Effect of exogenous melatonin on the ultrastructure of hepatocytes in rats with experimental toxic liver injury

Abstract

BACKGROUND: Prolonged exposure to constant light suppresses melatonin synthesis by the pineal gland and induces desynchronosis, increasing the risk of various pathological conditions, including liver dysfunction. Exogenous melatonin is known to exert a pronounced hepatoprotective effect; however, its role in protecting the liver against carbon tetrachloride (CCl4)-induced toxicity remains insufficiently understood. Moreover, the impact of disrupted circadian rhythmicity under melatonin deficiency on the development of liver pathology, as well as the mechanisms of melatonin’s hepatoprotective action in toxic injury. AIM: The work aimed to investigate the effects of dark deprivation and exogenous melatonin on the ultrastructure of mitochondria in rat hepatocytes under carbon tetrachloride-induced toxic liver injury. METHODS: The study involved male Wistar rats (n = 200), aged 6 months, with a body weight of (350 ± 15) g. The animals were divided into five groups: group 1, control group, fixed light–dark cycle; group 2, dark deprivation; group 3, fixed light–dark cycle with intraperitoneal CCl4 (in olive oil, 0.3 mg/kg) every 3 days; group 4, dark deprivation with CCl4 every 3 days; group 5, dark deprivation with CCl4 injections every 3 days, (intraperitoneally) and daily melatonin administration (Sigma-Aldrich, USA; intragastrically, 0.3 mg/kg). The experiment lasted 3 weeks. The ultrastructure of hepatocytes was evaluated using transmission electron microscopy. The micromorphometric analysis of mitochondria included measurement of organelle area, quantification and length of cristae, and calculation of the concentration of inner mitochondrial membranes. The statistical analysis was performed using GraphPad Prism v8.41 (GraphPad Software, USA). RESULTS: Dark deprivation caused marked structural changes in hepatocytes, including cytoplasmic swelling, nuclear deformation, ribosomal detachment from the endoplasmic reticulum, reduced mitochondrial number, shortened cristae, and decreased concentration of inner mitochondrial membranes. CCl₄ exposure resulted in more severe damage to hepatocytes, such as cytoplasmic vacuolization, mitochondrial swelling, and necrosis. Under dark deprivation, CCl₄ toxicity was exacerbated: total mitochondrial count decreased with compensatory enlargement, cristae were shortened, and the concentration of inner mitochondrial membranes declined, indicating reduced mitochondrial function. Melatonin has a protective effect, preserving nuclear morphology, reducing lipid vacuole accumulation, and normalizing micromorphometric parameters of mitochondria. CONCLUSION: Pineal melatonin deficiency under dark deprivation aggravates CCl₄-induced hepatotoxicity due to induction of oxidative stress and mitochondrial dysfunction. Melatonin demonstrates a pronounced hepatoprotective effect by stabilizing hepatocyte ultrastructure and supporting energy metabolism. These findings support the use of melatonin in preventing liver damage under chronic intoxication and circadian rhythmicity disruption.

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