Abstract
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]LGE2). Treatment of calpain-1 with iso [4]LGE2 in vitro results in covalent modification, inactivation, and resistance to protease digestion. Iso [4]LGE2-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]LGE2-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.
Keywords: Glaucoma, calpain, trabecular meshwork, isolevuglandin, lipid oxidation, posttranslational modifications, neuroprotection
CNS & Neurological Disorders - Drug Targets
Title: Neuroprotection in Glaucoma Using Calpain-1 Inhibitors: Regional Differences in Calpain-1 Activity in the Trabecular Meshwork, Optic Nerve and Implications for Therapeutics
Volume: 7 Issue: 3
Author(s): Bharathi Govindarajan, James Laird, Ronald Sherman, Robert G. Salomon and Sanjoy K. Bhattacharya
Affiliation:
Keywords: Glaucoma, calpain, trabecular meshwork, isolevuglandin, lipid oxidation, posttranslational modifications, neuroprotection
Abstract: 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]LGE2). Treatment of calpain-1 with iso [4]LGE2 in vitro results in covalent modification, inactivation, and resistance to protease digestion. Iso [4]LGE2-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]LGE2-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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Govindarajan Bharathi, Laird James, Sherman Ronald, Salomon G. Robert and Bhattacharya K. Sanjoy, Neuroprotection in Glaucoma Using Calpain-1 Inhibitors: Regional Differences in Calpain-1 Activity in the Trabecular Meshwork, Optic Nerve and Implications for Therapeutics, CNS & Neurological Disorders - Drug Targets 2008; 7 (3) . https://dx.doi.org/10.2174/187152708784936644
DOI https://dx.doi.org/10.2174/187152708784936644 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
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