Hepatoprotective and antinociceptive effects of terpinolene in streptozotocin-induced diabetic peripheral neuropathic rats
Paper Details
Hepatoprotective and antinociceptive effects of terpinolene in streptozotocin-induced diabetic peripheral neuropathic rats
Abstract
Diabetes induced oxidative stress impairs hepatic function, contributing to peripheral nerve injury. Growing evidence indicates that overactivation of NOX4 brings metabolic derangements in hepatic tissue, which concomitantly alter thermal behavior in experimental rats. This study investigated the hepatoprotective and antinociceptive effects of terpinolene in streptozotocin (STZ)-induced DPN rats. Male SD rats were made diabetic with STZ (55 mg/kg, b.w. i.p) prepared in 0.1 M citrate buffer (pH 4.5). After six weeks, diabetic animals were treated daily with terpinolene at doses of 12.5, 25, and 50 mg/kg for four weeks. Diabetic control rats exhibited a significant decrease in the levels of endogenous antioxidants (enzymic and non-enzymic), along with elevated lipid peroxidation products and transaminase (AST, ALT) activities, indicating severe hepatic dysfunction. An alteration in thermal behavior was observed in diabetic control rats. Oral administration of terpinolene dose-dependently improved hepatic antioxidant status and reduced lipid peroxidation markers. Histological examination revealed that terpinolene restored the architecture of hepatic tissue, and the effect was more pronounced at 50mg/kg b.w than the other two doses. Further in silico analysis revealed a strong binding interaction between terpinolene and NOX4 with a binding energy of -5.2 kcal/mol. This indicates that terpinolene effectively inhibits NOX4-mediated oxidative stress in the hepatic tissue and ameliorates thermal nociception in DPN rats. The efficacy of terpinolene was comparable to the standard drug, α-lipoic acid.
Ajiboye BO, Dada S, Fatoba HO, Lawal OE, Oyeniran OH, Adetuyi OY, Oyinloye BE. 2023. Dalbergiella welwitschia (Baker) Baker f. alkaloid-rich extracts attenuate liver damage in streptozotocin-induced diabetic rats. Biomedicine and Pharmacotherapy 168, 115681.
Arista RA, Priosoeryanto BP, Nurcholis W. 2023. Profile volatile compounds in essential oils on different parts of cardamom with antioxidant activity. Biointerface Res Appl Chem 13(4), 1-17.
Aydin E, Türkez H, Taşdemir Ş. 15, Anticancer and antioxidant properties of terpinolene in rat brain cells. Archives of Industrial Hygiene and Toxicology. 2013 Sep 64(3).
Carlberg I, Mannerviek B. 1975. Glutathione reductase levels in rat brain, Journal of Biological Chemistry 250, 5475e5480.
Chen MY, Meng XF, Han YP, Yan JL, Xiao C, Qian LB. 2022. Profile of crosstalk between glucose and lipid metabolic disturbance and diabetic cardiomyopathy: Inflammation and oxidative stress. Frontiers in Endocrinology 13, 983713.
Dragoev SG. 2024. Lipid peroxidation in muscle foods: Impact on quality, safety and human health. Foods 13(5), 797.
Ellman GL. 1959. Tissue sulfhydryl groups, Arch Biochem Biophys 82, 70e77.
Engwa GA, Nweke FN, Nkeh-Chungag BN. 2022. Free radicals, oxidative stress-related diseases and antioxidant supplementation. Alternative Therapies in Health and Medicine 28(1).
Fontes A, Jauch AT, Sailer J, Engler J, Azul A. M, Zischka H. 2024. Metabolic derangement of essential transition metals and potential antioxidant therapies. International journal of molecular sciences 25(14), 7880.
Gan C, Yuan Y, Shen H, Gao J, Kong X, Che Z, Xiao J. 2025. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduction and Targeted Therapy 10(1), 33. DOI: 10.1038/s41392-024-02072-z
González P, Lozano P, Ros G, Solano F. 2023. Hyperglycemia and oxidative stress: an integral, updated and critical overview of their metabolic interconnections. International journal of molecular sciences 24(11), 9352.
Habig W, Pabst M, Jakpby W. 1974. Glutathione-S-transferase, The first enzymatic step in mercapturic acid formation, Journal of Biological Chemistry 249, 7130e7139.
Huang J, Li R, Liu N, Yi N, Zheng H, Zhang Q, Lu B. 2021. Liver fibrosis is independently associated with diabetic peripheral neuropathy in type 2 diabetes mellitus. Journal of diabetes investigation 12(11), 2019-2027.
Jiang ZY, Hunt JV, Wolff SP. 1992. Detection of lipid hydroperoxides using the fox method. Anal Biochem 202, 384e389.
Kakkar P, Das B, Viswanathan PN. 1984. A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys 21, 130e132.
Kibibi Wairimu H. 2025. Targeting Oxidative Stress in Hepatorenal Injury: The Role of Antidiabetic Phytochemicals.
Kuhad A, Chopra K. 2009. Tocotrienol attenuates oxidative–nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. Neuropharmacology 57(4), 456-62.
Liu S, Liu J, Wang Y, Deng F, Deng Z. 2025. Oxidative Stress: Signaling Pathways, Biological Functions, and Disease. MedComm 6(7), e70268.
Macedo EM, Santos WC, Sousa BP, Lopes EM, Piauilino CA, Cunha FV, Sousa DP, Oliveira FA, Almeida FR. 2016. Association of terpinolene and diclofenac presents antinociceptive and anti-inflammatory synergistic effects in a model of chronic inflammation. Brazilian Journal of Medical and Biological Research 49(7), e5103.
Mangarov I, Voynikov Y, Petkova V, Iliev S, Kostadinova I, Marinov L, Nikolova I. 2025. Alpha-Lipoic Acid in Diabetic Peripheral Neuropathy: Addressing the Challenges and Complexities Surrounding a 70-Year-Old Compound. Current Issues in Molecular Biology 47(6), 402.
Niehaus. WG, Samuelson B. 1968. Formation of malondialdehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem 6, 126e130.
Park MN, Rahman MA, Rahman MH, Kim J. W, Choi M, Kim JW, Kim B. 2022. Potential therapeutic implication of herbal medicine in mitochondria-mediated oxidative stress-related liver diseases. Antioxidants 11(10), 2041.
Pei J, Pan X, Wei G, Hua Y. 2023. Research progress of glutathione peroxidase family (GPX) in redoxidation. Frontiers in pharmacology 14, 1147414.
Petropoulos SA, Daferera D, Polissiou MG, Passam, H. C. 2010. Effect of freezing, drying and the duration of storage on the composition of essential oils of plain‐leafed parsley [Petroselinum crispum (Mill.) Nym. ssp. neapolitanum Danert] and turnip‐rooted parsley [Petroselinum crispum (Mill.) Nym. ssp. tuberosum (Bernh.) Crov.]. Flavour and Fragrance Journal 25(1), 28-34.
Ramabadran K, Bansinath M, Turndorf H, Puig MM. 1989. Tail immersion test for the evaluation of a nociceptive reaction in mice: Methodological considerations. Journal of pharmacological methods 21(1), 21-31.
Reitman S, Frankel S. 1957. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. American Journal of Clinical Pathology 28(1), 56–63.https://doi.org/10.1093/ajcp/28.1.56
Rotruck J, Pope A, Ganther H, Selenium. 1973. Biochemical role as a component of glutathione peroxidase, Science 38(179), 588e590.
Savelieff MG, Elafros MA, Viswanathan V, Jensen TS, Bennett DL, Feldman EL. 2025. The global and regional burden of diabetic peripheral neuropathy. Nature Reviews Neurology 21(1), 17-31.
Sinha AK. Colorimetric assay of catalase, Anal Biochem 47(1972), 389e394. 10.
Tabassum N, Kheya IS, Asaduzzaman S, Maniha S, Fayz AH, Zakaria A, Noor R. 2020. A review on the possible leakage of electrons through the electron transport chain within mitochondria. Life Science 6(1), 105-113.
Tanase DM, Gosav EM, Botoc T, Floria M, Tarniceriu CC, Maranduca MA, Costea CF. 2023. Depiction of branched-chain amino acids (BCAAs) in diabetes with a focus on diabetic microvascular complications. Journal of Clinical Medicine 12(18), 6053.
Turkez H, Aydın E, Geyikoglu F, Cetin D. 2015.
Genotoxic and oxidative damage potentials in human lymphocytes after exposure to terpinolene in vitro. Cytotechnology 67, 09-18.
Visnagri A, Kandhare AD, Chakravarty S, Ghosh P, Bodhankar SL. 2014. Hesperidin, a flavanoglycone attenuates experimental diabetic neuropathy via modulation of cellular and biochemical marker to improve nerve functions. Pharmaceutical Biology 52(7), 814-28.
Ye D, Fairchild TJ, Vo L, Drummond PD. 2022. Painful diabetic peripheral neuropathy: role of oxidative stress and central sensitisation. Diabetic Medicine 39(1), e14729.
Yu DX, Guo S, Wang JM, Yan H, Zhang ZY, Yang J, Duan JA. 2022. Comparison of Different Drying Methods on the Volatile Components of Ginger (Zingiber officinale Roscoe) by HS-GC-MS Coupled with Fast GC E-Nose. Foods (Basel, Switzerland) 11(11), 1611. https://doi.org/10.3390/foods11111611
Ravishankar Sarumathi, Muthukumaran Preethi, Chandrasekaran Sankaranarayanan*, 2025. Hepatoprotective and antinociceptive effects of terpinolene in streptozotocin-induced diabetic peripheral neuropathic rats. Int. J. Biosci., 27(6), 156-166.
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