Effects of paracetamol and stress on morphology and gene expression in the rat hippocampus

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Abstract
Introduction. Chronic stress and paracetamol exposure are among the most relevant factors affecting neurochemical and molecular processes in the brain in modern humans. Excessive activation of inflammatory and oxidative pathways during chronic psychosocial stress can lead to a decrease in the expression of neuroprotective and antioxidant genes, exacerbating the neurotoxic effects of drugs such as paracetamol.Objective. To assess the effect of chronic unpredictable stress and oral administration of paracetamol, as well as their combined effect on the morphological state of the brain and on the expression of genes of the antioxidant system and neurotrophic factor in the hippocampus in rats.Materials and methods. The experiment was conducted on forty eight rats (males and females in equal numbers), divided into four groups: control, chronic stress, paracetamol, combined exposure to stress and paracetamol. A complex of various stressors was used to model chronic stress. Paracetamol was administered orally at a dose of 1000 mg/kg. The morphological state of the hippocampus was assessed histologically, gene expression - by quantitative real-time PCR. Statistical analysis included bootstrapping and correction for multiple comparisons using the Holm-Bonferroni method.Results. Macroscopic and histological examination of the rat brain showed the preservation of the normal anatomical structure and integrity of the hippocampal tissues in all groups. Statistical analysis of gene expression showed animals treated with paracetamol (groups III and IV) to show a significant decrease in the mRNA levels in the Sod1 and Bdnf genes in the hippocampus compared to the control and the group exposed to stress only (group II). The expression level of Sod1 and Bdnf was significantly lower in both males and females in these groups (p = 0.001). For the Hmox1 gene, a significant decrease in expression was found only in males in the paracetamol-treated group, while no changes were noted in females.Limitations. Laboratory animals of the same biological species were used for the experiment, and the toxicant was used in only one concentration.Conclusion. Thus, paracetamol, both in isolated use and in combination with chronic stress, has a more pronounced inhibitory effect on the expression of key genes of antioxidant protection and neurotrophic support than stress alone.Compliance with ethical standards. Date of the meeting of the bioethics commission of theUfa Research Institute of Occupational Medicine and Human Ecology dated 02/08/2024 No. 01–02. Throughout the study, the animals were kept in standard conditions with 12-hour artificial lighting during the daytime, a relatively constant level of humidity (30–70%) and an air temperature of 20–25 °C. All animal manipulations were carried out in strict compliance with the rules prescribed in the basic regulatory documents, including the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg, 1986) and the Helsinki Declaration on the Humane Treatment of Animals.Contributions: Gizatullina A.A. – concept and study design, material collection and processing, statistical analysis, manuscript writing; Valova Ya.V. – material collection and processing, statistical analysis; Mukhamadieva G.F. – editing; Karimov D.O. – concept and study design, statistical analysis; Karimov D.D. – material collection and processing; Ryabova Yu.V. – material collection and processing; Khusnutdinova N.Yu. – material collection and processing; Khmel A.O. – material collection and processing. All authors are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.Conflict of interest. The authors declare no conflict of interest.Funding. Industry research program of Rospotrebnadzor for 2021–2025 “Scientific substantiation of the national system for ensuring sanitary and epidemiological welfare, managing health risks and improving the quality of life of the population of Russia”, on the topic: 6.9.1.2 “Study of the impact of chemical production factors under conditions of chronic stress” No. NIOKTR I124021200153-3.Received: April 30, 2025 / Revised: July 9, 2025 / Accepted: October 15, 2025 / Published: April 17, 2026

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