Odesa National Medical University, Odesa, Ukraine
DOI 10.32782/2226-2008-2025-6-2
Background. The pathogenesis of chronic epilepsy is associated with the impairment of lipid metabolism and affects the liver.
The study aimed at investigating the serum lipid profile and liver histomorphology in a rat model of PTZ-induced kindling following the administration of rapamycin and pioglitazone.
Material and methods. Kindling was induced by repeated PTZ administration for three weeks; pioglitazone and rapamycin were administered during the last ten days. Total cholesterol, triglycerides, HDL and LDL levels were measured colorimetrically.
Results and discussion. PTZ kindling caused dyslipidemia (elevated cholesterol, triglycerides, LDL; lowered HDL) and histological signs of steatohepatitis, including activated Kupffer cells.
Combined treatment with pioglitazone and rapamycin was most effective in correcting the lipid profile and reducing heightened levels of cholesterol. The combination’s effect on cholesterol reduction significantly exceeded that of either drug administered separately (by 14.8% and 22.5%, respectively). Compared to untreated kindled animals, the combined therapy reduced triglycerides by 18.7% and LDL by 18.1%, while increasing HDL levels by 39.1%.
While the density of Kupffer cells exceeded that of the control group by 24.5% it was diminished by 20.3% compared with kindled animals after treatment with rapamycin and pioglitazone.
Conclusion. Fully developed PTZ kindling in rats leads to dyslipidemia and histological signs of steatohepatitis. Combined treatment with pioglitazone and rapamycin effectively prevented these disturbances while retarding seizure development, suggesting the model’s relevance for studying the pathogenesis of steatohepatitis and metabolic syndrome.
Key words: chronic epileptic syndrome, dyslipidemia, steatohepatitis, metabolic syndrome, morphological changes.
REFERENCES
- Li YX, Guo W, Chen RX, Lv XR, Li Y. The relationships between obesity and epilepsy: A systematic review with meta-analysis. PLoS One. 2024 Aug 9; 19(8): e0306175. DOI: 10.1371/journal.pone.0306175. PMID: 39121110; PMCID: PMC11315312.
- Nazish S. Obesity and metabolic syndrome in patients with epilepsy, their relation with epilepsy control. Ann Afr Med. 2023 Apr-Jun; 22(2): 136–144. DOI: 10.4103/aam.aam_139_22. PMID: 37026193; PMCID: PMC10262857.
- Wheless JW, Rho JM. Role of cholesterol in modulating brain hyperexcitability. 2025 Jan; 66(1): 33–46. DOI: 10.1111/epi.18174. Epub 2024 Nov 2. PMID: 39487852; PMCID: PMC11742637.
- Salamone A, Terrone G, Di Sapia R, et al. Cholesterol 24-hydroxylase is a novel pharmacological target for anti-ictogenic and disease modification effects in epilepsy. Neurobiol Dis. 2022 Oct 15; 173: 105835. DOI: 10.1016/j.nbd.2022.105835. Epub 2022 Aug 3. PMID: 35932989.
- Hufthy Y, Bharadwaj M, Gupta S, et al. Statins as antiepileptogenic drugs: Analyzing the evidence and identifying the most promising statin. 2022 Aug; 63(8): 1889–1898. DOI: 10.1111/epi.17303. Epub 2022 Jun 10. PMID: 35582761; PMCID: PMC9541605.
- Alqarni F, Eweis HS, Ali A, et al. The Effect of Coenzyme Q10 on Liver Injury Induced by Valproic Acid and Its Antiepileptic Activity in Rats. Biomedicines. 2022 Jan 13; 10(1): 168. DOI: 10.3390/biomedicines10010168. PMID: 35052847; PMCID: PMC8773341.
- Pervak M, Yehorenko O, Poshyvak O, et al. In: Advances in Health and Diseases. (Editor Dunkan L.T.) Chapter 4. Combined neuro-vascular modulators in the control of epileptic activity. Nova Science Publishers, Inc., New York, 2024; 79: 133–162.
- Zhao B, Zhang J, Zhao K, et al. Effect of rapamycin on hepatic metabolomics of non-alcoholic fatty liver rats based on non-targeted platform. J Pharm Biomed Anal. 2025 Jan 15; 253: 116541. DOI: 10.1016/j.jpba.2024.116541. Epub 2024 Oct 22. PMID: 39489928.
- Jamialahmadi T, Mirhadi E, Reiner Ž, et al. Effects of Pioglitazone On Lipoprotein(a): A Meta-analysis. Curr Atheroscler Rep. 2025 Sep 26; 27(1): 94. DOI: 10.1007/s11883-025-01346-3. PMID: 41003906.
- Pervak MP, Poshyvak OB, Yehorenko OS, Arabadzhy DR, Marchenko SV. Rapamycin combined with pitolizant alleviates anxiety and depression in pentylenetetrazol (PTZ)-kindled rats. Acta Neurobiol. Exp. 2024. 84: I–CLXVIII. Poster Session III-CLIX. https://ane.pl/index.php/ane/issue/view/271/2.
- Akyuz E, Ozenen C, Pinyazhko OR, Poshyvak OB, Godlevsky LS. Cerebellar contribution to absence epilepsy. Neuroscience 2021; 761: 136110. https://doi.org/10.1016/j.neulet.2021.136110.
- Al-Muzafar HM, Alshehri FS, Amin KA. The role of pioglitazone in antioxidant, anti-inflammatory, and insulin sensitivity in a high fat-carbohydrate diet-induced rat model of insulin resistance. Braz J Med Biol Res. 2021 May 24; 54(8): e10782. DOI: 10.1590/1414-431X2020e10782. PMID: 34037093; PMCID: PMC8148887.
- Li, Yf., Xie, Zf., Song, Q, Li, Jy. Mitochondria homeostasis: Biology and involvement in hepatic steatosis to NASH. Acta Pharmacol Sin. 2022; 43; 1141–1155. https://doi.org/10.1038/s41401-022-00864-z.
- Denefil OV, Sopel OV, Levchuk ОO, Sopel OM, Andriyishyn OP. Morphological changes in the liver of rats of both sex with fructose-induced nonalcoholic fatty liver disease. Odesa Medical Journal. 2024; 2(187): 14–18. https://doi.org/ 10.32782/2226-2008-2024-2-2.
- Park SJ, Garcia Diaz J, Um E, Hahn YS. Major roles of Kupffer cells and macrophages in NAFLD development. Front Endocrinol (Lausanne). 2023; 14: 1150118. DOI: 10.3389/fendo.2023.1150118. PMID: 37274349; PMCID: PMC10235620.
