Effect of the age cross-link breaker alagebrium on anterior segment physiology, morphology, and ocular age and rage.
OBJECTIVE
To determine the effects of the advanced glycation end product (AGE) cross-link breaker alagebrium on intraocular pressure (IOP), accommodation (ACC), outflow facility (OF), anterior segment morphology, and ocular AGE and receptors for AGE (RAGE) in older rhesus monkeys.


METHODS
Six rhesus monkeys (aged 19 to 20 years) received 3 or 4 intracameral and intravitreal (final concentration, 1 mM) injections of alagebrium to one eye over 2.5 to 3 weeks and vehicle to the opposite eye. ACC and OF responses to intramuscular or intravenous pilocarpine were measured at baseline and at 1 to 2 weeks and 2, 4, and 6 months postinjection. IOP was measured prior to all injections, ACC, and OF measurements. Monkeys were euthanized 3 to 6 months after the last injection, the eyes were enucleated, and anterior and posterior segments were examined by electron microscopy or immunohistochemistry.


RESULTS
No significant differences were found in ACC or IOP at any time point after alagebrium treatment. Baseline OF was higher (37.0 +/- 6.0%; P < or = .005) in alagebrium-treated vs control eyes at 6 months postinjection. In 3 monkeys, alagebrium-treated eyes, compared to control eyes, showed greater focal plaque formation, similar to that seen in primary open-angle glaucoma, in the juxtacanalicular meshwork/inner wall of Schlemm's canal. No changes in anterior segment AGE or RAGE were detectable. However, some areas of the retina and optic nerve head exhibited decreased AGE and increased RAGE immunostaining.


CONCLUSIONS
Intraocular injection of AGE cross-link breakers is an unlikely approach for glaucoma therapy. However, it may generate a model for further study of glaucomatous-like plaque formation. Immunohistochemical changes in the posterior segment in response to alagebrium warrant further functional studies.
Kiland
Julie A
JA
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, USA.
Gabelt
B'ann T
BT
Tezel
Gülgün
G
Lütjen-Drecoll
Elke
E
Kaufman
Paul L
PL
D000065:Accommodation, Ocular / Q000187:drug effects; D000818:Animals; D000869:Anterior Eye Segment / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D005123:Eye / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005902:Glaucoma, Open-Angle / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D007150:Immunohistochemistry; D007267:Injections; D007429:Intraocular Pressure / Q000187:drug effects; D008253:Macaca mulatta; D008854:Microscopy, Electron; D009898:Optic Disk / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D012029:Refraction, Ocular / Q000187:drug effects; D012160:Retina / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014822:Vitreous Body
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013844:Thiazoles; C406794:alagebrium