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Peter Koulen, Kent D. Chapman, Simon Kaja, Stephanie L. Burroughs; Structural and Functional Protection of the Retina by N-Acylethanolamines in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1135.
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Anandamide, N-Arachidonoylethanolamine, as the most extensively studied N-Acylethanolamine (NAE), is an endogenous ligand for cannabinoid and vanilloid receptors. In response to injury, NAEs become upregulated to exert their protective function as lipid signaling molecules. With little knowledge available about the function and physiological targets of many NAEs, such as N-palmitoylethanolamine (NAE 16:0), N-lauroylethanolamine (NAE 12:0) and N-linoleoylethanolamine (NAE 18:2), we measured their protective properties in a surgical model of glaucomatous retinopathy. We hypothesized that NAEs that do not bind cannabinoid and vanilloid receptors regulate intracellular calcium homeostasis thereby protecting retinal ganglion cells (RGCs), optic nerve head astrocytes (ONHAs) and the optic nerve from dysfunction and cell death.
Intraocular pressure was raised unilaterally in one eye of Brown Norway rats by episcleral vein injection of hypertonic saline. NAEs were delivered intravitreally or systemically (intraperitoneally) daily and visual acuity and contrast sensitivity were measured with visuo-spatial behavior testing of the optomotor reflex. Loss of function and viability of RGCs and ONHAs were assessed using TUNEL histochemistry, cell specific immunohistochemistry and live cell imaging of intracellular calcium signaling. The extent of optic nerve damage was determined with quantitative histology.
NAEs 16:0, 12:0 and 18:2, NAEs that do not bind cannabinoid and vanilloid receptors, significantly reduced the loss in synaptic connectivity, loss of axons and cell numbers of RGCs after systemic or intravitreal delivery. At the same time, NAE administration also significantly reduced the decline in visual function as measured by visuo-spatial behavior testing. In both RGCs and ONHAs, NAEs attenuated calcium toxicity after disease onset. Treated animals had visual performance and histological phenotypes indistinguishable from age-matched and contralateral controls while visual performance, RGC and axon counts continued to decline with age in vehicle treated controls.
Treatment with NAEs resulted in a highly significant, dose-dependent reduction of glaucomatous retinopathy-induced RGC death and of the loss in visual performance indicating that NAEs that do not bind to cannabinoid and vanilloid receptors and lack endocannabinoid activity have significant neuroprotective potential. These results provide a rationale for the use of NAEs as potential therapeutic agents in primary open angle glaucoma and potentially other forms of glaucomatous retinopathy.
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