Activation of trpv4 ion channel by physical stimuli and critical role for trpv4 in organ-specific inflammation and itch

Abstract

Provided are methods of treating and/or preventing dermatological disorders. Provided are methods of reducing skin inflammation, reducing pain, and/or reducing itch in a subject in need thereof. The methods may include administering to the subject an effective amount of a TRPV4 inhibitor. Further provided are compositions including a TRPV4 inhibitor compound in combination with a carrier, vehicle, or diluent that is suitable for topical application. Further provided is a transgenic mouse whose genome includes deletions of the Trpv4 gene in keratinocytes of the epidermis, wherein said transgenic mouse is a knockout for the Trpv4 gene in keratinocytes of the epidermis following keratinocyte-specific activation and expression of a site-specific recombination enzyme.

1 . A method of treating and/or preventing a dermatological disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a TRPV4 inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the dermatological disorder is selected from the group consisting of inflammation, pain, itch, cancer, autoimmune diseases, fibrotic diseases, skin pigmentation, and/or other dermatological disorders. 
     
     
         3 . The method of  claim 1 , wherein the TRPV4 inhibitor comprises a compound according to Formula I: 
       
         
           
           
               
               
           
         
         wherein A, B, and C are independently selected from the group consisting of aromatic, heteroaromatic, cycloalkenyl, and heterocycloalkenyl groups; 
         D is C 1 -C 3  alkylene; 
         E is a bond, or C 1 -C 2  alkylene; and 
         R is selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, alkenyl, heteroalkyl, aromatic ring, or heteroaromatic ring. 
       
     
     
         4 . The method of  claim 3 , wherein the TRPV4 inhibitor comprises a compound selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A method of reducing skin inflammation in a subject in need thereof, the method comprising administering to the subject an effective amount of a TRPV4 inhibitor. 
     
     
         6 . The method of  claim 5 , wherein the skin inflammation is related to UVB exposure. 
     
     
         7 . The method of  claim 5 , wherein the skin inflammation is associated with a dermatological disorder selected from sunburn, rosacea, Xeroderma pigmentosum, non-melanoma skin cancer, and photoaging, or with a disorder selected from non-UV skin burn, disturbed wound healing, and pain of bone fractures. 
     
     
         8 . The method of  claim 5 , wherein the method further comprises reducing pain in the subject. 
     
     
         9 . The method of  claim 5 , wherein the TRPV4 inhibitor comprises a compound according to Formula I: 
       
         
           
           
               
               
           
         
         wherein A, B, and C are independently selected from the group consisting of aromatic, heteroaromatic, cycloalkenyl, and heterocycloalkenyl groups; 
         D is C 1 -C 3  alkylene; 
         E is a bond, or C 1 -C 2  alkylene; and 
         R is selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, alkenyl, heteroalkyl, aromatic ring, or heteroaromatic ring. 
       
     
     
         10 . The method of  claim 9 , wherein the TRPV4 inhibitor comprises a compound selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A method of pain management, the method comprising administering to at least a portion of the skin of a subject in need thereof an effective amount of a TRPV4 inhibitor. 
     
     
         12 . The method of  claim 11 , wherein the pain is related to UVB exposure. 
     
     
         13 . The method of  claim 11 , wherein the pain is associated with a dermatological disorder selected from sunburn, rosacea, Xeroderma pigmentosum, non-melanoma skin cancer, and photoaging, or with a disorder selected from non-UV skin burn, disturbed wound healing, and pain of bone fractures. 
     
     
         14 . The method of  claim 11 , wherein the TRPV4 inhibitor comprises a compound according to Formula I: 
       
         
           
           
               
               
           
         
         wherein A, B, and C are independently selected from the group consisting of aromatic, heteroaromatic, cycloalkenyl, and heterocycloalkenyl groups; 
         D is C 1 -C 3  alkylene; 
         E is a bond, or C 1 -C 2  alkylene; and 
         R is selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, alkenyl, heteroalkyl, aromatic ring, or heteroaromatic ring. 
       
     
     
         15 . The method of  claim 14 , wherein the TRPV4 inhibitor comprises a compound selected from the following: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A method of reducing itch in a subject in need thereof, the method comprising administering to the subject an effective amount of a TRPV4 inhibitor. 
     
     
         17 . The method of  claim 16 , wherein the TRPV4 inhibitor comprises a compound according to Formula I: 
       
         
           
           
               
               
           
         
         wherein A, B, and C are independently selected from the group consisting of aromatic, heteroaromatic, cycloalkenyl, and heterocycloalkenyl groups; 
         D is C 1 -C 3  alkylene; 
         E is a bond, or C 1 -C 2  alkylene; and 
         R is selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, alkenyl, heteroalkyl, aromatic ring, or heteroaromatic ring. 
       
     
     
         18 . The method of  claim 17 , wherein the TRPV4 inhibitor comprises a compound selected from the following: