The Effect of Troxerutin Consumption on the Symptoms of Morphine Withdrawal Syndrome in Male Mice

Year 2023, Volume: 48 Issue: 2, 183 - 200, 01.08.2023

Ramin Ghasemi Shayan , Nasrin Hosseinzad Manie

https://doi.org/10.55262/fabadeczacilik.1177914

Abstract

Introduction: Chronic morphine use is associated with increased oxidative stress and inflammatory factors. Troxerutin is a natural bioflavonoid and has antioxidant and anti-inflammatory effects that could relieve morphine withdrawal syndrome.
Aim: The effects of troxerutin on morphine dependence in mice
Method: Troxerutin was prepared in three different doses (50, 100, and 200 mg/kg) via a normal saline solution. After examining the composition of troxerutin, the experiment was performed in five groups of 8 mice. One group received eight days of increasing doses (10, 20, 30, 40, 50, and 60 mg/kg) of morphine SC (subcutaneously) with normal saline (10 ml/kg) IP (Intraperitoneal), and one group received only normal saline and the other three groups received three different doses of troxerutin solved in normal saline as the carrier of troxerutin along with morphine. On the ninth day, withdrawal symptoms were recorded after naloxone injection and blood samples were examined for antioxidant factors.
Results: The total withdrawal score in the 50 mg/kg dose of the troxerutin group with morphine was significantly lower than the morphine-saline group (p<0.001***). The total withdrawal score in the 100 mg/kg dose of troxerutin group with morphine was significantly lower than the morphine-saline group (p<0.01**). Antioxidant tests showed a significant increase in the level of TAC of serum (p<0.001***) and a decrease in the level of MDA of serum (p<0.001***) in all doses of troxerutin. (50, 100 and 200 mg/kg) As performing the locomotion activity, no significant motility dysfunction or paralysis was observed in mice after using troxerutin. (All P>0.05).
Conclusion: Troxerutin reduces the symptoms of morphine withdrawal syndrome in a dose-dependent manner. The results of antioxidant tests declared that troxerutin would increase the level of TAC (Total Antioxidant Capacity) and decrease the level of MDA (Malondialdehyde) in the serum of mice possibly due to its antioxidant properties.

Keywords

: morphine, troxerutin, withdrawal syndrome, dependence, MDA, TAC, mice

References

• Adam, B. S., Pentz, R., Siegers, C. P., Strubelt, O., & Tegtmeier, M. (2005). Troxerutin protects the isolated perfused rat liver from a possible lipid peroxidation by coumarin. Phytomedicine, 12(1-2), 52-61. doi:10.1016/j.phymed.2004.01.007
• Asl, B. H., Hassanzadeh, K., Khezri, E., & Mohammadi, S. (2008). Evaluation the effects of dextromethorphan and midazolam on morphine induced tolerance and dependence in mice. Pak J Biol Sci, 11(13), 1690-1695. doi:10.3923/pjbs.2008.1690.1695
• Babri, S., Mohaddes, G., Feizi, I., Mohammadnia, A., Niapour, A., Alihemmati, A., & Amani, M. (2014). Effect of troxerutin on synaptic plasticity of hippocampal dentate gyrus neurons in a β-amyloid model of Alzheimer׳s disease: an electrophysiological study. Eur J Pharmacol, 732, 19-25. doi:10.1016/j.ejphar.2014.03.018
• Cappendijk, S. L., de Vries, R., & Dzoljic, M. R. (1993). Inhibitory effect of nitric oxide (NO) synthase inhibitors on naloxone-precipitated withdrawal syndrome in morphine-dependent mice. Neurosci Lett, 162(1-2), 97-100. doi:10.1016/0304-3940(93)90569-7
• Etemadzadeh, E. (1993). Cerebral catecholamine depletion in mice withdrawn from repeated morphine treatment and development of tolerance to the enhancing effect of morphine on noradrenaline depletion. J Pharmacol Exp Ther, 266(2), 749-755.
• Farajdokht, F., Amani, M., Mirzaei Bavil, F., Alihemmati, A., Mohaddes, G., & Babri, S. (2017). Troxerutin protects hippocampal neurons against amyloid beta-induced oxidative stress and apoptosis. EXCLI journal, 16, 1081-1089. doi:10.17179/excli2017-526
• Gohel, M. S., & Davies, A. H. (2009). Pharmacological agents in the treatment of venous disease: an update of the available evidence. Curr Vasc Pharmacol, 7(3), 303-308. doi:10.2174/157016109788340758
• Hosseinzadeh, H., & Jahanian, Z. (2010). Effect of Crocus sativus L. (saffron) stigma and its constituents, crocin and safranal, on morphine withdrawal syndrome in mice. Phytother Res, 24(5), 726-730. doi:10.1002/ptr.3011
• Hosseinzadeh, H., & Nourbakhsh, M. (2003). Effect of Rosmarinus officinalis L. aerial parts extract on morphine withdrawal syndrome in mice. Phytother Res, 17(8), 938-941. doi:10.1002/ptr.1311
• Hutchinson, M. R., Coats, B. D., Lewis, S. S., Zhang, Y., Sprunger, D. B., Rezvani, N., . . . Watkins, L. R. (2008). Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. Brain Behav Immun, 22(8), 1178-1189. doi:10.1016/j.bbi.2008.05.004
• Lu, J., Wu, D. M., Zheng, Y. L., Hu, B., Cheng, W., Zhang, Z. F., & Li, M. Q. (2013). Troxerutin counteracts domoic acid-induced memory deficits in mice by inhibiting CCAAT/enhancer binding protein β-mediated inflammatory response and oxidative stress. J Immunol, 190(7), 3466-3479. doi:10.4049/jimmunol.1202862
• Maldonado, R., Negus, S., & Koob, G. F. (1992). Precipitation of morphine withdrawal syndrome in rats by administration of mu-, delta- and kappa-selective opioid antagonists. Neuropharmacology, 31(12), 1231-1241. doi:10.1016/0028-3908(92)90051-p
• Maldonado, R., Saiardi, A., Valverde, O., Samad, T. A., Roques, B. P., & Borrelli, E. (1997). Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature, 388(6642), 586-589. doi:10.1038/41567
• Maurya, D. K., Salvi, V. P., & Krishnan Nair, C. K. (2004). Radioprotection of normal tissues in tumor-bearing mice by troxerutin. J Radiat Res, 45(2), 221-228. doi:10.1269/jrr.45.221 Medeiros, R., Prediger, R. D., Passos, G. F., Pandolfo, P., Duarte, F. S., Franco, J. L., . . . Calixto, J. B. (2007). Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein. J Neurosci, 27(20), 5394-5404. doi:10.1523/jneurosci.5047-06.2007
• Najafi, M., Noroozi, E., Javadi, A., & Badalzadeh, R. (2018). Anti-arrhythmogenic and anti-inflammatory effects of troxerutin in ischemia/reperfusion injury of diabetic myocardium. Biomed Pharmacother, 102, 385-391. doi:10.1016/j.biopha.2018.03.047
• Panat, N. A., Maurya, D. K., Ghaskadbi, S. S., & Sandur, S. K. (2016). Troxerutin, a plant flavonoid, protects cells against oxidative stress-induced cell death through radical scavenging mechanism. Food chemistry, 194, 32-45. doi:10.1016/j.foodchem.2015.07.078
• Salehpour, M., Habibi Asl, B., Charkhpur, M., & Mahmoudi, J. (1398). Effects of Vitamin C and Citicoline on Morphine-Inducing Tolerance In Mice. Paper presented at the همایش بین المللی تحقیقات سرطان 2019. https://civilica.com/doc/963401
• Sui, R., Zang, L., & Bai, Y. (2019). Administration of troxerutin and cerebroprotein hydrolysate injection alleviates cerebral ischemia/reperfusion injury by down-regulating caspase molecules. Neuropsychiatric disease and treatment, 15, 2345-2352. doi:10.2147/NDT.S213212
• Turton, E. P. L., Kent, P. J., & Kester, R. C. (1998). The Aetiology of Raynaud's Phenomenon. Cardiovascular Surgery, 6(5), 431-440. doi:10.1177/096721099800600501 Vela, G., Ruiz-Gayo, M., & Fuentes, J. A. (1995). Anandamide decreases naloxone-precipitated withdrawal signs in mice chronically treated with morphine. Neuropharmacology, 34(6), 665-668. doi:10.1016/0028-3908(95)00032-2
• W. Quimby, F., & H. Luong, R. (2007). Clinical Chemistry of the Laboratory Mouse. The Mouse in Biomedical Research, 171-216. doi:10.1016/B978-012369454-6/50060-1 Wang, Z. J., & Wang, L. X. (2006). Phosphorylation: a molecular switch in opioid tolerance. Life Sci, 79(18), 1681-1691. doi:10.1016/j.lfs.2006.05.023
• Yamaguchi, T., Hagiwara, Y., Tanaka, H., Sugiura, T., Waku, K., Shoyama, Y., . . . Yamamoto, T. (2001). Endogenous cannabinoid, 2-arachidonoylglycerol, attenuates naloxone-precipitated withdrawal signs in morphine-dependent mice. Brain Res, 909(1-2), 121-126. doi:10.1016/s0006-8993(01)02655-5
• Zhang, Z. F., Fan, S. H., Zheng, Y. L., Lu, J., Wu, D. M., Shan, Q., & Hu, B. (2009). Troxerutin protects the mouse liver against oxidative stress-mediated injury induced by D-galactose. J Agric Food Chem, 57(17), 7731-7736. doi:10.1021/jf9012357