SMALL MOLECULE THERAPEUTIC COMPOUNDS THAT REDUCE THE INCIDENCE OF INTRACEREBRAL HEMORRHAGE AND BRAIN MICROHEMMORHAGES
The described invention relates to small molecule therapeutic compounds capable of reducing the incidence of intracerebral hemorrhage and brain microhemorrhages identified using zebrafish and mouse models of intracerebral hemorrhage and brain microhemorrhages.
1 . A method for reducing incidence of vascular leakage in the brain comprising administering to a subject in need thereof a pharmaceutical composition containing a small molecule therapeutic compound selected from the group consisting of artemisinin or a derivative of artemisinin, a therapeutic amount of which is effective to reduce incidence of bleeding in the brain, wherein the brain vascular leakage is an induced brain microhemorrhage or a spontaneous intracerebral hemorrhage.
2 . The method according to claim 1 , wherein the derivative of artemisinin is dihydroartemisinin, artemether, or artesunate.
3 . The method according to claim 1 , wherein the small molecule therapeutic compound is selected from the group consisting of benidipine, lacidipine, ethynylestradiol or triptolide.
4 . The method according to claim 1 , wherein the vascular leakage is an induced vascular leakage, an induced brain hemorrhage or a brain microhemorrhage.
5 . The method according to claim 1 , wherein the vascular leakage is induced by a statin, by a lipopolysaccharide, or both.
6 . The method according to claim 4 , wherein the statin is atorvastatin.
7 . The method according to claim 1 , wherein the vascular leakage is a spontaneous intracerebral hemorrhage.
8 . The method according to claim 1 , wherein the brain vascular leakage is aging-related or related to a neural degenerative disease.
9 . The method according to claim 6 , wherein the spontaneous intracerebral hemorrhage occurs in association with a mutation of one or more genes selected from beta-pix, Pak2a, cdh5, ccm1, ccm2, ccm3, and Rap1b.
10 . The method according to claim 1 , wherein the vascular leakage includes a brain microhemorrhage.
11 . The method according to claim 8 , wherein the brain microhemorrhage occurs in association with administration of a statin.
12 . The method according to claim 1 , wherein the vascular leakage comprises a brain vascular malformation.
13 . The method according to claim 10 , wherein the brain vascular malformation is a cerebral cavernous malformation.
14 . The method according to claim 1 , wherein the brain hemorrhage or brain microhemorrhage is induced by dysfunction of β3 integrin signaling.
15 . The method according to claim 14 , wherein the dysfunction of β3 integrin signaling is associated with a disease state selected from the group consisting of a spontaneous intracerebral hemorrhage, an aging-related vascular leakage, an aging-related hemorrhage, an aging-related microhemorrhage, a vascular leakage from a neural degenerative disease, a hemorrhage from a neural degenerative disease, a microhemorrhage from a neural degenerative disease, a brain vascular malformation, or a cerebral cavernous malformation.
16 . A method for screening compounds effective to reduce incidence of a vascular leakage in brain comprising (i) administering to a zebrafish embryo a pharmaceutical composition containing a statin or LPS; (ii) inducing in the zebrafish embryo a vascular leakage or a brain hemorrhage; and (iii) administering to the zebrafish embryo a compound effective to reduce incidence of the vascular leakage or brain hemorrhage.