Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma.
Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma.
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DOI：
10.1016/j.nbd.2014.07.016
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发表时间：
2014-11
影响因子：
6.1
通讯作者：
John SW
中科院分区：
文献类型：
--
作者：
Howell GR;MacNicoll KH;Braine CE;Soto I;Macalinao DG;Sousa GL;John SW
The endothelin system is implicated in various human and animal glaucomas. Targeting the endothelin system has great promise as a treatment for human glaucoma, but the cell types involved and the exact mechanisms of action are not clearly elucidated. Here, we report a detailed characterization of the endothelin system in specific cell types of the optic nerve head (ONH) during glaucoma in DBA/2J mice. First, we show that key components of the endothelin system are expressed in multiple cell types. We discover that endothelin 2 (EDN2) is expressed in astrocytes as well as microglia/monocytes in the ONH. The endothelin receptor type A (Ednra) is expressed in vascular endothelial cells, while the endothelin receptor type B (Ednrb) receptor is expressed in ONH astrocytes. Second, we show that Macitentan treatment protects from glaucoma. Macitentan is a novel, orally administered, dual endothelin receptor antagonist with greater affinity, efficacy and safety than previous antagonists. Finally, we test the combinatorial effect of targeting both the endothelin and complement systems as a treatment for glaucoma. Similar to endothelin, the complement system is implicated in a variety of human and animal glaucomas, and has great promise as a treatment target. We discovered that combined targeting of the endothelin (Bosentan) and complement (C1qa mutation) systems is profoundly protective. Remarkably, 80% of DBA/2J eyes subjected to this combined inhibition developed no detectable glaucoma. This opens an exciting new avenue for neuroprotection in glaucoma.
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影响因子：
4.4
作者：
Johnson, Elaine C.;Jia, Lijun;Morrison, John C.
通讯作者：
Morrison, John C.
DOI：
10.1016/s0006-291x(05)80815-0
发表时间：
1992-07-15
影响因子：
3.1
作者：
HAMA, H;SAKURAI, T;GOTO, K
通讯作者：
GOTO, K
影响因子：
15.9
作者：
Howell, Gareth R.;Soto, Ileana;John, Simon W. M.
通讯作者：
John, Simon W. M.
影响因子：
6.2
作者：
Hernandez, MR;Agapova, OA;Aoi, S
通讯作者：
Aoi, S
影响因子：
4.4
作者：
Howell GR;Walton DO;King BL;Libby RT;John SW
通讯作者：
John SW