Brain-derived neurotrophic factor reduces TrkB protein and mRNA in the normal retina and following optic nerve crush in adult rats.
Brain-derived neurotrophic factor (BDNF) is a well-known retinal neuroprotectant, but its effectiveness is limited: higher doses do not yield increased cell survival, multiple applications are not additive, and long-term delivery does not reverse, ganglion cell death. These limitations might reflect either injury- or BDNF-induced retinal changes in TrkB, the high affinity tyrosine kinase receptor used by BDNF. Retinal levels of TrkB protein and mRNA were measured in rats following intravitreal application of BDNF alone, optic nerve crush alone, and both. Full-length receptor protein levels (TrkB.FL) were determined by Western blot analysis and mRNA (trkB.FL) levels were measured using RNAse protection assay (RPA). BDNF alone produced a rapid and prolonged decrease in normal retina TrkB.FL. Nerve crush also resulted in decreased TrkB.FL, but the reduction was not apparent before 2-week post-crush. BDNF applied at the time of the crush yielded reductions in TrkB.FL similar to that of BDNF alone. With respect to TrkB mRNA levels, injection of BDNF into normal eyes and optic nerve crush alone showed bell-shaped patterns of change: approximately 50% below normal at 24-h post-procedure, approximately 50% above normal at 3 days, normal at 7 days, and approximately 50% below normal at 2-week post-procedure. When BDNF and nerve crush were combined, trkB-FL levels reached 90% of normal 1-week post-crush/injection. The data suggest that the limitation of BDNF in promoting ganglion cell survival following optic nerve injury results, in part, due to drug-induced down-regulation of the full-length TrkB receptor needed to activate intracellular pathways.
Chen
Hao
H
Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Ave., Memphis, TN 38163, USA. hchen@utmem.edu
Weber
Arthur J
AJ
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D006801:Humans; D009409:Nerve Crush / Q000379:methods; D020221:Optic Nerve Injuries / Q000378:metabolism*; D051381:Rats; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB