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Shiama Indu Balendra, Ehtesham Shamsher, M Francesca Cordeiro; Trehalose is neuroprotective in in vitro models of glaucoma. Invest. Ophthalmol. Vis. Sci. 2020;61(7):640.
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Glaucoma is a multifactorial neurodegenerative disease; however current treatment consists of only intraocular pressure lowering agents. Neuroprotectants have the potential to fill the gap in treatment of normotensive glaucoma. Trehalose is a naturally occurring bioprotective disaccharide in non-mammalian species, allowing survival in unfavourable environments. It acts as a signalling molecule by activating autophagy and reducing cell death associated with apoptosis and inflammation. It is currently used clinically in ocular surface disease and is shown in vivo to be neuroprotective in neurodegenerative disease including Parkinson’s Disease, Huntington’s Disease and Amyotrophic Lateral Sclerosis. We hypothesised that trehalose could be solubilised into a solution to demonstrate a neuroprotective effect in vitro in glaucoma models.
Trehalose solution was formed by dissolving trehalose in phosphate buffer solution. Toxicity of trehalose was assessed by investigating the cell viability of increasing concentrations of trehalose co-incubated with retinal cells. Cultured retinal cells were treated with toxic insults of cobalt chloride, glutamate, paraquat and homocysteine. They were then co-incubated with either 70 mM trehalose solution or culture media only for 24 hours. Assessment of trehalose-mediated neuroprotection in vitro was achieved using an alamarBlue cell-viability assay.
Toxicity studies demonstrated that trehalose was not toxic to retinal cells up to its maximal solubility of 50 mg/mL (146 mM). 70mM trehalose was significantly neuroprotective in vitro in insults of cobalt chloride; IC50 trehalose 520.9μM vs vehicle 390.24μM (p<0.05); and in glutamate; IC50 trehalose 4.761mM vs vehicle 3.231mM (p<0.01). There was no significant neuroprotective effect in paraquat and homocysteine insults.
This work demonstrates that trehalose is safe at high concentrations and is neuroprotective in vitro. Its efficacy in cobalt chloride and glutamate insults suggests a mechanism of action of trehalose which interferes with HIF-1α and calcium excitotoxicity pathways. Ongoing in vivo work in glaucoma animal models is further investigating its potential for clinical translation to glaucoma clinics. This novel work could be beneficial not only as an adjunctive therapy in glaucoma but also in other neurodegenerative disorders. We thank Théa Pharmaceuticals for their support with this work.
This is a 2020 ARVO Annual Meeting abstract.
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