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De-Ann M Pillers, Xingyu Liu, Eshwar Udo, Ulas Cikla, Peter Ferrazzano, Pelin Cengiz, Bikash R Pattnaik; TRKB Receptor Agonist 7,8-DHF Alters Effect of Hypoxic-Ischemic Encephalopathy (HIE) on Mouse ERG. Invest. Ophthalmol. Vis. Sci. 2016;57(12):609.
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Hypoxic-ischemic encephalopathy (HIE) is a birth-related brain injury caused by oxygen and blood flow deprivation that may lead to neurodevelopmental delay in neonates. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that serves as a biomarker for HIE injury. BDNF likely supports neuron survival in brain, and encourages growth of new neurons and synapses via binding to the TRKB receptor. Brain and eye abnormalities are often associated. We have shown by electroretinography (ERG) that there are abnormalities in retinal function in an HIE mouse model. The a-wave is normal but the b-wave amplitude is severely subnormal, resulting in a reduced b/a wave amplitude ratio. We asked whether 7,8-Dihydroxyflavone, a small molecule TRKB receptor agonist which has been shown by our group to provide protection from brain damage in HIE, might similarly improve retinal function as demonstrated by the ERG.
Postnatal day 9 C57/BL6 mice were subjected to Vannucci’s neonatal HIE model by left common carotid artery (LCCA) cauterization and exposure to 10% O2 at 37 C for 50 min. Sham operated mice had skin incision and manipulation of the LCCA without hypoxia. ERGs were done on 6 wk old mice using the HMsERG system (Ocuscience) under Ketamine (90), Xylazine (7.5), and Acepromazine (1.75) mg/kg mixed anesthesia IP. Scotopic ERGs were done at half-log unit intervals from 0.03 to 30 log cd-s/m2 intensity. Amplitudes and implicit times for the a- and b-waves were measured and averaged. Oscillatory Potentials (OP) were extracted by filtering the ERG response at 300 Hz to reflect inner retinal integrity. The Student's t-test was used for statistical analysis and a P value < 0.05 was deemed significant.
A reduced ERG b/a-wave amplitude ratio of 1.4 was found for the eye on the side of the carotid manipulation in the HIE mouse, as compared to the contralateral control eye (2.5). When treated with 7, 8-DHF, the b/a-ratio for the eye on the side of HIE exposure improved to 2.2.
HIE is associated with visual deficits in the mouse with significant changes in the ERG b-wave. The b-wave abnormalities were lessened in mice treated with the TRKB agonist, 7,8-DHF, similar to the neuroprotection that occurs in brain. We propose that ERG analysis may provide insight into HIE retinal effects, and may be a useful tool to monitor attempts to rescue HIE in a non-invasive and longitudinal fashion.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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