Modulating the permeability of a physiological barrier with an agent that modulates tyrosine phosphorylation

Abstract

Permeability of the blood-brain barrier and other physiological barriers can be modulated by the degree of tyrosine phosphorylation of proteins. Agents which promote tyrosine protein dephosphorylation reduce the permeability of the blood-brain barrier and those which promote phosphorylation increase permeability. Increasing blood-brain barrier permeability is useful in delivering drugs having a desired effect upon the central nervous system; decreasing blood-brain barrier permeability and other physiological barrier permeability is useful in preventing undesired compounds reaching the CNS and in certain clinical conditions.

1 . The use of an agent which promotes tyrosine protein dephosphorylation in the preparation of a medicament for reducing permeability of a physiological barrier such as the blood-brain barrier.  
     
     
         2 . The use as claimed in  claim 1 , wherein the agent directly or indirectly activates tyrosine protein phosphatase and/or directly or indirectly inhibits tyrosine kinase.  
     
     
         3 . The use of an agent which promotes tyrosine protein phosphorylation in the preparation of a medicament for increasing permeability of a physiological barrier such as the blood-brain barrier.  
     
     
         4 . The use as claimed in  claim 3 , wherein the agent directly or indirectly inhibits tyrosine protein phosphatase and/or directly or indirectly activates tyrosine kinase.  
     
     
         5 . The use as claimed in any one of  claims 1  to  4 , wherein the phosphorylation or dephosphorylation promotion effect of the agent is reversible or sufficiently reversible to avoid untoward toxicity problems.  
     
     
         6 . The use as claimed in  claim 4  or  5 , wherein the agent is a vanadium-containing salt.  
     
     
         7 . The use as claimed in  claim 6 , wherein the agent is a pervanadate.  
     
     
         8 . The use as claimed in  claim 4 , wherein the agent is phenylarsine oxide.  
     
     
         9 . The use as claimed in any one of  claims 1  to  8 , wherein the tyrosine phosphorylation or dephosphorylation involves one or more components of the cadherin/catenin complex.  
     
     
         10 . The use as claimed in any one of  claims 1  to  8 , wherein the tyrosine phosphorylation or dephosphorylation involves E-cadherin, N-cadherin, P-cadherin, β-catenin, ZO-1, ZO-2, p100 or p120.  
     
     
         11 . The use as claimed in  claim 9 , wherein the tyrosine phosphorylation or dephosphorylation involves β-catenin, ZO-1, ZO-2, p100 or p120.  
     
     
         12 . The use of an agent which promotes tyrosine protein dephosphorylation in the preparation of a medicament for decreasing brain oedema, such as following stroke or associated with brain tumours.  
     
     
         13 . The use of an agent which promotes tyrosine protein dephosphorylation in the preparation of a medicament for treating or preventing peripheral oedema, such as high altitude pulmonary oedema.  
     
     
         14 . The use of an agent which promotes tyrosine protein dephosphorylation in the preparation of a medicament for blocking the entry into the brain of leukocytes that mediate an immune response.  
     
     
         15 . The use of an agent which promotes tyrosine protein dephosphorylation in the preparation of a medicament for treating multiple sclerosis.  
     
     
         16 . The use of an agent which promotes tyrosine protein dephosphorylation in the preparation of a medicament for preventing cancer metastasis.  
     
     
         17 . The use of an agent which promotes tyrosine protein phosphorylation and the use of a blood-brain barrier or other physiological barrier-impermeant drug in the preparation of a medicament for delivering the drug to the brain or other part of the body (such as a tumour) the other side of the barrier.  
     
     
         18 . The use of an agent which promotes pulmonary epithelial cell tyrosine protein phosphorylation in the preparation of a medicament for treating or preventing accumulation of mucous in the airways.  
     
     
         19 . The use of an agent which promotes tyrosine protein dephosphorylation in the preparation of a medicament for treating gastric ulcers.  
     
     
         20 . A composition comprising an agent which promotes tyrosine protein phosphorylation and a drug to be delivered across a physiological barrier such as the blood-brain barrier.