EFFECT OF OZONE THERAPY IN NEURODEGENERATIVE DISEASES
On the basis of the oxidant properties of ozone, we postulate that controlled ozone administration is able to promote a slight and transient oxidative stress which in turn re-establishes the signalling pathways which have been lost in pathological conditions, preserving the cellular redox balance (increasing antioxidant endogenous system), mitochondrial function, as well as the regulation of transcription factors and the modulation of the immunological system. Ozone therapy can activate nuclear factor-erythroid 2-related factor (Nrf2) via moderate oxidative stress, upregulating the synthesis of antioxidant enzymes. Activation of Nrf2 results in protection against neurodegenerative diseases, such as Alzheimer's dementia, Parkinson's disease, Multiple Sclerosis (neurodegenerative process that sparks an inflammatory response in which axonal loss is the major cause of irreversible neurological disability), among others. Also, levels of nitric oxide, myeloperoxidase (MPO), intracellular calcium and pro-inflammatory cytokines, like tumor necrosis factor α and interleukin 1 and 6, were able to be modulated by ozone. Nitric oxide modulation, as well as the increase in A1 adenosine receptors (A1AR) achieved with this therapy has an important role in brain blood flux, in the formation of memory, in the release of neurotransmitters, in regulating synaptic and neuronal function and in the inflammatory processes. In this lecture the scientific bases that justify the application of ozone therapy in neurodegenerative diseases such as dementia, Parkinson and multiple sclerosis are presented, as well as the results of clinical trials. In the three examples, where an oxidative stress is present, ozone achieved a cell redox balance. A stimulation of neurotransmitters as dopamine, serotonin and norepinephrine up to physiological levels were obtained. An immune modulatory effect was obtained in multiple sclerosis, increasing the anti-inflammatory cytokines and decreasing the pro-inflammatory ones. It is known that A1AR inhibition is accompanied by increased expression and release of pro-inflammatory cytokines (IL-1β and MMP-12), inducing demyelination and axonal injury upon oligodendrocyte degeneration. Then, A1AR signaling activation produced by ozone therapy attenuates pro-inflammatory responses and maintains myelin sheath integrity by augmenting antiinflammatory responses. Modulation of neuroinflammation by the A1AR represents a novel mechanism that provides new therapeutic opportunities for neurodegenerative and demyelinating diseases. On the other hand, MPO plays a major role in progressive MS oxidative injury, thus MPO modulation conferred by ozone, could be an important therapeutic tool for progressive MS patients. The lack of side effects obtained with ozone therapy, as the improvement in the quality of life achieved by these patients, make this procedure an excellent therapeutic option.
Keywords: ozone therapy, ozone oxidative preconditioning, antioxidant defense system, oxidative stress, cellular redox balance, nitric oxide, reactive oxygen species, adenosine A1 receptors, myeloperoxidase, cytokines, senile dementia, Parkinson, multiple sclerosis.
OZONE THERAPY. POSSIBLE INDICATIONS IN OBSTETRICS AND GYNECOLOGY
Ozone is a powerful oxidant, surpassed, in this regard, only by fluorine. Its doubtless strong reactivity has contributed to establish the dogma that ozone is always toxic and its medical application must be proscribed. However, ozone therapy has been used for therapeutic purposes since the beginning of the last century and its use is increasingly demanded nowadays. For proper enlightenment and guidance of the person interested in the use of ozone for medical purposes, scientific documentation on the safety/toxicity profile of this acclaimed procedure becomes necessary. Taking into account that the National Health Regulatory Agencies require of documentation with scientific trials for sanitary registration of drugs and therapy procedures, different toxicological tests were performed in Cuba using experimental animals, following the guidelines from the Cuban Regulatory Agency, Food Drug Administration, International Standards Organization and the Health World Organization aimed at proving the safety of ozone therapy administration. In this lecture, the teratogenic study of ozone by rectal insufflation (RI) is presented. Female Wistar rats (200-250 g) were divided into 3 experimental groups: 1- control (n=15), without any treatment; 2- treated with 1 mL of ozone (n=17) at a concentration of 34 μg/mL (150 μg/kg); 3- treated with 4 mL of ozone (n=17) at a concentration of 90 μg/mL (1600 μg/kg). Ozone was administered by RI during 10 sessions, from the 6th to the 15th day of gestation. The pregnancy was confirmed by the presence of spermatozoa in the vaginal exudates. In the 19th day of gestation, animals were euthanized by an ether overdose and the fetuses were obtained by cesarean. No toxic effect was observed in the pregnant rats subjected to the ozone treatment by RI. Mother weight gain did not show significant differences among the groups, neither the other indicators (number of corpus luteum, implantations, alive and dead fetus, reabsorptions). In respect to the fetus morphology, no external, skeletal or visceral malformations were observed. The weight and the length cranium-causal did not show significant differences among the groups. It is concluded that no teratogenic nor embriotoxic effects were found after the ozone application by rectal insufflation at the doses studied. With respect to the application of ozone therapy in Obstetrics, an update of the papers published about this topic was presented. They referred the use of ozone therapy in: pregnant women with hypertension, genital or no genital infections during pregnancy, threatened abortion, intrauterine fetal hypoxia, among others. For example, the effect of ozone therapy by rectal insufflation on fetoplacental blood flow in hypertensive pregnant women, with 24 weeks of gestation, indicated a better fetoplacental blood flow, achieving a greater oxygenation in the group treated with ozone plus antihypertensive treatment (methyldopa) in comparison with a control group treated only with the conventional treatment. Also, a reduction of methyldopa in 23.7 % of the initial doses was found in the ozone group as opposed to an increase of 40.8% in the control group. Another study about ozone therapy as the main component of the complex treatment of threatened abortion, using ozonated saline solution in the first (group I) or second semester (group II) showed a decrease in the molecular products of lipid peroxidation and a simultaneous increase in the antioxidant activity. Also, with ozone therapy the pregnancy was preserved and prolonged to the physiological terms of labor in 86% of patients inside group I and in 85% of patients inside group II. However, in the control group (conventional treatment) I and II, it was possible to preserve the pregnancy in 65 and 60% of cases, respectively. In the ozone group, 80% of newborn babies received 7-10 points (maximum value) according to Apgar’s score, however, only 58.3% in the control group. In Gynecology, an interesting paper was reviewed about distal fallopian tube recanalization using ozone treatment. In the ozone group, the ozone was introduced in the uterine cavity and in the case of the control group, anti-inflammatory drugs and antibiotics were used. The overall recanalization rate was significantly higher in the ozone group (93%) as compared to the control group (79%) 6-months after intervention (p < 0.01). The re-adhesion rate in the ozone group was significantly lower than the control group (p < 0.01). The pregnancy rate after 12 months of intervention was significantly higher in the ozone group (59%) compared to the control group (43%) (p < 0.05). These results were highly encouraging and hold promise for treating distal tubal obstruction in infertile females. For inflammatory diseases in female genital organs, intravaginal ozone has been used. Ozone restores the body’s own defense abilities by the normalization of vaginal mucosa local immunity, prevents the generalization of inflammatory processes, facilitates uterus healing, and reduces the treatment time with no complications or side effects. In Cuba we have a vast experience in the use of ozonated sunflower oil in the treatment of vulvovaginitis, human papillomavirus, acuminate condyloma, genitalis herpes virus with very good results. In summary, we can state that preclinical and clinical studies presented here about the application of ozone therapy in Obstetrics and Gynecology, in the different ways of ozone applications, do not demonstrate any adverse effect or complication. However, more controlled clinical trials are necessary to perform in order to prove the inocuity of ozone therapy, mainly in Obstetrics, where there are still questions to be clarified.
Keywords: Ozone therapy, teratogenic study, gynecology, obstetrics, ozonated sunflower oil, vulvovaginitis, human papillomavirus, threatened abortion, fetal hypoxia
Dr. SILVIA MENENDEZ CEPERO
Dr. Silvia Menéndez Cepero
Collaborator of the National Center for Scientific Research. Havana, Cuba.
Doctor in Chemical Sciences, Full Researcher, Specialist in Ozone therapy and Head of the Ozone Clinic of the Ozone Research Center (belonging to the National Center for Scientific Research) till 2011. Now, collaborator of the National Center for Scientific Research and coordinator of the International and National Courses of Ozone Therapy. She has introduced ozone therapy in Cuba in 1986. She has act as consultant or tutor, int he field of ozone medical applications, in 40 thesis of Medical Specialist, in 10 thesis of Master (Biology, Pharmacology, Medical Urgency, Traditional and Natural Medicine, Bioenergetic Medicine and in Dentistry Urgency) and in 3 thesis of PhD (in Medical and Pharmaceutical Sciences). She is the author of more than 50 articles, published in peered review journal, in the last 15 years, of two patents, 2 medicament registrations (oral and topical OLEOZON®) and a new therapeutic indication (topic OLEOZON® for the treatment of impetigo). She has imparted 60 courses in ozone therapy and participated in 65 international congresses with over 300 works in ozone therapy matter. As a lecturer, has been invited to different countries such as: Spain, Italy, Austria, Germany, Mexico, Brazil, Argentina, Colombia, Peru, USA, Barbados, Japan, Egypt and India. She has contributed in the clarification of the ozone mechanisms of action, by increasing knowledge of its biochemical and pharmaco- dynamics properties and demonstrating that ozone therapy, carried on in controlled conditions, can be used for beneficial effects in apparently non related diseases. She has received several international and national medals and awards for her work deployed in the field of ozone therapy.