The ion channels in the rod cells of the retina make their energy use high in the dark but considerably lower even with moderate background light. The energy expenditure could be much higher for the cones, which continue to respond in bright lighting conditions and make many more synapses on the retinal cells. In most mammals, cones represent only a small fraction of the total number of photoreceptors, making direct measurements of ATP turnover with laboratory techniques problematic. But a few years ago, scientists used recent measurements of mammalian cone light responses and voltage-dependent currents to calculate the cone’s ATP utilization and compare it to that of rods. The increased expenditure of ATP results from ion transport, particularly the removal of Na + entering the light-dependent channels in the outer segment, the channels activated by rest, and the ATP-dependent pumping of the Ca2 + ion entering the voltage-dependent channels at the level terminal synaptic.
Single cones consume nearly double the energy of single rods in the dark, mainly because they make more synapses with second-order retinal cells and therefore have to extrude more Ca2 +. In daylight, cone ATP utilization per cell remains high because the cones never stay saturated and must continue to export synaptic Na + and Ca2 + even in bright lighting conditions. In the mouse and human retina, the rods far outweigh the cones and consume more energy in general even in background light conditions. Because rods outnumber cones in most mammals, the total ATP consumption of rods still exceeds that of cones. In the primate retina, however, the high density of cones in the fovea produces a large increase in the use of energy in the center of the retina. Several recent publications have implicated glucose transport or availability in cone degeneration, and it is possible that this high ATP requirement of the cone plays a role in the progression of cone loss.
It almost seems a contradiction if we consider that diabetic retinopathy is given precisely by an excess of glucose in the blood, which triggers inappropriate reactions that will become complications such as cataracts, retinopathy, retinal detachment and blindness. However, in the case of diabetic retinopathy the problem is not the transport of glucose, but the opposite, i.e. an excess of consumption by oxidative and non-oxidative pathways. Apart from the attack of proteins, in fact, glucose takes alternative metabolic pathways that are harmful to the cells. The degeneration of photoreceptors and retinal pigment epithelium, however, is the underlying cause of several progressive retinopathies, excluding diabetes. Many of these conditions have only minimally effective treatment options or none at all. Prevention in this sense has shown that a good intake of foods rich in carotene, lutein, vitamin C, zinc and omega-3 fatty acids, can help delay the onset of retinal diseases, the most common of which is degeneration. macular senile.
This implies that oxidative stress is a cellular component that contributes to cell loss in the retina from external insults or actual degenerative diseases. Aside from prevention, food or with supplements, therefore, new therapeutic approaches are urgently needed to combat these disorders and reduce vision loss in clinical practice. Researchers at the University of California, Irvine, have now discovered that the absence of the adiponectin receptor 1 (AdipoR1), one of the main proteins that regulate ceramide homeostasis in the retina, leads to an accumulation of ceramides in the tissue. resulting in the progressive death of photoreceptors and eventually loss of vision. Ceramide derives from the sphingolipids that form the cell membrane, are essential for the stability of the eukaryotic cell membrane and act as powerful signal molecules in inflammation, cell cycle arrest, cell death and in the response to thermal and oxidative shock. .
Ceramide imbalance has also been found in cancer, Alzheimer’s disease, type 2 diabetes, multiple sclerosis, cardiovascular disease and fatty liver disease. The results of the study show that ceramide imbalance damages the neural retina and retinal pigment epithelium, accompanied by a significant reduction in electroretinogram (ERG) amplitudes, decreased vitamin A and retinol content, reduced expression of the opsin of the cone and massive inflammatory response. An accumulation of ceramides in the retina, probably due to insufficient activity of the ceramidase enzyme, led to the death of the photoreceptors. The team also found that a combination of desipramine and L-cycloserine reduced ceramide levels, helped preserve retinal structure and function, and improved vision. Desipramine, an old antidepressant, is also an inhibitor of acid sphingomyelinase, an enzyme that degrades the sphingolipids inside the cell and produces ceramide.
Cycloserine, on the other hand, is an old antituberculosis that blocks the synthesis of ceramide from its precursors in animal cells. When the mice were treated with the L-cycloserine + desipramine combination, the ceramide levels were lowered, which helped preserve the retinal cells. Mice treated with L-cycloserine had better vision in daylight. Their prolonged treatment significantly improved the electrical responses of the primary visual cortex to visual stimuli. The researchers’ intention to primarily target the AdipoR1 receptor was not accidental: although this protein is found in multiple organs, the highest levels are found in the eyes and brain, suggesting its critical importance in these neural tissues. The research results highlight the central role of AdipoR1 and some of its downstream molecules, ceramides, in the retina and show that pharmacologically blocking the generation of ceramide can provide a therapeutic strategy for patients with retinitis pigmentosa or related retinopathies, such as diabetic retinopathy.
In the latter, in fact, the oxidative stress that causes the complications triggers the production of ceramide as a response to the insult, and has a similar effect of lethality on the photosensitive cells of the retina. Non-invasive drug treatment is certainly easier in humans than gene therapy, which requires many years of pre-clinical and clinical trials. The use of drugs already known and used for a long time in clinical practice, on the other hand, significantly shortens the time and expands the arsenal of possibilities against retinal diseases which, as anticipated above, is in practice void of effective options.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.
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Dott. Gianfrancesco Cormaci
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