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Welcome to CE on ReachMD. This activity, titled Photobiomodulation: A Non-Invasive Treatment for Ocular Disease and Trauma is provided by Evolve Medical Education.

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Dr. Janis T. Eells:
This is CE on ReachMD. I'm Janis Eells from the University of Wisconsin-Milwaukee. Thanks for joining me. My talk will focus on the mechanism and efficacy of photobiomodulation in ocular disease. Photobiomodulation is a process by which a chain of biochemical reactions is triggered by exposure to light. Light exposure in the far-red to near-infrared range stimulates mitochondrial function and activates protective intracellular pathways. Cytochrome C oxidase is a key enzyme in the mitochondrial respiratory chain and a critical photo acceptor for far-red to near-infrared light. PBM modifies the redox state of cytochrome oxidase, increasing the electrochemical protein gradient, thus increasing mitochondrial membrane potential and ATP synthesis. It photodissociates nitric oxide from its binding site on cytochrome oxidase, enhancing the activity of the enzyme and activating transcription factors. This leads to changes in gene expression, culminating in the upregulation of cytoprotective pathways, immune modulation, mitochondrial biogenesis, and improved cell survival.

Photobiomodulation acts on mitochondria to switch cellular metabolism from glycolysis to oxidative phosphorylation. This metabolic shift has major consequences. The shift in macrophage metabolism from glycolysis to oxidative phosphorylation shifts proinflammatory M1 macrophages to anti-inflammatory M2 macrophages. This change accounts for the pronounced anti-inflammatory effects of photobiomodulations. Shifts in retinal stem cell metabolism from glycolysis to oxidative phosphorylation is followed by stem cell differentiation into tissue repairing cells. Stimulation of mitochondrial biogenesis, which is essential for tissue repair, development, and immune responses also occurs as a cellular consequence, as does the modulation of intracellular calcium metabolism, which plays a role in cell signaling, proliferation, and differentiation. Retinal neurons have high energy requirements and large amounts of ATP are needed to generate membrane potential and power membrane pumps. With aging and disease, there's an increase in mitochondrial dysfunction and oxidative damage and corresponding decrements in antioxidants and repair systems. This results in retinal dysfunction and retinal cell loss, which leads to visual impairment.

Many age-related retinal diseases, including age-related macular degeneration, have been associated with mitochondrial dysfunction. Mitochondria are thus a promising therapeutic target for the treatment of retinal disease. Age-related macular degeneration is a leading cause of age-related blindness, primarily affecting the central retina. It is characterized by the development of drusen in the early stages of the disease, followed by the loss of photoreceptors and retinal pigment epithelium. Choroidal neovascularization develops in later stages of the disease known as wet AMD. Dry or atrophic AMD is the most common form of AMD. Recent studies of human subjects with AMD support the hypothesis that defects in retinal pigment epithelium mitochondria drive AMD pathology. Photobiomodulation has been shown to be retinal protective in experimental models of AMD. In cultured retinal pigment epithelial cells, there's evidence of improved mitochondrial function, increased ATP synthesis, decreased reactive oxygen species production and improved phagocytosis. And then mouse models correspondingly improved mitochondrial function, increased cytochrome oxidase expression, accompanied by increased ATP concentrations, decrease in inflammatory factors, cytokines, decreased oxidative damage, and improved retinal function.

Examples of these studies follow here, this first study is from Glen Jeffery's Lab University College London, showing that photobiomodulation 670 nm photobiomodulation is cytoprotective in the complement factor H knockout mouse decreasing inflammation, increasing cytochrome oxidase, decreasing retinal stress, and modifying macrophage morphology. In our laboratory, we've actually shown that photobiomodulation is retinal protective in another model of AMD, the Nrf2 knockout mouse. And in this animal model, what we saw was an improvement in ERG responses in the animals treated with far-red light. 

So in summary, the key takeaways here are that photobiomodulation by far-red to near-infrared light acts on cytochrome C oxidase, stimulates mitochondrial function, upregulates cytoprotective factors, and improves cell survival. It shifts metabolism from glycolysis to oxidative phosphorylation with profound cellular consequences, including reduced inflammation and increased mitochondrial synthesis or biogenesis, improved tissue repair. It exerts beneficial effects in animal models of retinal injury and disease. And what you will hear following me is that it is actually therapeutically effective in dry AMD in clinical studies. Our time is up. Thank you very much for listening.

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