Brain-derived neurotrophic factor promotes retinal ganglion cell survival and reduces tyrosine receptor kinase B protein andmRNA in vivo

Glaucoma is a disease of the visual system that often is characterized by elevated intraocular pressure, compressive damage to optic nerve (ON), and a loss of ganglion cells within the retina. Since direct mechanical damage to the ON also results in a progressive loss of ganglion cells, ON crush is commonly used as a model to evaluate treatment strategies for different retinal disorders. Brain-derived neurotrophic factor (BDNF) has been shown to be one of the most effective neuroprotectants in the rat eye, a fact confirmed by the present studies (94% survival rate in treated eyes).; Since the rodent and primate eyes differ in many respects, a cat optic nerve crush model was developed as an intermediate test of whether BDNF might also serve as an effective neuroprotectant in primate-sized eyes. Here, treatment with 15, 30, 60, and 90μg of BDNF at the time of the ON crush resulted in ganglion cell survival rates of 52%, 81%, 77%, and 70%, respectively. Cell size comparisons showed that 30μg saved a wider range of ganglion cells, while 90μg minimized the loss of medium-sized neurons and retained normal proportions of large, medium, and small ganglion cells.; To test whether Müller cells, the primary glia of the retina, are affected by ON injury or are involved in BDNF-mediated responses, two glia specific proteins were studied. Glia fibrillary acidic protein (GFAP) increased ∼7–9 fold 3 days post ON crush and remained elevated for the 2 week period examined. Glutamine synthetase (GS), an enzyme typically located within Müller cell bodies, showed a temporary shift from the cell soma to the Müller endfeet of the inner retina within 24 hours. The change was not accompanied by an increase in total GS protein. BDNF, however, did not affect GFAP or GS levels, suggesting that Müller cells do not contain BDNF receptors.; The biological effects of BDNF are mediated primarily by its high affinity receptor tyrosine kinase B. Although this receptor is present in both truncated and full length form, it is the full length receptor (TrkB-FL) that is responsible for initiation of the intracellular signaling cascade that underlies the neuroprotective role of BDNF. Interestingly, intravitreal application of BDNF results in a rapid, dramatic, and long lasting reduction in TrkB-FL protein in the normal rat retina; only 4.8% and 31.4% of protein remains at 1 and 14 days post-injection, respectively. Optic nerve crush reduced TrkB-FL protein 14 days post-crush. When BDNF is applied at the time of the ON nerve crush, TrkB-FL protein decreases to levels similar to that seen in animals receiving the BDNF injection alone. These data suggest that the failure to enhance RGC survival in the cat via multiple injections of BDNF most likely resulted from a BDNF-induced reduction in the overall level of full length receptors within those eyes. In all cases, the changes in TrkB-FL protein were accompanied by changes in TrkB-FL mRNA levels as well. The pattern of change in TrkB-FL mRNA followed a bell-shaped curve, with that measured on days 1 and 14 below normal. In summary, these results provide encouraging data indicating that BDNF is a potential neuroprotectant for use in glaucoma patients.