Temirova E. Pharmacological approach into combined administration of N acetylcysteine and melatonin in case of type 1 diabetes mellitus

The dissertation deals with experimental studying of the neuroprotective properties of N-acetylcysteine and melatonin combined administration in type 1 diabetes mellitus (DM1). During the first stage, by selecting the most effective dose of combined administration of N-acetylcysteine and melatonin, changes in blood glucose levels, body weight, and survival of animals were performed in DM1. It was found that separate and combined administration of N acetylcysteine (1500 mg/kg/day, intragastrically) and melatonin (10 mg/kg/day, intragastrically) had a hypoglycemic effect, contributed to the normalization of body weight, and increased the survival of animals with experimental DM1. Lower doses of the combined administration of the studied drugs were not effective. N-acetylcysteine, melatonin, and their combined administration improved the fatty acid spectrum, reduced the processes of lipid peroxidation and contributed to the activation of the endogenous antioxidant defense system in brain tissues of experimental animals. In particular, the induction of N-acetylcysteine contributed to the highest increase in the level of reduced glutathione by 1.8 times (p<0.05), while melatonin increased the activity of catalase by 1.6 times (p<0.05), and the combined administration of drugs increased superoxide dismutase activity by 1.8 times (p<0.05). On the background of N acetylcysteine, melatonin and their combined administration decreased the content of free iron also (in 8.5, 2.2, and 3.9 times accordingly, р<0.05). Administration of N-acetylcysteine contributes to increasing the density of intact neurons and reducing the thickness of damaged neurons, saving of cortical nerve fibers, and the increase of the area of the neuron by 2.2 times and the nucleus by 1.3 times (p<0.05). Melatonin therapy also caused a rise in the field of the neuron by 1.5 times and the nucleus by 1.2 times (p<0.05). According to the results of the electron-microscopic examination, N-acetylcysteine influences the development of compensatory and adaptive changes in almost all structural components of the cortex. Melatonin slightly reduces neuropile swelling and preserves most neurons. The combined administration of the investigational drugs showed an increase in the number of glial cells – astrocytes, indicating the neuroprotective effect of this regimen. The obtained results can be theoretical and experimental justification for further research and clinical trials to expand knowledge about the pharmacodynamics of these drugs and amendment to the instructions for medical use.