TrkB signalling pathway mediates the protective effects of exercise in the diabetic rat retina

• Type of Material: Article
• Authors: Rachael S Allen, Atlanta VA Medical Center; Adam M Hanif, Atlanta VA Medical Center; Marissa A Gogniat, Atlanta VA Medical Center; Brian C Prall, Atlanta VA Medical Center; Raza Haider, Atlanta VA Medical Center; Moe H Aung, Atlanta VA Medical Center; Megan C Prunty, Atlanta VA Medical Center; Lukas M Mees, Atlanta VA Medical Center; Monica M Coulter, Atlanta VA Medical Center; Cara T Motz, Atlanta VA Medical Center; Jeffrey Boatright, Emory University; Machelle Pardue, Emory University
• Language: English
• Date: 2018-05-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
• Final Published Version (URL): http://dx.doi.org/10.1111/ejn.13909
• Title of Journal or Parent Work: European Journal of Neuroscience
• ISSN: 0953-816X
• Volume: 47
• Issue: 10
• Start Page: 1254
• End Page: 1265
• Grant/Funding Information: This work was supported by the National Institutes of Health [grant numbers P30 EY006360, R01 EY014026, and T32 EY007092-27 ]; the Rehabilitation R&D Service of the Department of Veterans Affairs (Merit Award I01RX000951; and Research Career Scientist Award to MTP); Research to Prevent Blindness; and the Abraham J. and Phyllis Katz Foundation.
• Keywords: COGNITIVE FUNCTION; MICROVASCULAR DISEASE; HIPPOCAMPAL NEUROGENESIS; diabetic retinopathy; NEUROTROPHIC FACTOR; DOPAMINERGIC AMACRINE CELLS; AXON REGENERATION; exercise; Science & Technology; PHYSICAL-ACTIVITY; AEROBIC EXERCISE; Neurosciences & Neurology; Neurosciences; diabetes; Life Sciences & Biomedicine; GANGLION-CELLS; neurotrophin-4; TrkB; IMPROVES MEMORY
• Research Categories: Biology, Neuroscience; Health Sciences, Opthamology

Abstract

Diabetic retinopathy is a leading cause of vision loss. Treatment options for early retinopathy are sparse. Exercise protects dying photoreceptors in models of retinal degeneration, thereby preserving vision. We tested the protective effects of exercise on retinal and cognitive deficits in a type 1 diabetes model and determined whether the TrkB pathway mediates this effect. Hyperglycaemia was induced in Long Evans rats via streptozotocin injection (STZ; 100 mg/kg). Following confirmed hyperglycaemia, both control and diabetic rats underwent treadmill exercise for 30 min, 5 days/week at 0 m/min (inactive groups) or 15 m/min (active groups) for 8 weeks. A TrkB receptor antagonist (ANA-12), or vehicle, was injected 2.5 h before exercise training. We measured spatial frequency and contrast sensitivity using optokinetic tracking biweekly post-STZ; retinal function using electroretinography at 4 and 8 weeks; and cognitive function and exploratory behaviour using Y-maze at 8 weeks. Retinal neurotrophin-4 was measured using ELISA. Compared with non-diabetic controls, diabetic rats showed significantly reduced spatial frequency and contrast sensitivity, delayed electroretinogram oscillatory potential and flicker implicit times and reduced cognitive function and exploratory behaviour. Exercise interventions significantly delayed the appearance of all deficits, except for exploratory behaviour. Treatment with ANA-12 significantly reduced this protection, suggesting a TrkB-mediated mechanism. Despite this, no changes in retinal neurotrohin-4 were observed with diabetes or exercise. Exercise protected against early visual and cognitive dysfunction in diabetic rats, suggesting that exercise interventions started after hyperglycaemia diagnosis may be a beneficial treatment. The translational potential is high, given that exercise treatment is non-invasive, patient controlled and inexpensive.