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Stuart Graham, Yuyi You, Jonathan Li, Vivek Kumar Gupta; TrkB Receptor Agonists as Neuroprotective Molecules in Glaucoma -Effect of 7,8 Dihydroxyflavone. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4944.
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Tropomyosin related kinase B (TrkB) receptor activation through neurotrophic factors plays an important role in the protection of retinal ganglion cells (RGCs) in glaucoma. We recently reported that TrkB receptor signalling is regulated by Shp2 phosphatase under ocular hypertensive conditions. A novel flavanoid 7,8 Dihydroxyflavone (DHF) is a high-affinity TrkB agonist that provokes receptor dimerization and autophosphorylation and activation of downstream signalling in vivo, here we examine the structural, functional and molecular effects of administration of this compound on the retina, ganglion cell layer (GCL) and optic nerve in experimental glaucoma.
A unilateral chronic ocular hypertensive model was established by weekly microbead injections in adult SD rats (n=16). One group of rats was administered 7,8 DHF intraperitoneally for 20 weeks (n=8). Electroretinogram (ERG) and scotopic threshold response (STR) were performed to assess retinal function. Changes in retinal morphology were evaluated by H & E staining. The optic nerve was examined for atrophic changes. The molecular effects of 7,8 DHF on retinal TrkB receptor and its downstream signalling were assessed ex vivo in retinal organ cultures followed by western blotting.
While ERG was unchanged in both groups, administration of 7,8 DHF prevented selective loss of STR in the ocular hypertensive eyes (p<0.01). No perceptible differences were detected in the scotopic ERG recordings. A structural protection against rarefaction of GCL was also observed by qualitative assessment and optic nerve morphology was conserved. Molecular anlaysis of the rat retinas upon 7,8 DHF treatment revealed a robust activation of the retinal TrkB receptor (p<0.05) and its downstream Akt and Erk survival signalling pathways.
This study demonstrates for the first time that the natural flavanoid 7,8 DHF could stimulate the TrkB receptor signalling in the retina. Administration of this natural flavanoid derivative significantly reduces the RGC structural and functional loss and optic nerve damage elicited by experimental glaucoma.
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