| Neuroprotection in glaucoma using calpain-1 inhibitors: regional differences in calpain-1 activity in the trabecular meshwork, optic nerve and implications for therapeutics. | |
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MedLine Citation:
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PMID: 18673213 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glaucoma is a group of irreversible blinding eye diseases affecting over 70 million people worldwide. Systemic delivery of calpain-1 inhibitors was proposed as a neuroprotection strategy for the prevention of progressive optic nerve damage in glaucoma. We present a general review of calpain-1 and an account of vast differences in processing of calpain-1 in the trabecular meshwork (TM) and the optic nerve. Calpain-1 accumulates in the glaucomatous TM tissues in vivo. However, calpain-1 activity is substantially lower in the glaucomatous TM compared to controls, apparently owing to partial degradation, and modification by lipid oxidation products such as iso [4]levuglandin E2 (iso [4]LGE(2)). Treatment of calpain-1 with iso [4]LGE(2) in vitro results in covalent modification, inactivation, and resistance to protease digestion. Iso [4]LGE(2)-modified calpain-1 appeared to undergo ubiquitination in the TM by cellular degradation machinery mediated by ubch1-2, ubch5,6 and E6-AP, E2 and E3 enzymes respectively. In the TM, iso [4]LGE(2)-modified calpain-1 loading impairs the cellular proteasome activity consistent with competitive inhibition and formation of suicidal high molecular weight aggregates. In contrast, higher calpain-1 activity, that appears to be under translational control, was observed in glaucomatous optic nerve compared to control. Therapeutic neuroprotection strategies using calpain-1 inhibitors will require consideration of such anatomic differences in its activity and biosynthesis. |
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Authors:
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Bharathi Govindarajan; James Laird; Ronald Sherman; Robert G Salomon; Sanjoy K Bhattacharya |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review |
Journal Detail:
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Title: CNS & neurological disorders drug targets Volume: 7 ISSN: 1871-5273 ISO Abbreviation: CNS Neurol Disord Drug Targets Publication Date: 2008 Jun |
Date Detail:
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Created Date: 2008-08-04 Completed Date: 2008-11-05 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 101269155 Medline TA: CNS Neurol Disord Drug Targets Country: United Arab Emirates |
Other Details:
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Languages: eng Pagination: 295-304 Citation Subset: IM |
Affiliation:
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Bascom Palmer Eye Institute, University of Miami, Miami, FL 33136, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Calpain / metabolism* Glaucoma / drug therapy*, pathology Glycoproteins / chemistry, metabolism, therapeutic use* Humans Neuroprotective Agents / chemistry, metabolism, therapeutic use* Optic Nerve / drug effects, metabolism* Trabecular Meshwork / drug effects, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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EY015266/EY/NEI NIH HHS; GM021249/GM/NIGMS NIH HHS; R03 EY015266-03/EY/NEI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Glycoproteins; 0/Neuroprotective Agents; 0/calpain inhibitors; EC 3.4.22.-/Calpain |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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