Neuroprotective strategies for retinal disease

Abstract

Diseases that affect the eye, including photoreceptor degeneration, diabetic retinopathy, and glaucoma, affect 11.8 million people in the US, resulting in vision loss and blindness. Loss of sight affects patient quality of life and puts an economic burden both on individuals and the greater healthcare system. Despite the urgent need for treatments, few effective options currently exist in the clinic. Here, we review research on promising neuroprotective strategies that promote neuronal survival with the potential to protect against vision loss and retinal cell death. Due to the large number of neuroprotective strategies, we restricted our review to approaches that we had direct experience with in the laboratory. We focus on drugs that target survival pathways, including bile acids like UDCA and TUDCA, steroid hormones like progesterone, therapies that target retinal dopamine, and neurotrophic factors. In addition, we review rehabilitative methods that increase endogenous repair mechanisms, including exercise and electrical stimulation therapies. For each approach, we provide background on the neuroprotective strategy, including history of use in other diseases; describe potential mechanisms of action; review the body of research performed in the retina thus far, both in animals and in humans; and discuss considerations when translating each treatment to the clinic and to the retina, including which therapies show the most promise for each retinal disease. Despite the high incidence of retinal diseases and the complexity of mechanisms involved, several promising neuroprotective treatments provide hope to prevent blindness. We discuss attractive candidates here with the goal of furthering retinal research in critical areas to rapidly translate neuroprotective strategies into the clinic.

Keywords: Dopamine; Electrical stimulation; Exercise; Neuroprotection; Retina; TUDCA.

Fig. 1.

Prevalence in the US of the four main types of retinal diseases that lead to severe vision loss and blindness (left) compared to the relative number of publications from a Pubmed Central search related to neuroprotective research for each disease (right). The prevalence numbers were obtained from the NIH website for the year 2010 with the number of people affected provided in the graph (https://nei.nih.gov/eyedata). The Pubmed Central search was performed with the key words “neuroprotection” and the disease name with the number of citations highlighted. M = millions; K = thousands.

Fig. 2.

Functional and structural benefits of TUDCA in rd10 mice at 30 days of age. A) Dark-adapted ERG responses show significantly larger aand b-wave amplitudes in TUDCA-treated mice, indicating preservation of rod and mixed rod-cone retinal pathways. B) Light-adapted ERG b-wave amplitudes are significantly larger in TUDCA treated mice, indicating preservation of isolated cone function. C) Total photoreceptor cell counts at different locations across the retina are significantly preserved in the TUDCA treated mice. Asterisks indicate significance from Holm-Sidak post-hoc comparisons after finding significant interaction effects with two-way repeated ANOVA, *p < 0.05, **p < 0.01, ***p < 0.001 Mean ± SEM. Modified from (Phillips et al., 2008).

Fig. 3.

Relative comparisons for functional and structural improvements in studies using UDCA or TUDCA to treat retinal disease. Functional values are ERG amplitude differences compared to vehicle treated groups. Structural values are retinal neuron counts or layer thickness. LIRD: Light-induced retinal degeneration; Other RD: retinal detachment, Lrat−/− mice and Bardet-Biedl mice; NMDA injection into the eye causes RGC death. Note that the values in Boatright et al. (2006) were collected much earlier after retinal injury than other studies (24 h vs 1 week).

Fig. 4.

A rodent model of retinal degeneration (rd1 mice) treated with oral progesterone showed reductions in gliosis and glutamate and increases in glutathione, leading to delays in photoreceptor cell death and a partial preservation of photoreceptor function (ERG response). Used with permission from (Sanchez-Vallejo et al., 2015).

Fig. 5.

Daily L-DOPA treatments in diabetic rats (A, B) and mice (C, D) provide significant preservation to visual function (A, B) and retinal function (C, D). C and D are from data collected at 5 weeks post STZ. Asterisks indicate post hoc comparisons *p < 0.05, **p < 0.01, ***p < 0.001. The color of the asterisk indicates the treatment groups in which significance was reached. Mean ± SEM. Modified from (Aung et al., 2014).

Fig. 6.

Running wheel treatment in rd10 mice protected against visual function loss (A) and photoreceptor cell death (B: rd10 inactive, C: rd10 active at 44 days of age), including cones (arrowheads) and rods (arrows). Treatment with the TrkB pathway inhibitor, ANA 12, blocked the protective effects of exercise on both visual function (D) and cell death (E) at 41 days of age. Asterisks indicate post hoc comparisons *p < 0.05, **p < 0.01, ***p < 0.001. The color of the asterisk indicates the treatment groups in which significance was reached. Mean ± SEM. Modified from (Hanif et al., 2015).

Fig. 7.

Summary of possible neuroprotective mechanisms of transcorneal electrical stimulation. Electrical stimulation preserves both photoreceptors and RGCs while also benefiting other retinal neurons through the release of neurotrophic factors and increasing other survival factors while decreasing apoptotic signals. PG: primary microglia, MCs: Muller cells, GS: glutamine synthetase. See text for more detail. Used with permission from (Sehic et al., 2016).

Fig. 8.

Stages of retinal disease that reflect when neuroprotective strategies should be started to provide the most benefit. The black line shows the hypothetical progression of retinal disease through adaptive, early and late pathology. During early pathology, retinal disease is detectable and potentially reversible while irreversible damage occurs in late stage pathology. Starting neuroprotective treatments at the first signs of retinal disease would provide the most benefit in preserving vision.