Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma
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 th...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-11-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114002381 |
| _version_ | 1829489464239456256 |
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| author | Gareth R. Howell Katharine H. MacNicoll Catherine E. Braine Ileana Soto Danilo G. Macalinao Gregory L. Sousa Simon W.M. John |
| author_facet | Gareth R. Howell Katharine H. MacNicoll Catherine E. Braine Ileana Soto Danilo G. Macalinao Gregory L. Sousa Simon W.M. John |
| author_sort | Gareth R. Howell |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-15T00:08:07Z |
| format | Article |
| id | doaj.art-077da25fbcd54fca9c3a2724d72494d4 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-15T00:08:07Z |
| publishDate | 2014-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-077da25fbcd54fca9c3a2724d72494d42022-12-21T22:42:40ZengElsevierNeurobiology of Disease1095-953X2014-11-01714452Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucomaGareth R. Howell0Katharine H. MacNicoll1Catherine E. Braine2Ileana Soto3Danilo G. Macalinao4Gregory L. Sousa5Simon W.M. John6The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA; Corresponding authors at: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA.The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USAThe Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USAThe Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USAThe Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USAThe Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USAThe Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA; The Howard Hughes Medical Institute, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA; Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA; Corresponding authors at: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA.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.http://www.sciencedirect.com/science/article/pii/S0969996114002381GlaucomaEndothelinComplementDBA/2JOptic nerve head |
| spellingShingle | Gareth R. Howell Katharine H. MacNicoll Catherine E. Braine Ileana Soto Danilo G. Macalinao Gregory L. Sousa Simon W.M. John Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma Neurobiology of Disease Glaucoma Endothelin Complement DBA/2J Optic nerve head |
| title | Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma |
| title_full | Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma |
| title_fullStr | Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma |
| title_full_unstemmed | Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma |
| title_short | Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma |
| title_sort | combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma |
| topic | Glaucoma Endothelin Complement DBA/2J Optic nerve head |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114002381 |
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