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

CNS Neurol Disord Drug Targets. 2008 Jun;7(3):295-304. doi: 10.2174/187152708784936644.

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]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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Calpain / metabolism*
  • Glaucoma / drug therapy*
  • Glaucoma / pathology
  • Glycoproteins / chemistry
  • Glycoproteins / metabolism
  • Glycoproteins / therapeutic use*
  • Humans
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / therapeutic use*
  • Optic Nerve / drug effects
  • Optic Nerve / metabolism*
  • Trabecular Meshwork / drug effects
  • Trabecular Meshwork / metabolism*

Substances

  • Glycoproteins
  • Neuroprotective Agents
  • calpain inhibitors
  • Calpain