Neuroprotection in glaucoma using calpain-1 inhibitors: regional differences in calpain-1 activity in the trabecular meshwork, optic nerve and implications for therapeutics.
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.
Govindarajan
Bharathi
B
Bascom Palmer Eye Institute, University of Miami, Miami, FL 33136, USA.
Laird
James
J
Sherman
Ronald
R
Salomon
Robert G
RG
Bhattacharya
Sanjoy K
SK
D000818:Animals; D002154:Calpain / Q000378:metabolism*; D005901:Glaucoma / Q000188:drug therapy* / Q000473:pathology; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D009900:Optic Nerve / Q000187:drug effects / Q000378:metabolism*; D014129:Trabecular Meshwork / Q000187:drug effects / Q000378:metabolism*
D006023:Glycoproteins; D018696:Neuroprotective Agents; C039304:calpain inhibitors; D002154:Calpain