Effects of Novel Free Radical Scavengers on Intraocular Pressure and ERGs in Rat Glaucoma Models

Abstract

Abstract: : Introduction: Glaucoma is often associated with elevated intraocular pressure (IOP) and free radical damage to retinal ganglion cells (RGC). 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 IOP reduction and RGC neuroprotection. Methods: Rats were treated topically with 20 ml of MP compounds (0.3 – 100 mM) on the operated eyes of a unilateral, surgical rat glaucoma model. The MP compounds were compared to topical amifostine, a free radical scavenger. MP esterified chelators were diethylenetriaminepentaacetic acid (DTE), iminodiacetic acid (IDE), methyl iminodiacetic acid (MIDE), ethylenediaminetetraacetic acid (EDTAE), cyclohexanediaminetetraacetic acid(CEDTAE) and a combined thiol/EDTAE (SEDE). IOP was measured using a Goldmann tonometer. Slit lamp and confocal microscopy were used to detect toxic effects of 10 or 87 mM MPDTE on normal rats dosed 3x/day for 30 days. 14C labeling was used to determine pharmacokinetics/drug distribution. To examine RGC neuroprotection, 2 ml intravitreal injections of 10 mM NMDA, sufficient to change ERG a and b–waves within 2 weeks, were challenged with co–administered intravitreal 2mM MPSEDE in a unilateral rat model. Results: (1) Topical MPDTE and MPSEDE (3–100 mM) decreased the IOP to that of the normal contralateral eye, with a T1/2s of 1–2 hr. (2) There was some IOP reduction by both the MPEG backbone and the chelators, but these effects were not additive to those of the "assembled" scavengers. (3) 10 or 87 mM amifostine did not reduce IOP or cause acute toxicity. (4) No acute or chronic adverse ocular effects occurred with MP compounds. (5) Pharmacokinetic tests showed permeation of MP compounds into the eye after topical administration and elimination via the urine. (6) Co–administration of MPSEDE with NMDA maintained 70% a–wave and 65% b–wave amplitudes in comparison to only 35% a–wave and 65% b–wave amplitudes when NMDA was used alone. Conclusions:(1) MP compounds are new agents that can lower IOP significantly for up to 3–4 hr with a single dose without toxicity and can be used chronically without adverse effects. (2) Their ability to reduce IOP is in addition to a free radical scavenging/neuroprotection activity in the NMDA RGC neurotoxicity model, demonstrating at least two mechanisms that would be beneficial in treating glaucoma.

Keywords: neuroprotection • oxidation/oxidative or free radical damage • pharmacology