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A. Hosseini, F. A. Lattanzio, Jr., K. Schellenberg, J. Schaeffer, S. Samudre, M. Frazier, P. B. Williams; Novel Free Radical Scavengers Both Improve Retinal Cell Survival and Reduce IOP. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4381.
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© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is associated with elevated intraocular pressure (IOP) and damage to retinal cells. Novel free radical scavengers with a methoxypolyethylene glycol (MP) backbone and attached esterified ion chelator side groups were evaluated as anti-glaucoma agents in terms of neuroprotection and IOP reduction.
MP esterified chelators, MPDTE and MPSEDE, were compared with amifostine, a known free radical scavenger. To examine for neuroprotective effects, a 2 ul intravitreal injection of 10 mM NMDA, sufficient to damage ERG A and B waves within 2 weeks, was challenged by co-injection of MPDTE, MPSEDE or amifostine in a unilateral rat model (6/group). In another series, using topical administration, rats were pretreated separately with each drug for 5 days (at 3 doses/day) prior to NMDA injection, and then for an additional 3 days following the injection (6/group). All retinas were fixed, flat mounted and stained with H&E. Their effects on IOP were examined in a surgically modified unilateral rat glaucoma model. Non-operated eyes served as controls. Rats were treated topically with MP compounds on the operated eyes and compared to topical amifostine or WIN 55-212-2, a synthetic cannabinoid. IOP was measured using a Goldmann tonometer.
- NMDA alone reduced A and B waves up to 51% of control, but both MPDTE and MPSEDE, co-injected or topically applied, significantly protected A and B waves from NMDA damage up to 90% of control (p< 0.05), as did amifostine (P<0.05). - H&E stained retina flat mounts confirmed that after NMDA alone, cell density decreased to 50% of the cells in control eye. By comparison in both MP and amifostine treated groups up to about 90% of cells remained viable. - Topical MPDTE, MPSEDE and Win 55-212-2, but not amifostine, significantly decreased the IOP up to 5 mm Hg, with a T1/2 of 1-2 hr with no acute or chronic adverse ocular effects. - When given as solo components, there was IOP reduction by the MPEG backbone and by the chelators, but these effects were less than the complete MP compounds.
- Based upon their structure the MP compounds were expected to have free radical scavenging/neuroprotective activity similar to that of amifostine. - The MP compounds decreased IOP significantly for up to 3-4 hr with a single dose without acute or chronic toxicity, as did the cannabinoids. - In summary, compared to cannabinoids and amifostine, this new class of compounds exhibits a dual mechanism of action, which would be beneficial in treating glaucoma.
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