Noninvasive electrical stimulation as a neuroprotective strategy in retinal diseases: a systematic review of preclinical studies

Abstract

Background: Electrical activity has a crucial impact on the development and survival of neurons. Numerous recent studies have shown that noninvasive electrical stimulation (NES) has neuroprotective action in various retinal disorders.

Objective: To systematically review the literature on in vivo studies and provide a comprehensive summary of the neuroprotective action and the mechanisms of NES on retinal disorders.

Methods: Based on the PRISMA guideline, a systematic review was conducted in PubMed, Web of Science, Embase, Scopus and Cochrane Library to collect all relevant in vivo studies on "the role of NES on retinal diseases" published up until September 2023. Possible biases were identified with the adopted SYRCLE's tool.

Results: Of the 791 initially gathered studies, 21 articles met inclusion/exclusion criteria for full-text review. The results revealed the neuroprotective effect of NES (involved whole-eye, transcorneal, transscleral, transpalpebral, transorbital electrical stimulation) on different retinal diseases, including retinitis pigmentosa, retinal degeneration, high-intraocular pressure injury, traumatic optic neuropathy, nonarteritic ischemic optic neuropathy. NES could effectively delay degeneration and apoptosis of retinal neurons, preserve retinal structure and visual function with high security, and its mechanism of action might be related to promoting the secretion of neurotrophins and growth factors, decreasing inflammation, inhibiting apoptosis. The quality scores of included studies ranged from 5 to 8 points (a total of 10 points), according to SYRCLE's risk of bias tool.

Conclusion: This systematic review indicated that NES exerts neuroprotective effects on retinal disease models mainly through its neurotrophic, anti-inflammatory, and anti-apoptotic capabilities. To assess the efficacy of NES in a therapeutic setting, however, well-designed clinical trials are required in the future.

Keywords: Neuroprotection; Noninvasive electrical stimulation (NES); Retina; Transcorneal electrical stimulation (TES); Transorbital electrical stimulation; Transpalpebral electrical stimulation (TpES); Transscleral electrical stimulation (TsES); Whole-eye electrical stimulation (WES).

Fig. 1

Flow chart of the results according to the search strategies

Fig. 2

Main categories of noninvasive electrical stimulation (NES) and possible neuroprotective mechanisms underlying the effects. The cellular structure in the figure represents an enlarged image of the retina. Gray cells represent damaged cells in retinal diseases. It has been discovered that NES protects the structure and function of retinal ganglion cells and photoreceptors and has a positive effect on other cell components, including Müller cells, and microglia. The neuroprotective effect of NES involved a variety of mechanisms, including neuro-nutrition (No. ①, green), alleviation of inflammation (No. ②, blue), and inhibition of apoptosis (No. ③, pink). The red upward arrow represents upregulation, while the blue downward arrow represents downregulation. CNTF ciliary neurotrophic factor, BDNF brain-derived neurotrophic factor, bFGF basic fibroblast growth factor, FGF-2 fibroblast growth factor 2, IGF-1 insulin-like growth factor 1, GS glutamine synthetase, p-TrkB phosphorylated tyrosine kinase receptor B, p-NFκB-p65 phosphorylated nuclear factor-κB-p65, TNF-α tumor necrosis factor-α, IL-6 interleukin 6, COX-2 cyclooxygenase-2, IL-10 interleukin 10, Bcl-2 B-cell lymphoma-2, Bax BCL-2-associated X protein