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J. Wang, S. Chollangi, J. D. Ash; Neuroprotection by Leukemia Inhibitory Factor Does Not Require Reduced Phototransduction. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4360. doi: https://doi.org/.
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Previous studies have shown that leukemia inhibitory factor (LIF) can protect retinal photoreceptors from cell death. Unfortunately, LIF also has the unwanted side effect of reducing photoreceptor function which limits it clinical utilization. The purpose of this study is to determine if the neuroprotective mechanism of Leukemia Inhibitory Factor (LIF) is mediated by its inhibition of photoreceptor function or by an independent mechanism.
Mice were intravitreally injected with doses of LIF from 0.25 to 2.5µg. Mice were exposed to 3000lux fluorescent white light for 5 hour to induce light damage. Retinal function and the rows of photoreceptors were measured using electroretinograms (ERG) and histological morphometric analysis. ERG a-wave analysis was used to calculate the maximal response and gain of phototransduction cascade. We assessed expression of phototransduction genes by Western blots and real-time PCR.
Our data show that LIF protected photoreceptors over a broad range of concentrations. The lowest concentrations that were protective had no measurable effect on the maximal A-wave response (Rm) or on phototransduction gain (S). The highest concentration of LIF significantly reduced Rm, S and reduced mRNA and protein levels of rod opsin, transducins-α and -β and Pde6α. Reduced function and protein expression recovered 15 days post injections.
Our study demonstrates that the neuroprotective activity of LIF can be induced over a broad range of concentrations that do not inhibit retinal function. These results suggest that the mechanism for protection is distinguishable from mechanisms that inhibit photoreceptor function. Utilizing LIF for therapeutic neuroprotection is possible over abroad range without significant inhibition on photoreceptor function. Our data also suggest that the negative activity of reducing function is reversible.
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