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Peter Koulen, Oloruntoyin A. Mafe, R. Scott Duncan, Simon Kaja; Functional and Structural Protection by N-Acylethanolamines in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3937.
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N-Acylethanolamines (NAEs) are lipids upregulated in response to injury and have neuroprotective function. The well-researched N-Arachidonoylethanolamine, NAE 22:4 or anandamide, is an endogenous ligand at cannabinoid and vanilloid receptors. The function and molecular target of other NAEs that do not bind to these receptors, such as NAE 16:0 and NAE 18:2, are unclear and have thus prompted us to measure their neuroprotective properties in the retina affected by diabetic retinopathy. We hypothesized that such NAEs that do not bind cannabinoid and vanilloid receptors regulate intracellular calcium homeostasis thereby protecting retinal ganglion cells from dysfunction and cell death in diabetic retinopathy.
Type 1 diabetes was chemically induced in C57BL/6 mice by streptozotocin injection and fasting blood glucose levels monitored. NAEs were delivered intravitreally or systemically and visual acuity and contrast sensitivity were measured with visuo-spatial behavior testing of the optokinetic reflex (OptoMotry, CerebralMechanics, Lethbride, Alberta, Canada). Loss of neuronal viability and death of retinal ganglion cells were assessed using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) histochemistry, cell specific immunohistochemistry and fluorescence microscopy.
Streptozotocin-induced hyperglycemia resulted in elevated blood glucose and glycated hemoglobin levels. Visual performance and the number of viable retinal ganglion cells decreased with time in the diabetic animals while NAE administration in diabetic animals significantly reduced the decline in visual function and RGC death. Long-term treated animals had visual performance and RGC numbers indistinguishable from non-diabetic age-matched controls while control treated animals’ visual performance and RGC numbers continued to decline with age.
The highly significant, dose-dependent reduction of diabetes-induced RGC death and of the loss in visual performance by treatment with NAEs reveals a neuroprotective function for NAEs that do not bind to cannabinoid and vanilloid receptors and lack endocannabinoid activity. These results provide a rationale for the use of NAEs as potential therapeutic compounds in diabetic retinopathy.
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