Abstract
Abstract: :
Purpose: Glatiramer acetate, also known as copolymer 1 (Cop–1, Copaxone‘), is copolymer approved by the Food and Drug Administration for treatment of patients with multiple sclerosis. Cop–1 acts as a weak "universal antigen" was found by us to have an immune–dependent neuroprotective effect in animal models of acutely and chronically increased intraocular pressure (IOP). The aim of this study was to establish the optimal route, dosage, and formulation of vaccination with adjuvant–free Cop–1 in rat models of acute and chronic glaucoma as the final step before the initiation of clinical trials. Methods: For generation of chronically elevated unilateral IOP in the rat, the episcleral veins and limbal plexus were subjected to argon laser photocoagulation. For acute IOP elevation a 30–gauge needle, connected to an infusion bag of normal saline (0.9%) placed 60 cm above the rat’s head, was inserted into the anterior chamber of the eye and kept there for 1 h. In each rat the IOP was measured 10 times with Tono–Pen (XL, Mentor®). After induction of glaucoma, rats were immunized with Cop–1 at different intervals, dosages, and routes of administration. After 1 or 2 weeks in the acute model and after 3 weeks in the chronic model, IOP–generated damage was assessed by retrograde labeling of viable retinal ganglion cells (RGCs) with rhodamine dextran. Control rats with acute or chronic IOP were sham–immunized with PBS. Results: Vaccination with Cop–1 was found to be neuroprotective both with and without the use of an adjuvant (complete Freund’s adjuvant; CFA). In the chronic glaucoma model, the most effective regimen was a single subcutaneous injection of 500 mg of Cop–1. This dosage resulted in 72.48% ± 11.56% protection (n = 7) compared to no mprotection in control rats after 3 weeks (P < 0.0001). Despite the relatively narrow therapeutic window that characterizes acute glaucoma, Cop–1 evoked neuroprotection if injected during the first 24 h after acute elevation of IOP. Topical vaccination with eye drops also reduced secondary degeneration in both the acute and the chronic glaucoma models. The successful outcome of vaccination administered in the undamaged contralateral eye indicated that the neuroprotective effect was exerted systemically (protection rates of 44.72 ± 3.0%). Conclusion: These results encourage the inauguration of clinical trials of Cop–1 as a treatment for patients with glaucoma. The use of Cop–1 in combination with anti–hypertensive drugs appears to offer, for the first time, the dual possibility of minimizing primary risk factor, while also halting future disease progression.
Keywords: autoimmune disease • degenerations/dystrophies • drug toxicity/drug effects