Abstract
High intraocular pressure (IOP)-induced retinal ischemia leads to acute glaucoma, which is one of the leading causes of irreversible visual-field loss, characterized by loss of retinal ganglion cells (RGCs) and axonal injury in optic nerves (ONs). Oxidative stress and the inflammatory response play an important role in the ischemic injury of retinal and optic nerves. We focus on 5α-androst-3β, 5α, 6β-triol (TRIOL), a synthetic neuroactive derivative of natural marine steroids 24-methylene-cholest-3β, 5α, 6β, 19-tetrol and cholestane-3β, 5α, 6β-triol, which are two neuroactive polyhydroxysterols isolated from the soft coral Nephthea brassica and the gorgonian Menella kanisa, respectively. We previously demonstrated that TRIOL was a neuroprotective steroid with anti-inflammatory and antioxidative activities. However, the potential role of TRIOL on acute glaucoma and its underlying mechanisms remains unclear. Here, we report TRIOL as a promising neuroprotectant that can protect RGCs and their axons/dendrites from ischemic–reperfusion (I/R) injury in an acute intraocular hypertension (AIH) model. Intravitreal injection of TRIOL significantly alleviated the loss of RGCs and the damage of axons and dendrites in rats and mice with acute glaucoma. As NF-E2-related factor 2 (Nrf2) is one of the most critical regulators in oxidative and inflammatory injury, we further evaluated the effect of TRIOL on Nrf2 knockout mice, and the neuroprotective role of TRIOL on retinal ischemia was not observed in Nrf2 knockout mice, indicating that activation of Nrf2 is responsible for the neuroprotection of TRIOL. Further experiments demonstrated that TRIOL can activate and upregulate Nrf2, along with its downstream hemeoxygenase-1 (HO-1), by negative regulation of Kelch-like ECH (Enoyl-CoA Hydratase) associated Protein-1 (Keap1). In conclusion, our study shed new light on the neuroprotective therapy of retinal ischemia and proposed a promising marine drug candidate, TRIOL, for the therapeutics of acute glaucoma.
Highlights
Retinal ischemia has been well-recognized as a key pathological factor for various eye diseases, including acute glaucoma [1], diabetic retinopathy [2], and retinal arterial occlusion [3]
Ischemia–reperfusion (I/R) injuries of the retina in glaucoma are mainly caused by the rapid elevation and reduction of intraocular pressure (IOP), followed by apoptosis of retinal ganglion cells (RGCs), axonal damage, and subsequent vision loss
Compared with regular and dense Tuj1-labelled axons and dendrites in the control group, we found that acute intraocular hypertension (AIH) treatment induced a significant decrease and breaking of RGC axons and dendrites, while TRIOL dose-dependently attenuated the injury and kept the integrity of the axon networks
Summary
Retinal ischemia has been well-recognized as a key pathological factor for various eye diseases, including acute glaucoma [1], diabetic retinopathy [2], and retinal arterial occlusion [3]. Acute glaucoma is the most common and hazardous eye disorder, especially in East Asian ethnicities [1]. Strategies of reducing IOP, such as filtering surgery and hypotensive agents, are widely used in clinical practice, it was reported in the Early Manifest Glaucoma Trial that some patients with open-angle glaucoma cannot benefit from IOP-lowering therapy with no significant changes of the visual field [4,5]. The application of IOP-lowering agents, such as prostaglandin analogs and miotics, have been reported with various local or systematic side effects [6,7]. The development of alternative strategies, such as neuroprotection-targeting oxidative and inflammatory responses, could support and supplement
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