Effects of Blue Light on the Retina and Innovative Ways for Protection (a Review)

    Functional anatomy of retina and photoreceptors

    The mammalian retina is generally an inversed retina. That means the photoreceptors are looking outward into the direction of the choroid. This is, however, unfavorable for an optimal resolution of the depicted image. On the other hand, the direct contact with the very well perfused choroid is a guarantee for a good oxygenation of the maximally consuming photoreceptor discs harboring the light transduction chain (see below). A new finding is that the Muller glia cells act like light guides leading the light more precisely from the inner retina to the photoreceptor outer segments. Furthermore in higher mammalian and some birds the inner retina is shifted away in a zone called fovea forming physiologically a spot of optimal sight.

    The photoreceptors in the human retina are specialized nerve cells possessing two completely different cell compartments: The inner (neural) part (ellipsoid, perikaryon and axon with the synapses) and the outer part (outer segment). Within the outer segments, membrane discs harbor the visual pigments. During photo-transduction radicals are formed: radicals originating in the rhodopsin cycle transform all-trans-retinal into di-retinoid-pyridinium-ethanolamine (A2E). This metabolite then accumulates as most dangerous component of lipofuscin in the retinal pigment epithelium (RPE) and blocks cytochrome c oxidase in the mitochondria [1]. Thus, the radical product A2E itself is blocking the respiratory chain and leads to new ROS.

    This renders the outer segment discs susceptible for ROS damage [2], partly circumvented by a regeneration of the outer segments by steady renewal and shedding of discs. About 10 of the average 700 discs in the outer segments are shed per day. Then, they are phagocytised by the RPE, which also can by a victim of the oxidized byproducts.

    The high pO2 coming from the choroid in the direction of the retina decreases almost linearly to the inner portion of the photoreceptors [3], because the photoreceptors are indeed, those cells with the highest oxygen consumption of all cells within the human body [4]. Moreover, mitochondria are especially susceptible to oxidative stress [5] as they harbor enzymes of the respiratory chain, which handle electrons. Here, electrons normally can deviate, however under situations of mitochondrial stress this radical producing electron deviation is much higher [5].

    We recently found together with an Italian group that enzymes of the respiratory chain are located directly within the membranes of the photoreceptor outer segments [6, 7]. In isolated outer segments, we could show that a proton potential difference exists across the disc membranes - formed as double membranes like the double membranes of the mitochondria. This fact contributes to the high oxygen demand, too.

    Effect of blue light on retinal cells

    The effect of short wavelength light on the metabolism of the mitochondria has been an important topic of experimental in in vitro and in vivo studies. Indeed, these studies could show that blue light impact leads to an enhanced production of radicals in mitochondria [8]. Enzymes of the respiratory chain like flavins and cytochrome oxidases can absorb at wavelengths of 440 – 450 nm and they can cause the production of ROS and oxidative stress [9]. Thus, after blue light exposure, more ROS are produced by mitochondria, resulting in further damage. Furthermore, the high content of polyunsaturated fatty acids renders the outer segment discs susceptible for ROS [10]. Thus, the first signs of the most devastating neurodegenerative retinal disease – the age related macular disease (AMD) - can be explained.

    In our recent studies we found after irradiation with blue light an increased ROS production not only in the mitochondria of the inner segment (IS) but also within the outer segments (OS). This was done by fluorescence microscopy in living mouse retinae. A quantitative analysis of the fluorescence measurements shows a peak of ROS production after 0.5 hours and a decrease (probably by exhaustion) after 1 hour [11, 12]. The further sequence of events was like this: after 3 hours we found a disorganization of the photoreceptor aligning. Later, after 6 hours breaks within the shape and within the outer segment discs appeared, depicted by transmission and scanning electron microscopy. After 12 hours we noted biochemically a compensatory up-regulation of anti-oxidative enzymes and a further cell fate decision into the direction of damaged cells or cell death (apoptosis) [11].

    Red light in therapy

    Quite opposite to the action of blue light, red or infrared light can have positive (protective) effects to different tissues and organs – a fact which is described in an increasing amount of recent studies [13, 14].

    Several authors have also shown positive effects of red or infrared light for regeneration processes in the retina []. Here also, the mitochondrion and the respiratory chain within the mitochondria seem to play a major role [18]. As one causal explanation, recent studies reveal that red and NIR light is absorbed by heme structures and copper centers of the cytochrome c oxidase. Here, absorption maxima exist in the range of 760 – 900 nm with peaks at 767, 791 and 880 nm [14]. A dimeric copper complex with four ligands is absorbing in the 810 – 820 nm range. Copper atoms in the redox active centers in the Cco show absorption peaks at 620, 680, 760 and 820 nm and have a maximum of biological activity at an adsorption wavelength of 670 and 830 nm with a nadir in both spectra of around 728 nm [14]. In preliminary studies of red or infrared irradiation of blue light treated retina, we found a recovery of retinal cells via reduced production of superoxides, reduced production of free radicals and a positive effect on electron transport chain activity.

    In the light of the newly found analogy between photoreceptors and mitochondria it is possible that the positive protective effects found by Tang et al. [20]; Begum et al. [17] and Albarracin et al. [16] are also due to amelioration of the metabolic situation within the outer segment and not only by an enhancement of the respiratory chain in photoreceptor mitochondria – a fact, which we could corroborate in our preliminary studies.

    Electric fields as therapy?

    Within the last two decades, elaborated studies could show that electrical and ion gradient phenomena are intrinsic to biological systems. Electric field (EF) gradients (“bioelectricity”) are not only created by small ions but are also driven by larger biomolecules. The nature of these fields comes principally from membrane potentials producing endogenous electric fields and here from the segregation of charges by molecular machines like pumps, transporters and ion channels mostly situated within the plasma membrane [21-24]. Charge driven EFs trigger pathways such as cell signaling, tissue factors, growth hormones, transmitters etc. Since about twenty years from now, new methods like membrane potential– and ion– sensitive in vivo dyes as well as constructs for imaging and molecular tracing are available, allowing a direct observation of the mentioned processes in cells, tissues and living systems.

    In living organisms, EFs are generated endogenously mostly as direct current fields (DC) or ultra-low frequency (ULF)-EMF [23]. The situations, where we find EFs in an organism are those where a fast change in morphology happens. These are processes where tissues develop or where fast changing or tissue remodeling is needed: in embryology, in wound healing and in regeneration. The organism uses this way because EF can spread very fast. Ions and EFs are further transferred by gap junctions from cell to cell and by conducting biological structures [21]. Here, a pre – formative capacity of this EF patterning bears the major component of early information and coordination. Today, many comprehensive reviews allow to go deeper into the topics and details of endogenous EFs [21, 23, 24–28]. We have nowadays a proven background that cells and tissues intrinsically produce EFs. Thus, treatment with EF makes again more sense. Furthermore, with therapeutic approaches we can couple more deliberately into these endogenous EFs.

    Indeed, Yang et al. [29] could show a neuroprotective action of EMF on injured brains in rats. Transcorneal electrical stimulation in rats rescued axotomized retinal ganglion cells [30] and delayed photoreceptor degeneration in light exposed adult Sprague Dawley rats [31]. In patients with traumatic optic neuropathy, improved visual function in was found [32]. Many factors may be responsible for these phenomena like upregulation of growth factors or anti-apoptotic mechanisms; however, the real cascade of events at molecular level still remains unclear.

    In a recent preliminary study our group could find in a photoreceptor cell line that static (DC) EF had a neuroprotective effect, indeed. Blue light damaged cells hat an improved membrane potential, enhanced ATP synthesis and enhanced expression of chaperones – all observations, which point to enhanced neuroprotective actions. So, the positive effects of EF on patient have some explanation.

    Conclusion. In this short review have taken together three points, which emerged in the last decades: blue light damage and the possible rescue by red light and electric stimulation. Whereas the impact of blue light on the retina and the needs for prevention of unnecessary exposition are now fully accepted, the other two physical rescue or at least partly protecting mechanisms are still under debate. Hopefully the outlines of this article could help for the understanding of the action mechanisms of these latter two biophysical approaches.