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Barbara Lorber, Alessia Tassoni, Natalie D. Bull, Marilita M. Moschos, Keith R. Martin; Retinal Ganglion Cell Survival And Axon Regeneration In Wlds Transgenic Rats After Optic Nerve Crush And Lens Injury. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3486.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously shown that the slow Wallerian degeneration mutation (WldS) delays axonal degeneration after optic nerve crush (ONC) but does not protect retinal ganglion cell (RGC) bodies in adult rats. To test whether a combination approach protecting both axons and cell bodies would enhance the therapeutic potential of the Wallerian degeneration mutation we performed ONC and lens injury (LI), which results in both enhanced RGC survival as well as axon regeneration past the lesion site in wildtype animals.
Adult Sprague Dawley (SD) or WldS rats received (a) ONC (SD: n=8; WldS: n=9), (b) ONC + LI (SD: n=11; WldS: n=13), or were left untreated (SD: n=8; WldS: n=9). 14 days after treatment, RGC survival (number of Islet+ RGC) and retinal glia activation (intensity of GFAP labeling) were quantified in retinal sections. In addition, the number of GAP43+ RGC axons regenerating past the optic nerve lesion site was assessed.
As previously reported, we found that the WldS mutation does not protect RGC bodies after ONC alone (SD: 36.6 ± 2.6%; WldS: 36.1 ± 1.6% RGC survival versus untreated). Surprisingly, we found that WldS transgenic rats did not exhibit the enhanced RGC survival response after ONC + LI that was observed in wildtypes (SD: 47.5 ± 2%; P<0.01 versus SD ONC; WldS: 35.2 ± 1.5%). After ONC, only few GAP43+ axons were able to grow past the lesion site in both wildtype and WldS rats (SD: 14.7 ± 5.2; WldS: 18.1 ± 10.8). ONC + LI led to a significant increase in RGC axon regeneration past the lesion site in both wildtype (140.4 ± 29.6; P<0.01 versus ONC) and WldS rats (95.1 ± 35.5; P<0.05 versus ONC), although the difference between wildtype and WldS rats was not statistically significant. Furthermore, activation of retinal glia, previously shown to be associated with enhanced RGC survival and axon regeneration after ONC + LI, was unaffected in WldS transgenic rats (SD: 2.9 ± 0.2; WldS: 2.7 ± 0.2 fold increase over untreated).
The RGC axon regeneration potential is similar between WldS transgenic and wildtype rats, but WldS transgenic rats do not exhibit enhanced RGC survival after combined ONC + LI suggesting that the neuroprotective effects of LI on RGC survival may be limited by the WldS protein.
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