Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells

PLoS One. 2012;7(4):e34152. doi: 10.1371/journal.pone.0034152. Epub 2012 Apr 10.


Background: Alopecia is the common hair loss problem that can affect many people. However, current therapies for treatment of alopecia are limited by low efficacy and potentially undesirable side effects. We have identified a new function for valproic acid (VPA), a GSK3β inhibitor that activates the Wnt/β-catenin pathway, to promote hair re-growth in vitro and in vivo.

Methodology/ principal findings: Topical application of VPA to male C3H mice critically stimulated hair re-growth and induced terminally differentiated epidermal markers such as filaggrin and loricrin, and the dermal papilla marker alkaline phosphatase (ALP). VPA induced ALP in human dermal papilla cells by up-regulating the Wnt/β-catenin pathway, whereas minoxidil (MNX), a drug commonly used to treat alopecia, did not significantly affect the Wnt/β-catenin pathway. VPA analogs and other GSK3β inhibitors that activate the Wnt/β-catenin pathway such as 4-phenyl butyric acid, LiCl, and BeCl(2) also exhibited hair growth-promoting activities in vivo. Importantly, VPA, but not MNX, successfully stimulate hair growth in the wounds of C3H mice.

Conclusions/ significance: Our findings indicate that small molecules that activate the Wnt/β-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / metabolism*
  • Alopecia / drug therapy
  • Alopecia / metabolism
  • Animals
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Dermis / drug effects
  • Dermis / enzymology
  • Dermis / metabolism
  • Enzyme Activation / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hair Follicle / drug effects*
  • Hair Follicle / growth & development
  • Hair Follicle / metabolism
  • Hair Follicle / physiology*
  • Humans
  • Intermediate Filament Proteins / metabolism
  • Keratin-15 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C3H
  • Minoxidil / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Regeneration / drug effects*
  • Regeneration / physiology
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects
  • Valproic Acid / pharmacology*
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway / drug effects
  • beta Catenin / metabolism


  • Intermediate Filament Proteins
  • KRT15 protein, human
  • Keratin-15
  • Membrane Proteins
  • Wnt Proteins
  • beta Catenin
  • filaggrin
  • loricrin
  • Minoxidil
  • Valproic Acid
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Alkaline Phosphatase