title: TRPV1 antagonist can suppress the atopic dermatitis-like symptoms by accelerating skin barrier recovery.
abstract: BACKGROUND
  Transient receptor potential vanilloid type 1 (TRPV1) is a cation channel activated by diverse obnoxious stimuli like capsaicin, low pH or heat. Recently, it was revealed that TRPV1 might be deeply associated with skin permeability barrier function, suggesting that modulation of TRPV1 might be beneficial for the skin disorders with barrier damages.
  
  
  OBJECTIVE
  We aimed to investigate whether the blockade of TRPV1 activation might accelerate skin barrier recovery and alleviate atopic dermatitis (AD)-like symptoms, employing a novel TRPV1 antagonist, PAC-14028.
  
  
  METHODS
  TRPV1 antagonistic effects of PAC-14028 in human keratinocytes and skin were confirmed through capsaicin-evoked calcium influx assay and capsaicin-induced blood perfusion increase. Effects of PAC-14028 on skin barrier recovery were examined in vivo tape-stripping-induced barrier disruption in hairless mice. To determine the effects of PAC-14028 on AD, Dermatophagoides farina (Df)- and oxazolone (OXZ)-induced AD models were employed.
  
  
  RESULTS
  PAC-14028 could inhibit capsaicin-evoked calcium influx in keratinocytes at sub-micromolar concentrations. This potent TRPV1 antagonistic activity in keratinocytes was manifested in vivo as the blockade of capsaicin-induced blood perfusion increase, and the accelerated barrier recovery from tape-stripping-induced barrier damages in hairless mice. PAC-14028 could also attenuate dermatitis-associated barrier damages in Df and OXZ models as determined by lower TEWL (trans-epidermal water loss), reformation of neutral lipid layer and reversion of changes in loricrin and filaggrin expression. Importantly, along with accelerated recovery of skin barrier function, PAC-14028 alleviated the general AD-like symptoms, including serum IgE increase, mast cell degranulation, scratching behavior and clinical severity of dermatitis.
  
  
  CONCLUSIONS
  These results reflect that the blockade of TRPV1 activation can suppress the atopic dermatitis-like symptoms by accelerating skin barrier recovery.
authors.affiliation: Pharmaceutical Research Institute, Amorepacific Corporation R&D Center, 314-1, Bora-dong, Giheung-gu, Yongin 446-729, Republic of Korea.
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Yun
authors.forename: Jung A
authors.initials: JA
authors.lastname: Seo
authors.forename: Yeon Su
authors.initials: YS
authors.lastname: Jeong
authors.forename: Il-Hong
authors.initials: IH
authors.lastname: Bae
authors.forename: Won-Hee
authors.initials: WH
authors.lastname: Jang
authors.forename: Jihae
authors.initials: J
authors.lastname: Lee
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Song-Seok
authors.initials: SS
authors.lastname: Shin
authors.forename: Byoung-Young
authors.initials: BY
authors.lastname: Woo
authors.forename: Ki-Wha
authors.initials: KW
authors.lastname: Lee
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
mesh_terms: D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D003872:Dermatitis / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000378:metabolism*; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007381:Intermediate Filament Proteins / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry; D008407:Mast Cells / Q000378:metabolism; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D010081:Oxazolone / Q000494:pharmacology; D010477:Perfusion; D010539:Permeability; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D012867:Skin / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D000178:Acrylamides; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008055:Lipids; D008565:Membrane Proteins; C559614:N-(1-(3,5-difluoro-4-methanesulfonylaminophenyl)ethyl)-3-(2-propyl-6-trifluoromethylpyridine-3-yl)acrylamide; D011725:Pyridines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; C064554:loricrin; D010081:Oxazolone; D007073:Immunoglobulin E; D002211:Capsaicin; D002118:Calcium