zins, G. R. (1988). The history of the development of minoxidil. Clinics in dermatology, 6(4), 132-147.
  5. ↑ Randolph, M., & Tosti, A. (2021). Oral minoxidil treatment for hair loss: A review of efficacy and safety. Journal of the American Academy of Dermatology, 84(3), 737-746 PMID: 32622136 DOI: 10.1016/j.jaad.2020.06.1009
  6. ↑ Rønnow, S. R., Kristensen, J. H., Thorlacius-Ussing, J., Karsdal, M. A., & Heinz, A. (2024). Elastin. In Biochemistry of Collagens, Laminins and Elastin (pp. 279-289). Academic Press. https://doi.org/10.1016/B978-0-443-15617-5.00016-0
  7. ↑ Trębacz, H., & Barzycka, A. (2023). Mechanical Properties and Functions of Elastin: An Overview. Biomolecules, 13(3), 574. PMID: 36979509 PMC10046833 DOI: 10.3390/biom13030574
  8. ↑ Wang, K., Meng, X., & Guo, Z. (2021). Elastin structure, synthesis, regulatory mechanism and relationship with cardiovascular diseases. Frontiers in Cell and Developmental Biology, 9, 596702. PMID: 34917605 PMC8670233 DOI: 10.3389/fcell.2021.596702
  9. ↑ Heinz, A. (2021). Elastic fibers during aging and disease. Ageing research reviews, 66, 101255. PMID: 33434682 DOI: 10.1016/j.arr.2021.101255
  10. ↑ Cocciolone, A. J., Hawes, J. Z., Staiculescu, M. C., Johnson, E. O., Murshed, M., & Wagenseil, J. E. (2018). Elastin, arterial mechanics, and cardiovascular disease. American Journal of Physiology-Heart and Circulatory Physiology, 315(2), H189-H205. https://doi.org/10.1152/ajpheart.00087.2018
  11. ↑ Coquand-Gandit, M., Jacob, M. P., Fhayli, W., Romero, B., Georgieva, M., Bouillot, S., ... & Faury, G. (2017). Chronic treatment with minoxidil induces elastic fiber neosynthesis and functional improvement in the aorta of aged mice. Rejuvenation research, 20(3), 218-230. PMID: 28056723 DOI: 10.1089/rej.2016.1874
  12. ↑ Fhayli, W., Boyer, M., Ghandour, Z., Jacob, M. P., Andrieu, J. P., Starcher, B. C., ... & Faury, G. (2019). Chronic administration of minoxidil protects elastic fibers and stimulates their neosynthesis with improvement of the aorta mechanics in mice. Cellular Signalling, 62, 109333. PMID: 31176018 DOI: 10.1016/j.cellsig.2019.05.018
  13. ↑ Knutsen, R. H., Beeman, S. C., Broekelmann, T. J., Liu, D., Tsang, K. M., Kovacs, A., ... & Kozel, B. A. (2018). Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness. American Journal of Physiology-Heart and Circulatory Physiology, 315(1), H18-H32. PMID: 29498532 PMC6087770 DOI: 10.1152/ajpheart.00683.2017
  14. ↑ Hayashi, A., Suzuki, T., Wachi, H., Tajima, S., Nishikawa, T., Murad, S., & Pinnell, S. R. (1994). Minoxidil stimulates elastin expression in aortic smooth muscle cells. Archives of biochemistry and biophysics, 315(1), 137-141. PMID: 7979390 DOI: 10.1006/abbi.1994.1482
  15. ↑ Tajima, S. (1996). Modulation of elastin expression and cell proliferation in vascular smooth muscle cells in vitro. The Keio journal of medicine, 45(1), 58-62. PMID: 8882470 DOI: 10.2302/kjm.45.58
  16. ↑ Tajima, S., Hayashi, A., Suzuki, T., & Nishikawa, T. (1995). Stimulation of elastin expression by minoxidil in chick skin fibroblasts. Archives of dermatological research, 287, 494-497. PMID: 7625861 DOI: 10.1007/BF00373434
  17. ↑ Tsoporis, J., Fields, N., Lee, R. M., & Leenen, F. H. (1993). Effects of the arterial vasodilator minoxidil on cardiovascular structure and sympathetic activity in spontaneously hypertensive rats. Journal of hypertension, 11(12), 1337-1345. PMID: 8133016 DOI: 10.1097/00004872-199312000-00004
  18. ↑ 18.0 18.1 Lannoy, M., Slove, S., Louedec, L., Choqueux, C., Journé, C., Michel, J. B., & Jacob, M. P. (2014). Inhibition of ERK1/2 phosphorylation: a new strategy to stimulate elastogenesis in the aorta. Hypertension, 64(2), 423-430. PMID: 24866134 DOI: 10.1161/HYPERTENSIONAHA.114.03352
  19. ↑ 19.0 19.1 Lin, C. J., Cocciolone, A. J., & Wagenseil, J. E. (2022). Elastin, arterial mechanics, and stenosis. American Journal of Physiology-Cell Physiology, 322(5), C875-C886. PMID: 35196168 PMC9037699 DOI: 10.1152/ajpcell.00448.2021
  20. ↑ Van Der Slot, A. J., Zuurmond, A. M., Van Den Bogaerdt, A. J., Ulrich, M. M., Middelkoop, E., Boers, W., ... & Bank, R. A. (2004). Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon. Matrix biology, 23(4), 251-257.
  21. ↑ Hautala, T., Heikkinen, J., Kivirikko, K. I., & Myllylä, R. (1992). Minoxidil specifically decreases the expression of lysine hydroxylase in cultured human skin fibroblasts. Biochemical Journal, 283(1), 51-54.
  22. ↑ Zuurmond, A. M., van der Slot-Verhoeven, A. J., van Dura, E. A., De Groot, J., & Bank, R. A. (2005). Minoxidil exerts different inhibitory effects on gene expression of lysyl hydroxylase 1, 2, and 3: implications for collagen cross-linking and treatment of fibrosis. Matrix biology, 24(4), 261-270.
  23. ↑ 23.0 23.1 Shao, S., Zhang, X., Duan, L., Fang, H., Rao, S., Liu, W., ... & Zhang, X. (2018). Lysyl hydroxylase inhibition by minoxidil blocks collagen deposition and prevents pulmonary fibrosis via TGF-β1/Smad3 signaling pathway. Medical science monitor: international medical journal of experimental and clinical research, 24, 8592.PMID: 30481795 PMC6278642 DOI: 10.12659/MSM.910761
  24. ↑ Zappacosta, A. R. (1980). Reversal of baldness in patient receiving minoxidil for hypertension. The New England Journal of Medicine, 303(25), 1480-1481. PMID: 7432414 DOI: 10.1056/nejm198012183032516
  25. ↑ Suchonwanit, P., Thammarucha, S., & Leerunyakul, K. (2019). Minoxidil and its use in hair disorders: a review. Drug design, development and therapy, 2777-2786. PMID: 31496654 PMC6691938 DOI: 10.2147/DDDT.S214907
  26. ↑ Song, D., Pan, S., Jin, W., Wu, R., Zhao, T., Jiang, J., & Zhu, M. (2023). Minoxidil delivered via a stem cell membrane delivery controlled release system promotes hair growth in C57BL/6J mice. Frontiers in Bioengineering and Biotechnology, 11. PMID: 38260729 PMC10800965 DOI: 10.3389/fbioe.2023.1331754
  27. ↑ Ong, M., Do, H., Ho, B., & Lipner, S. R. (2024). Low-dose oral minoxidil for androgenetic alopecia is not associated with clinically significant blood-pressure changes: A retrospective study. Journal of the American Academy of Dermatology, 90(2), 425-427. PMID: 37839733 DOI: 10.1016/j.jaad.2023.10.010
  28. ↑ Roberts, J., Desai, N., McCoy, J., & Goren, A. (2014). Sulfotransferase activity in plucked hair follicles predicts response to topical minoxidil in the treatment of female androgenetic alopecia. Dermatologic Therapy, 27(4), 252-254. PMID: 24773771 DOI: 10.1111/dth.12130
  29. ↑ PMID: 35950120 PMC9326921 DOI: 10.5114/ada.2020.99947
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