Mechanism and drug targets for reducing cell edema (neuroprotection) and cytoplasmic excitability in astrocytes in normal and pathological states

Abstract

The present invention pertains to a method for screening a compound useful in reducing astroglial edema, said method comprising: (i) providing a compound; (ii) bringing said compound in contact with an astrocyte; and (iii) determining the cAMP level in said astrocyte contacted with said compound; wherein said compound is identified as a compound useful in reducing astroglial edema, if the cAMP level in the astocyte increases after contact. The present invention further pertains to an agent elevating the cAMP level in astrocytes for use in reducing astroglial edema.

1 . A method for treating a subject having astroglial edema, comprising administering to said subject a therapeutic amount of an agent for elevating the cAMP level in astrocytes, wherein said agent is an agonist for a β-adrenergic receptor (β-AR), an agonist for a lactate receptor or a phosphodiesterase (PDE) inhibitor. 
     
     
         2 . The method according to  claim 1 , wherein said agonist for a β-adrenergic receptor (β-AR) is selected from the group consisting of adrenaline (ADR), noradrenalin (NA), dobutamine, dobutamine chloride, isoproterenol (β1 and β2), xamoterol, salbutamol, levosalbutamol, fenoterol, formoterol, metaproterenol, salmeterol, terbutaline, clenbuterol, isoetarine, pirbuterol, procaterol, ritodrine, arbutamine, befunolol, bromoacetylalprenololmenthan, broxaterol, cimaterol, cirazoline, denopamine, dopexamine, etilefrine, hexoprenaline, higenamine, indakaterol, salbutemol, isoxsuprine, mabuterol, methoxyphenamine, nylidrin, oxyfedrine, prenalterol, ractopamine, reproterol, rimiterol, tretoquinol, tulobuterol, zilpaterol, and zinerol. 
     
     
         3 . The method according to  claim 1 , wherein said agonist for a β-adrenergic receptor (β-AR) is adrenaline (ADR). 
     
     
         4 . The method according to  claim 1 , wherein said agonist for a β-adrenergic receptor (β-AR) is noradrenalin (NA). 
     
     
         5 . The method according to  claim 1 , wherein said agonist for a lactate receptor is an agonist for the lactate receptor GPR81. 
     
     
         6 . The method according to  claim 1 , wherein said agonist for a lactate receptor is selected from the group consisting of lactate, such as D-lactate or L-lactate, hydroxybenzoic acid, such as 3-hydroxy benzoic acid, 3-hydroxy-5-substituted benzoic acid, such as 3-Chloro-5-hydroxybenzoic acid (3-Cl-5-HBA), 3-hydroxy butyrate, 3-hydroxy-yoctanoate, 3H-imidazo[4,5-b] pyridin-5-ol derivatives. 
     
     
         7 . The method according to  claim 1 , wherein said agonist for a lactate receptor is lactate. 
     
     
         8 . The method according to  claim 1 , wherein said agonist for a lactate receptor is D-lactate. 
     
     
         9 . The method according to  claim 1 , wherein said agonist for a lactate receptor is L-lactate. 
     
     
         10 . The method according to  claim 1 , wherein said agonist for a lactate receptor is hydroxybenzoic acid. 
     
     
         11 . The method according to  claim 1 , wherein said agonist for a lactate receptor is 3-Chloro-5-hydroxybenzoic acid (3-Cl-5-HBA). 
     
     
         12 . The method according to  claim 1 , wherein said phosphodiesterase (PDE) inhibitor is selected from the group consisting of caffeine, aminophylline, 3-isobutyl-1-methylxanthine, paraxanthine, pentoxifylline, theobromine, theophylline, vinpocetine, erythro-9-(2-hydroxy-3-nonyl)adenine, BAY 60-7550, oxindole, inamrinone, PDP (9-(6-Phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), milrinone, enoximone, cilostazol, mesembrine, rolipram, ibudilast, piclamilast, rolipram, luteolin, drotaverine, and roflumilast. 
     
     
         13 . The method of  claim 1 , wherein said agent is rapamycin.