Bukhtiyarova I.P., Shchokina K.G., Pozdniakova A.Yu.

Department of Pharmacology, National University of Pharmacy,

Kharkiv, Ukraine

The research of raleukin antioxidant effect on the model of dexamethasone diabetes in rats

In the structure of endocrine diseases diabetes mellitus (DM) takes one of the first places. Experts of the World Health Organization claim that there were 135 million diabetic patients in 1995, and in 2001 their number reached 175 million, in 2010 the number of patients increased to 200-239.4 million. The International Diabetes Federation (IDF) has recently published renewed data, which shows the number of diabetic patients that has reached 347 million. In 2014 in Ukraine there were about 1.3 million patients with diabetes, 90% of them have insulin non-dependent type II diabetes. Therefore, optimization of type II diabetes therapy is one of the topical health and social issues of nowadays.

According to modern ideas, an important part of type II diabetes pathogenesis is oxidative stress. It is proved that hyperglycemia can induce the development of oxidative stress directly in pancreatic β-cells. It is believed that the decrease in insulin effect due to oxidative stress may occur through inhibition of the expression of glucose transporters by β-cells, which are especially sensitive to the toxic effects of free radicals. There is a large amount of data that indicate a relationship between elevated levels of free radicals and insulin resistance. This justifies the expediency of anti-oxidants in the treatment of diabetes. Anti-diabetic drugs, which along with hypoglycemic effect have antioxidant effect and the ability to maintain the integrity of β-cells attract attention. According to current researches, an important role in the pathogenesis of both types of diabetes mellitus plays an anti-inflammatory cytokines, namely interleukin-1 (IL-1).

The aim of this work is the experimental study of the influence of original recombinant receptor antagonist IL-1 raleukin on the content of primary and secondary products of lipid peroxidation, unesterified fatty acids and triglycerides (TG) in blood plasma on the model of dexamethasone diabetes in rats. raleukin was created in the State Research Institute of Pure Biochemicals (St. Petersburg, Russia).

The model pathology was reproduced by subcutaneous injection of dexamethasone at a dose of 0.125 mg per kg on 18-month rats for 13 days. As reference medicines metformin and anakinra were selected. The choice of reference medicines is made due to the fact that metofmin is a standard hypoglycemic drug, which is included into the treatment of both types of diabetes; and anakinra, which is a recombinant receptor antagonist IL-1 with proven hypoglycemic activity and is an analog to the substance under research. These drugs were administered in the therapeutic regimen, beginning from 14^th day after the reproduction of pathology model within 10 days 1 time per day: raleukin at a dose of 7 mg per kg and anakinra at a dose of 8 mg per kg – subcutaneously, metformin 30 mg per kg – intragastricaly.

Following the introduction of the substance under research the experimental animals were taken from the experiment in the state of euthanasia and took the blood samples. In the blood plasma samples the diene, triene, tetraen and oxydien conjugates (the Platser S. et al. method). The content of reduced glutathione (RG) (the Beutler E. et al. method) and TBA-active products (TBA-AP) (Stalnaya I.D., Harishvili G.T. method), unesterified fatty acids (photocolorimetric) and TG (using test-kits «Lachema» (Czech Republic) on the semi-automatic biochemical analyzer FP-901) were measured.

The development of diabetic model was accompanied by oxidative stress, as was shown by significantly increased concentration of diene, triene, tetraen and oxydien conjugates average in 1.4-2.7 times, TBA-AP were increased in 3.7 times in blood plasma of animals of control pathology group compared with rats of intact control group. In addition, blood plasma of animals of control pathology group showed increased content of unesterified fatty acids and TG, confirming the breach of tolerance to carbohydrates. Under the influence of raleukin the content of diene conjugates in blood plasma of rats was reduced in 1.5 times, the content of triene conjugates decreased in 1.7 times, the content of tetraen and oxydien conjugates – in 1.3 and 1.5 times in accordance with the responsible markers of animals of the pathology group. Under the influence of anakinra diene conjugates content in blood plasma of rats significantly decreased in 1.8 times, triene conjugates – in 2.1 times, tetraen and oxydien conjugates – in 1.2 times comparing with the same markers of rats of control pathology group. The administration of metformin also contributed to the normalization of lipid peroxidation products, but significantly reduced only the content of triene and oxydien conjugates in blood plasma of experimental animals in 1.5 and 1.7 times, respectively. Changes in other markers were not reliable.

Under the influence of raleukin the level of TBA-AP in blood plasma was significantly decreased in 2.2 times comparing with the corresponding markers in blood plasma of control pathology group animals. Under the influence of anakinra TBA-AP in blood plasma of rats was significantly decreased in 1.8 times, under the influence of metformin – in 1.6 times. Therefore, according to normalizing influence on the content of primary and secondary lipid peroxidation products raleukin and anakinra exceeded metformin. Under the influence of raleukin unesterified fatty acids level in blood plasma of rats were significantly decreased in 1.8 times, the level of TG – in 1.3 times comparing with the markers of the control pathology group. Under the influence of anakinra the content of unesterified fatty acids and TG were significantly decreased in 1.9 times and 1.4 times, respectively. Metformin introduction contributed to a significant reduction of these indicators in 1.5 and 1.3 times, respectively. therefore, the positive influence of raleukin and anakinra on unesterified fatty acids and TG level in blood plasma of experimental animals significantly exceeded metformin action.

Thus, in dexamethasone diabetes in rats raleukin showed distinct antioxidant effect, reducing the concentration of primary and secondary products of lipid peroxidation and caused antidiabetic effect, as evidenced by the reduction of unesterified fatty acids and TG level in blood plasma of experimental animals. according to normalizing influence on the above-written markers raleukin was not inferior to the reference medicine anakinra and exceeded metformin. The combination of antioxidant effect of raleukin with antidiabetic effect is very valuable and confirms the prospect of further pre-clinical study with the purpose of use in type II diabetes treatment.