• DOI:10.2174/187152708784936644
• Corpus ID: 33495310

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

@article{Govindarajan2008NeuroprotectionIG,
  title={Neuroprotection in glaucoma using calpain-1 inhibitors: regional differences in calpain-1 activity in the trabecular meshwork, optic nerve and implications for therapeutics.},
  author={Bharath Madapusi Govindarajan and James M. Laird and Ronald Sherman and Robert G. Salomon and Sanjoy K. Bhattacharya},
  journal={CNS \& neurological disorders drug targets},
  year={2008},
  volume={7 3},
  pages={
          295-304
        }
}

• B. Govindarajan, James M. Laird, +2 authors S. Bhattacharya
• Published 31 May 2008
• Biology, Medicine
• CNS & neurological disorders drug targets

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.