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Yujing Bai, Jing Xu, Fouad Brahimi, Yehong Zhuo, Marinko V. Sarunic, H. Uri Saragovi; An Agonistic TrkB mAb Causes Sustained TrkB Activation, Delays RGC Death, and Protects the Retinal Structure in Optic Nerve Axotomy and in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2010;51(9):4722-4731. doi: 10.1167/iovs.09-5032.
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Brain-derived neurotrophic factor (BDNF) receptors TrkB and p75NTR are expressed in the retina. However, exogenous BDNF does not provide retinal ganglion cells (RGCs) with long-lasting neuroprotection in vivo during optic nerve axotomy or in glaucoma rat models of neurodegeneration. The authors set out to answer the hypothesis that a selective TrkB agonist might afford more efficient neuroprotection.
Animal models of acute neurodegeneration (complete optic nerve axotomy) and chronic neurodegeneration (ocular hypertension, glaucoma) were used. After intravitreal delivery of test agents or controls, surviving RGCs were quantified. Transient or sustained activation of TrkB receptors in vivo was quantified by Western blot analysis retinal samples for TrkB-phosphotyrosine. Time-dependent changes to the neuronal retinal layers were quantified longitudinally by Fourier domain–optical coherence tomography.
The authors show that a selective TrkB agonist caused long-lived TrkB activation and significantly delayed RGC death in these models of acute and chronic retinal injury in vivo. Importantly, using noninvasive retinal imaging, they also show that a selective TrkB agonist caused preservation of the retinal structure in both animal models, with maintenance of the layers comprising neurons and neuronal fibers.
In animal models of acute and chronic neurodegeneration, a TrkB agonist affords long-lasting neuroprotection by causing sustained TrkB activation. The use of structural end points could have prognostic value to evaluate neuroprotection. This work contributes to the understanding of neurotrophic mechanisms underlying RGC death in glaucoma and optic nerve axotomy.
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