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Stephanie L. Foster, Allia K. Lindsay, Sheree S. Mosley, Cristina Kendall, Micah A. Chrenek, P M. Iuvone, Keqiang Ye, Jeffrey H. Boatright; Systemic Treatment with 7,8,3'-Trihydroxyflavone Activates TrkB Receptors and Protects Photoreceptor Cell Function in Mouse Models of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2585.
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© ARVO (1962-2015); The Authors (2016-present)
The purpose of this study is to test whether the flavonoid derivative 7,8,3’-trihydroxyflavone (THF), an agonist of the brain-derived neurotrophic factor (BDNF) tropomyosin-related kinase B (TrkB) receptor, is protective in models of retinal degeneration.
Systemic THF-treatment was assessed in light-induced retinal degeneration (LIRD) mice, an environmental stress model, and Pde6brd10 (rd10) mice, a model of retinitis pigmentosa. BALB/C mice were injected intraperitoneally with vehicle (PBS) or vehicle containing THF (37.5 mg/kg), dark-adapted overnight, injected once more, and exposed to 3 hours of bright (8,000 lux) or dim (200 lux) light. Visual function was assessed 3 days later by electroretinography (ERG). Immunoblots were performed on protein extracts from retina and hippocampal tissue with antibodies for total and activated (phosphorylated) TrkB as well as total and activated AKT (protein kinase B; PKB), a pathway target of activated TrkB. The rd10 mice were injected daily with THF or vehicle from postnatal (P) day 6 until P24, at which point visual function was assessed by ERG.
LIRD mice were classified by light exposure (dim or bright) and treatment type (vehicle or THF). Bright light exposure significantly suppressed ERG a- and b-wave mean amplitudes in vehicle mice by 70 and 75 percent respectively, compared to dim vehicle. This loss of function was prevented with THF treatment. Mean a-wave amplitudes (in microvolts ± SEM) were: dim vehicle= 320±64; bright vehicle=96±64; bright THF=352±32. Mean b-wave amplitudes were: dim vehicle: 640±64, bright vehicle 160±96; bright THF=672±128 (n=7 per group, P<0.05). Statistical analysis was by ANOVA-SNK for LIRD data and Student's t-test for rd10 data. Immunoblots showed that the ratio of p-TrkB to total TrkB increased over threefold in retina and hippocampal tissue from THF mice, and remained unchanged for vehicle mice. THF-treated rd10 mice (n=4) exhibited significantly greater ERG a-wave mean amplitudes as compared to vehicle-treated mice (n=3, P=0.0497).
Systemic treatment with THF is protective of photoreceptor function in genetic and environmental stress models of retinal degeneration. This is accompanied by TrkB and AKT activation in the retina and brain, suggesting that THF treatment resulted in TrkB activation and in turn activation of the AKT signaling pathway.
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