Mechanisms of Action of Red Light Therapy(PBMT)(2)

Red Light Therapy(PBM) might also function by increasing the bioavailability of nitric oxide (NO) by prompting its release from intracellular stores such as heme-containing proteins^[37]–^[38]. Accordingly, absorption measurements from HeLa cells carried out by Karu et al^[30] demonstrated that PBM leads to NO photo-dissociation from cytochrome C oxidase's heme 3A under normoxic conditions. Since NO functions as an inhibitor of the mitochondrial respiration, its dissociation from cytochrome C oxidase would restore mitochondria's oxygen consumption, which in turn should increase energy production and thus boost cellular metabolism. It is also conceivable, as pointed out by Poyton and Ball^[39] in their review, that the dissociated NO could function both as a signal for hypoxia inside the cell and extracellularly where NO diffuses out of the cell and can function as a vasodilator and/or lead to potential additional and still-to-be-discovered downstream effects. However, it is necessary to mention that another study carried out by Tang et al^[35] failed to demonstrate a link to NO as there was no change in the NO concentration in cultured retinal cell lines (RGC5 and 661W) after PBM treatment. Nor was the beneficial effect of PBM in cell culture, under high-glucose stress conditions, diminished by the NO scavenger carboxy-PTIO, indicating an NO-independent mode of action for PBM. Of course, the main caveat to the Karu et al^[30]. and Tang et al^[35] studies is that they did not use the same cell line and experimental conditions.

In addition to the direct effect of PBM on the gene expression and metabolism of photoreceptor cells, it is likely that other cell types in the vicinity contribute to the beneficial outcomes. Namely, research has focused on Müller cells which function as microgia in the retina and offer protection to photoreceptors^[40]–^[43]. Albarracin and Valter^[44] demonstrated that pre-treatment with 670 nm light (prior to damaging light exposure in the rat model of light-induced retinal degeneration) resulted in amelioration of the light damage-induced changes in Müller cells. These included: 1) protection of the structural integrity of Müller cells as visualized by anti-S100β staining; 2) weaker stress response, as demonstrated by weaker staining with vimentin; 3) the absence of gliosis, as shown by the absence of vimentin staining in the subretinal space. The normal metabolic state was maintained, as measured by the preserved expression of glutamine synthetase in Müller cells, which is paramount for the clearing of the excess glutamate released by nearby photoreceptors. On the other hand, Müller cells are known for the production of free radicals and the secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα) and interleukin (IL-1) in degenerating retinas. Also, early inflammatory changes in photoreceptors trigger immune responses that speed up the disease progression and Müller cells play a vital role in this inflammation propagation process. Interestingly, Albarracin and Valter^[44] demonstrated that pre-treatment with 670 nm light in the light-induced model of retinal degeneration curbed the upregulation of TNFα in Müller cells and decreased the subsequent induction of NO synthase that produces the reactive radical NO-a major disruptor of photoreceptor metabolism^[45].

In conclusion, great strides have been made towards understanding the mechanisms underlying PBM's success. Yet, ideas for the involvement of new signal transduction pathways are emerging each year and there are still many remaining pieces of the puzzle to be discovered.

Excerpted from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768515/