The in vitro retardation of porcine cataractogenesis by the calpain inhibitor, SJA6017.
Calpain inhibitors show the potential to serve as non-surgical alternatives in treating diabetic cataract and other types of these disorders. Here, we have tested the recently developed calpain inhibitor, SJA6017, for its ability to inhibit cataractogenesis in porcine lenses. These lenses were incubated in increasing levels of extralenticular calcium (Ca2+; 5-30 mM). Atomic absorption spectroscopy was used to determine total internal lens Ca2+ and a correlation between porcine lens Ca2+ uptake and levels of lens opacification were found with a total internal lens Ca2+ level of 5.8 microM Ca2+ g(-1) wet lens weight corresponding to the onset of catarctogenesis. A total internal lens Ca2+ level of 8.0 microM Ca2+ g(-1) wet lens weight corresponded to cataract occupying approximately 70% of the lens cell volume. This degree of cataract was reduced by approximately 40%, when SJA6017 (final concentration 0.8 microM) was included in the extralenticular medium, suggesting that the Ca2+-mediated activation of calpains may be involved in the observed opacification. Supporting this suggestion atomic absorption spectroscopy showed that the effect of SJA6017 (final concentration 0.8 microM) on lens opacification was not due to the compound restricting porcine lens Ca2+ uptake. The results indicate that calpain-induced cataractogenesis is dependent on extracellular Ca2+ and the calpain inhibitor SJA6017 (0.8 microM) had no significant effect on Ca2+ uptake by lens. Its inhibitory effect on lens opacification may be due to a direct action on the activity of calpain.
Biswas
Suman
S
Department of Ophthalmology, Royal Preston Hospital, Preston, England, UK.
Harris
Frederick
F
Singh
Jaipaul
J
Phoenix
David A
DA
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002122:Calcium Chloride / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors*; D002386:Cataract / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004151:Dipeptides / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism; D013552:Swine
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C109145:N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal; D002154:Calpain; D002122:Calcium Chloride