Abstract
Abstract: :
Purpose: We reported last year at ARVO (#3312) that ischemic tolerance resulted from administration of a single intraperitoneal dose of cobalt chloride 24 h before retinal ischemia. In the present study, we assessed whether this protection extended to another "hypoxia-mimetic" drug, and whether repeated treatments could prolong the duration of the ischemia-tolerant state. Methods: Male Swiss-Webster ND4 mice received a single dose of desferroxamine (DFX; 200 mg/kg i.p.) or multiple doses three times per week (once every other day for one or two weeks). Thirty min of retinal ischemia was induced by elevated IOP 1 day, or 1, 2, or 4 weeks after the last dose of DFX. At one week postischemia, eyes were perfusion fixed, embedded in paraffin, and thin-sectioned. Results: Detailed histopathologic analysis of eyes from untreated controls revealed that 30-min ischemia resulted in a 17, 24, and 20% reduction in the thickness of the INL, IPL, and overall inner retina (OLM-ILM), and a 22 and 27% reduction in cell counts in the INL and GCL, respectively. Significant (70-90%) protection across all these endpoints was promoted 24 h as well as 1 week after a single dose of DFX. Two weeks after a one-week DFX treatment regimen, protection was sustained at virtually 100% for morphometrics, and 80-90% of the cells in the INL and GCL were protected. A two-week DFX treatment regimen promoted retinal protection 4 weeks later, with near complete preservation of layer thickness and a 60-75% protection of cells in the INL and GCL. Neither the single nor multiple DFX treatment regimens resulted in morphologic retinal abnormalities relative to untreated controls. Conclusions: A sustained period of retinal ischemic tolerance is achieved following repeated treatments with DFX. Because this drug is well tolerated clinically, pretreatment may be warranted in cases of expected retinal ischemia. DFX is known to activate hypoxia inducible factor-1α (HIF-1α), a transcription factor for a host of survival-promoting genes; we have observed increased expression of HIF-1α in INL and GCL after hypoxic preconditioning, with similar experiments on DFX forthcoming. Additional studies are warranted to define the contribution of this and other mechanisms to the ability of DFX to promote a long lasting neuroprotective phenotype in retina.
Keywords: neuroprotection • ischemia • retina: proximal(bipolar, amacrine, and gangli