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 journalArticle

13 Citations (Scopus)

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
Pages (from-to)295-304
Number of pages10
JournalCNS and Neurological Disorders - Drug Targets
Volume7
Issue number3
DOIs
StatePublished - Jun 1 2008

Fingerprint

Trabecular Meshwork
Calpain
Optic Nerve
Glaucoma
Eye Diseases
calpain inhibitors
Neuroprotection
Ubiquitination
Proteasome Endopeptidase Complex
Digestion
Peptide Hydrolases
Molecular Weight
Lipids

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Pharmacology

Cite this

Neuroprotection in glaucoma using calpain-1 inhibitors : Regional differences in calpain-1 activity in the trabecular meshwork, optic nerve and implications for therepeutics. / Govindarajan, Bharathi; Laird, James; Sherman, Ronald; Salomon, Robert G.; Bhattacharya, Sanjoy K.

In: CNS and Neurological Disorders - Drug Targets, Vol. 7, No. 3, 01.06.2008, p. 295-304.

Research output: Contribution to journalArticle

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