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HYPOTHESIS
The anatomic-pathological situation can be dealt by the application of ozonetherapy. We have studied this problem for over two decades and we have clarified the biochemical, molecular and pharmacologic events [7-10]. It is interesting to know that ozone is ten-fold more soluble in the water of plasma than oxygen: this fact implies that mixing human blood with an equivalent volume of a gas mixture composed of about 96% O2 and 4% O3 leads to a very rapid solubilization of ozone, which, owing to its reactivity, reacts with hydrosoluble antioxidants (ascorbic acid, uric acid, trace of reduced glutathione) and with the unsaturated lipids carried out by albumin as follows:
R-CH = HC-R + O3 + H2O → H2O2 + 2 R-CHO
This means that in 2-3 minutes all the ozone has completely reacted and generated its messengers such as hydrogen peroxide and aldehydes derived from the unsaturated fatty acids peroxidation. The formation of aldehydes leads to the final formation of alkenals such as trans-4-hydroxy-2-nonenal (4-HNE from n-6) and a small quantity of trans-4-hydroxy-2-hexenal (from n-3) [11]. Consequently ozone acts simply as a pro-drug and generates these two messengers. The unionized hydrogen peroxide immediately enters into the mass of erythrocytes and activates glycolysis with ATP increase and, most important, enhances the production of 2,3 di-phospho-glygerate (2,3-DPG), which is able to shift to the right the oxyhemoglobin dissociation curve, thus increasing the release of oxygen in the ischemic areas such as the macula lutea and the foveola [12].
Although the alkenals are intrinsically toxic, owing to the minimal ozone concentration, are produced in the range of a few micromoles and undergo to either dilution, degradation by specific enzymes, elimination via the bile and urine but, most important, submicromolar quantities form adducts with either the Cys34 of albumin or the-SH group of reduced GSH [9]. This step represents for the patient, who has been infused with his or her own ozonated blood, a calculated and well tolerated oxidative stress because the albumin adducts transport and deliver the alkenals to cells of many organs [13-15]. Alkenals, inside the cell, binds to two-SH-groups (Cys272 and Cys288) of a large protein denominated Keap-1. Normally Keap-1 is bound to Nrf2 and, as many other transcription factors, is floating freely in the cell cytoplasm. This complex has a half-life of about 20 min because is continuously digested by the proteasome. However, when the two SH groups of the Keap1 have bound two molecules of 4-HNE, the protein Nrf2 is released and translocates into the cell nucleus where, after making an heterodimer with a small Maf protein, binds to the antioxidant response elements (ARE). This is the crucial event able to stimulate the upregulation of about 200 genes responsible for the transcription of a great number of antioxidant proteins (SOD, catalase, GSH-Px, GSH-Tr, etc) phase II enzymes and heme-oxygenase-1[16-18], which is a very protective enzyme. With the progress of ozonetherapy, these enzymes will be able to reverse the chronic oxidative stress induced by the chronic inflammation. At the same time, the enhanced oxygen release and possibly of lutein helps to stop the progress of ARMD. So far, millions of ozonated autohemotherapy, performed with small and precise ozone dosages, have never caused any side effects. In fact, most patients report a feeling of wellness which is likely due to a transitory increase of cortisol [17]. Lastly, ozonetherapy has also a minimal cost.
For the dry ARMD there are no useful therapies with the exception of the controversial oral administration of antioxidants such as vitamin A, C and E [5] with the addition of lutein and zeaxantin [19]. These compounds are certainly not harmful but at the best they may only delay the progression of the diseases after an average treatment period of at least six years, difficult to comply.