Trans-scleral electrical stimulation effects in acute ocular hypertension animal models

Abstract

Glaucoma is the major cause of irreversible blindness in the world. Elevated intraocular pressure (IOP) caused by a perturbation in aqueous humor dynamics is known to be a leading risk factor for vision loss in glaucoma patients. However, even under proactive medical or surgical treatments to reduce the IOP, a significant number of glaucoma patients under management still progress to irreversible blindness. In the recent decade, low-intensity electrical stimulation (ES) was proven to be an auspicious therapeutic modality against various retinal diseases, such as retinitis pigmentosa and age-related macular degeneration. The most widely used method to conduct the ES is using trans-corneal ES (TcES) in animal study and human trials. To achieve the best neuroprotective results, multiple TcES treatment was recommended. While the retina might be preserved, the cornea will be damaged by frequent TcES treatment. Hence, there is a pressing need for cornea-free ES application.

A set of novel method called trans-scleral ES (TsES) was developed to deliver the electric to the eye without touching the cornea. To find ways to studying how to safeguard retinal neurons suffering from IOP elevation, acute ocular hypertension (AOH) was conducted in mouse and rabbit eyes with the elevated hydrostatic saline bag. Different treatment parameters were tested to identify the best protective effect in mouse and rabbit AOH model. The modulatory effects of TsES on retinal cellular and metabolic responses were evaluated.

Investigations on TsES treatment parameters have revealed that the best electrical power for the AOH mouse model is 350µA. When applied immediately, a single session of 30-minute TsES with the effective dose after AOH injury could significantly preserve the retinal ganglion cells (RGCs) survival and retinal function against AOH insult at one week after injury. More explorations on different TsES treatment plans have confirmed that TsES is also protective when applied within 12 hours after AOH injury, and its neuroprotection could be enhanced with double session treatment.

Further investigations revealed that TsES might play its neuroprotective role through modulation on the calpains activities, inhibition on the expression of pro-apoptosis regulators, enhancement on the retinal resistance against oxidative stress, and suppression on inflammatory responses. Moreover, the metabolomics study indicated that TsES stabilized the retinal metabolism against the perturbations induced by AOH. Critical metabolic metabolisms were modulated by TsES toward a pro-survival and anti-inflammation state, including glycolysis, citric acid cycle, and Glycine-serine-threonine metabolism, etc. Furthermore, the neuronal protection effect of TsES on AOH mouse model was successfully translated to rabbit eye under AOH challenge, which stands strong support in promoting the study of TsES in the clinic.

Taken together, my study represented a novel cornea-free application method of ES treatment and proved its neuroprotective efficacy in AOH injured retinas with both mouse and rabbit models. The results elucidated the great potential of TsES as a non-invasive therapeutic strategy for retinal degeneration. (468 words).