Novel Complexes Reduce Nitrogen Mustard-Induced Ocular Injury

Abstract

Abstract: : Purpose: Mustard agents are highly toxic and abundant warfare chemicals, primarily affecting ocular tissues, with no specific treatment antidote. The purpose of the present study was to examine the efficacy of novel metallo-complexes, known to inhibit the formation of highly reactive free radicals, in reducing ocular injury induced by nitrogen mustard (NM). Methods: One eye in each of 72 rabbits was exposed to 1-2% NM. Topical treatment with eye drops of a metallo-complex – either Zinc- or Gallium-Desferrioxamine (Zn/DFO and Ga/DFO) - was compared to treatment with saline, zinc (chloride) or DFO alone. Examiners masked to the treatment groups assessed the extent of ocular injury and the response to treatment using clinical, histological and biochemical criteria. Results: Exposure to NM caused severe and long-lasting injury to ocular anterior segment structures. Topical application of Zn/DFO or Ga/DFO markedly reduced conjunctival, corneal, iris, and anterior chamber injury. In the cornea, faster healing of epithelial erosions occurred: at 3 days post-injury, average erosion size was 11.2 ± 3.9 and 28.3 ± 3.2 mm² for Zn/DFO and saline-treated eyes, respectively. Long-term corneal opacification was reduced by more than 50% (p<0.05) in Zn/DFO treated eyes as compared to controls, and was associated with lower levels of neovascularization. In the anterior chamber, decreased inflammation and better maintenance of IOP was achieved: average IOP at 4 days post-injury was 19.3 ± 2.0, 27.4 ± 1.9 and 38.0 ± 2.4 mmHg for control non-exposed eyes, exposed and Zn/DFO-treated and exposed and saline-treated eyes, respectively. Iris pigmentation and atrophy were reduced by more than 60% (p<0.05), less posterior synechiae formed, and cataractous changes were also markedly milder. Zinc chloride or DFO alone provided lower levels of protection. Systemic anti-oxidant status was preserved in Zn/DFO and Ga/DFO treated animals as compared with saline-treated. No toxic effects of the complexes were observed. Conclusions: We hypothesize that Zn/DFO and Ga/DFO act via combined "Push and-Pull" mechanisms that interfere with transition metal-dependent formation of free radicals, thus reducing mustard ocular injury. Topical use of these complexes should be considered following exposure to Mustard gas, which poses a threat in future terror attacks or on the battlefield. Further evaluation of the safety and efficacy in humans is required.

Keywords: antioxidants • oxidation/oxidative or free radical damage • animal model