Neuroprotection in glaucoma using calpain-1 inhibitors: Regional differences in calpain-1 activity in the trabecular meshwork, optic nerve and implications for therepeutics

Bharathi Govindarajan, James Laird, Ronald Sherman, Robert G. Salomon, Sanjoy K. Bhattacharya

Research output: Contribution to journalReview article

13 Scopus citations

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]leviglandin 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.

Original languageEnglish (US)
Pages (from-to)295-304
Number of pages10
JournalCNS and Neurological Disorders - Drug Targets
Volume7
Issue number3
DOIs
StatePublished - Jun 2008

Keywords

  • Calpain
  • Glaucoma
  • Isolevuglandin
  • Lipid oxidation
  • Neuroprotection
  • Posttranslational modifications
  • Trabecular meshwork

ASJC Scopus subject areas

  • Neuroscience(all)
  • Pharmacology

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