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Editors Selection IGR 8-4
Basic Research: Effect CNTF on RGC survival
Comment by Leonard A. Levin on:
23941 Effect of CNTF on retinal ganglion cell survival in experimental glaucoma, Pease ME; Zack DJ; Berlinicke C et al., Investigative Ophthalmology and Visual Science, 2009; 50: 2194-2200
One of the major theories explaining retinal ganglion cell (RGC) death in glaucoma is the failure of target-derived neurotrophic factors such as brainderived neurotrophic factor (BDNF) to reach the cell body because elevated intraocular pressure reduces retrograde axonal transport. In development of the nervous system, the deprivation of target-derived neurotrophic factors is an important signal for apoptosis of half of the RGCs that initially overpopulate the retina, but are then culled. A parallel mechanism in the adult nervous system explains many observations relating neurotrophin absence and cell death. A natural consequence of the neurotrophin theory is that replacement of neurotrophin by exogenous delivery should (and shown to) rescue RGCs in a variety of axonal injury models.
Neuroprotective effects in animal studies may depend heavily on dose of neuroprotectant, and possibly route or mechanism of deliveryThis paper by Pease et al. (605) showed that the neurotrophin ciliary neurotrophic factor (CNTF), transduced via adeno-associated virus, is neuroprotective in a rat laser model of experimental glaucoma, consistent with what has been found in other models of axonal injury. What makes this work particularly instructive is that the investigators also found that another neurotrophic factor, BDNF, was not neuroprotective, despite several other studies in the literature to the contrary. Through some excellent detective work, they demonstrated that the levels of transduced BDNF were probably too low, using in vitro studies of RGC outgrowth. Another interesting finding was that the BDNF or its delivery seemed to interfere with the neuroprotective action of CNTF. The mechanism for this is unclear.
Overall, one critical conclusion that can be drawn from this wellperformed study is that neuroprotective effects in animal studies may depend heavily on dose of neuroprotectant, and possibly on route or mechanism of delivery. If this is the case, we can presume that the translation from animal to human studies may be governed by similar issues, and have the same potential for proving efficacy.
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