Effect of a novel thienopyridine derivative on liver structure in rats with diet-induced obesity

Abstract

BACKGROUND: The search for novel compounds that exert a positive impact on liver morphology and function having a beneficial effect on carbohydrate and lipid metabolism remains an urgent research priority.

AIM: This work aimed to evaluate the effect of a novel thienopyridine derivative on liver structure in rats with diet-induced obesity.

MATERIAL AND METHODS: A novel thienopyridine derivative AZ-020 was selected through in silico screening using online platforms based on its potential effects on the liver, as well as carbohydrate and lipid metabolism. An in vivo study was conducted in Wistar rats, which were randomized into five groups (8 per group): an intact group (maintained under standard conditions), control group (received excess palm oil 30 g/kg for 8 weeks), two reference groups (rats on high-fat diet received either metformin 300 mg/kg or vildagliptin 8 mg/kg during 2 weeks), and a test group (received AZ-020 1 mg/kg for 2 weeks under the same diet). Liver structure was assessed using histological and morphometric analyses, including hepatocyte count, binucleated hepatocyte count per field of view, hepatocyte size, hepatocyte cytoplasmic and nuclear area, and hepatocyte nuclear-to-cytoplasmic ratio. Statistical evaluation was performed using the fourfold table method with Pearson’s χ² test, normalized Pearson’s test, Yates’ correction, and Fisher’s exact test. Parametric statistical methods and Student’s t-test were applied to morphometric data with normal distribution.

RESULTS: Administration of AZ-020 normalized liver histoarchitecture disrupted by prolonged dietary overload and confirmed a positive trend in key morphometric parameters of hepatocytes compared with the control group. A statistically significant 1.7-fold increase (66%) in binucleated hepatocyte count (an essential marker of liver regeneration) was observed following AZ- 020 administration. Treatment with AZ-020 led to normalization of the nuclear-to-cytoplasmic ratio, which showed a statistically significant 16% decrease compared with the control group. In the test group (treated with AZ-020), hepatocyte cytoplasmic area was 76.04 ± 0.35 μm² (vs. 75.54 ± 0.31 μm² in the control group, p = 0.0186); nuclear area was 11.13 ± 0.24 μm² (vs. 13.9 ± 0.3 μm², p < 0.001); and average hepatocyte area was 87.17 ± 0.59 μm² (vs. 89.44 ± 0.61 μm², p < 0.001).

CONCLUSION: The novel thienopyridine derivative with the laboratory code AZ-020, which belongs to the cyanothioacetamide class, demonstrated hepatoprotective effects in an experimental model of liver damage and metabolic disturbances.

Keywords

novel thienopyridine derivative / cyanothioacetamide derivatives / diet-induced obesity / hepatoprotective activity / metformin / vildagliptin / liver structural condition

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Funding

Минобрнауки России по теме: шифр FREE-2023-0002Ministry of Education and Science of Russia on the topi (code: FREE-2023-0002

Минздрав России по теме: (шифр ZUNP-2024-0002)Ministry of Health of Russia on the topic (code: ZUNP-2024-0002)

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