Protektivni efekat blokatora kalcijumovih kanala na intoksikaciju aluminijumom - eksperimentalni model
Committee membersĐinđić, Boris
Živančević Simonović, Snežana
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Introduction. Aluminum is a non-essential element, the third most abundant in the Earth's crust. Since the second half of the twentieth century, the use and exposure of the living world to the toxic effects of bioavailable aluminum has been progressively increasing. We are exposed to aluminum through water, food, pharmaceutical and cosmetic products, as well as through air pollution. The results of modern research link aluminum intoxication with the occurrence of anemia, osteoporosis, encephalopathy and a number of neurodegenerative diseases (Alzheimer's disease, parkinsonism, autism), reproductive toxicity, respiratory diseases (asthma, chronic bronchitis), immune disorders and breast cancer. Aluminum is used as an adjuvant in vaccines, because it strengthens the immune response. At the time of the emergence of new viruses and the strengthening of the anti-vaccine movement and the fear that aluminum from vaccines is responsible for the increase in autism, it is very important to find ...a way to reduce its accumulation and toxic effects. The pathogenetic mechanisms of the toxic action of aluminum are insufficiently elucidated. The results of clinical and experimental studies indicate that there are several pathogenetic mechanisms by which Al exhibits toxic effects on cells: oxidative stress, disruption of membrane function, alteration or inhibition of enzyme function, and disruption of intracellular signaling. It has been found that aluminum ions can modify various signaling pathways and functions of secondary messengers, which are involved in essential processes such as cell growth, differentiation and apoptosis. The objectives of the study were based on the hypothesis that the disturbance of calcium homeostasis regulation represents a strong pathogenetic mechanism in the development of aluminum toxicity and that blocking its channels can mitigate and/or eliminate the effect of chronic exposure to aluminum. The aim was: - to elucidate the mechanism of toxic action of aluminum through the effect on calcium channels and determine the possible protective effect of pretreatment by blocking calcium channels with verapamil, - to examine the influence of chronic administration of aluminum and premedication with verapamil on changes in hematological and biochemical parameters - to assess the deposition of aluminum in the liver, testis and kidney tissues and the possible protective effect of verapamil - to examine the influence of chronic exposure to different doses of aluminum trichloride and premedication with verapamil on testicular morphology. - to examine the effect of chronic exposure to different doses of aluminum trichloride and premedication with verapamil on liver morphology and function. - to examine the degree of apoptosis after chronic administration of aluminum and premedication with verapamil in testicular and liver tissues using proteins of the Bcl-2 family. Material and methods: 36 male Sprague Dawley rats were included in the experiment, which were divided into 6 groups and were treated as follows: control (K) with saline, V with verapamil, E1 with 10 mg and E2 with 20 mg AlCl3. Sixty minutes after premedication with verapamil, E3 received 10 mg and E4 20 mg AlCl3. After 8 weeks, the animals were sacrificed and blood was taken for analysis of hematological and biochemical parameters and tissues for both pathohistological and aluminum content examinations. Results. The results of hematological tests are presented (counts of erythrocytes, leukocytes, thrombocytes, relative and absolute leukocyte counts, hemoglobin concentrations, hematocrit, MCV, MCH, MCHC, iron, ferritin, transferrin, hepcidin, UIBC, TIBC, TSAT activity; aminotransferase, alanine aminotransferase, alkaline phosphatase, amylase, lactate dehydrogenase, creatine kinase and gamma-glutamyl transferase; CRP concentration; aluminum concentration in liver, testis and kidney tissues; pathohistological findings in liver and testis tissues; testicular morphometry and immunohistochemical cytoplasmic expression of Bax, Bid, and BCL-2 in liver and testicular tissues. Discussion: the results are explained and discussed. The pathogenetic aspects of hematological and biochemical changes caused by aluminum intoxication and the protective effects of premedication with verapamil are discussed, as well as on the accumulation of aluminum in the liver and testicular tissue The analysis of the pathogenetic aspect of the toxic effect of aluminum through the influence on calcium homeostasis is given and the latest literature data are discussed in comparison. Conclusion: it has been proven that chronic application of aluminum leads to significant changes in hematological and biochemical parameters with a pronounced dose-dependent character; The changes in biochemical and hematological parameters (microcytic-hypochromic anemia, leukocytosis, thrombocytosis and elevated values of hepcidin and ferritin) have shown a statistically significant improvement with verapamil premedication. Significant deposition of aluminum in the liver, kidney and testicular tissue was proven, as well as that premedication with verapamil led to a statistically significant reduction in the deposition of aluminum in the mentioned tissues. Immunohistochemical staining has showed a high expression of proapoptotic markers Bax and Bid, which is the most pronounced in testicular tissue, and a high degree of apoptosis expressed by proapoptotic markers Bax and Bid in young germ epithelial cells, but also in Leydig cells. These changes have shown to be mitigated in cases of premedication with verapamil and that the possible protective effect of pharmacological blockade of calcium channels by verapamil is indicated.