Applied Chemical Engineering

Ursolic acid alleviates alcohol induced nerve damage by regulating MAPK signaling pathway and extracellular matrix remodeling

Wei Zhu

Department of Public Health, International College, Krirk University, Bangkok, Thailand

Na Ge

Department of Public Health, International College, Krirk University, Bangkok, Thailand

DOI: https://doi.org/10.59429/ace.v8i2.5663

Keywords: Ursolic acid; alcohol; nerve damage; zebrafish

---

Abstract

The central nervous system (CNS) is one of the primary targets of alcohol-induced damage. Chronic alcohol consumption leads to cognitive deficits, motor impairments, anxiety-like behaviors, and even irreversible neuronal degeneration and death. However, therapeutic strategies for alcohol-related neurotoxicity remain limited, posing a significant public health concern. Ursolic acid (UA), with its antioxidant, anticancer, anti-inflammatory, hepatoprotective, and immunomodulatory properties, may confer protective effects against neurological damage. In this study, we established a zebrafish model of alcohol-induced neurotoxicity and investigated the potential of UA to mitigate neural injury. Using confocal live imaging in transgenic zebrafish lines, we observed that UA significantly alleviated alcohol-induced reductions in neuronal and dopaminergic neuron populations. Behavioral assays further demonstrated that UA restored normal locomotor activity in zebrafish embryos, indicating functional recovery of the nervous system. Transcriptomic sequencing revealed that UA ameliorated alcohol-induced neurotoxicity potentially by modulating the MAPK signaling pathway and promoting extracellular matrix (ECM) remodeling. This study provides experimental evidence for UA as a therapeutic candidate against alcohol-related neural damage and identifies potential molecular targets for clinical interventions.

---

References

[1]. Rodriguez-Gonzalez, A. & Orio, L. Microbiota and Alcohol Use Disorder: Are Psychobiotics a Novel Therapeutic Strategy? Current pharmaceutical design 26, 2426-2437, doi:10.2174/1381612826666200122153541 (2020).

[2]. Cohen, A. C., Tong, M., Wands, J. R. & de la Monte, S. M. Insulin and insulin-like growth factor resistance with neurodegeneration in an adult chronic ethanol exposure model. Alcoholism, clinical and experimental research 31, 1558-1573, doi:10.1111/j.1530-0277.2007.00450.x (2007).

[3]. Tiwari, V. & Chopra, K. Resveratrol abrogates alcohol-induced cognitive deficits by attenuating oxidative-nitrosative stress and inflammatory cascade in the adult rat brain. Neurochemistry international 62, 861-869, doi:10.1016/j.neuint.2013.02.012 (2013).

[4]. Buhler, M. & Mann, K. Alcohol and the human brain: a systematic review of different neuroimaging methods. Alcoholism, clinical and experimental research 35, 1771-1793, doi:10.1111/j.1530-0277.2011.01540.x (2011).

[5]. Zuccoli, G. et al. Neuroimaging findings in alcohol-related encephalopathies. AJR. American journal of roentgenology 195, 1378-1384, doi:10.2214/AJR.09.4130 (2010).

[6]. Zahr, N. M. & Pfefferbaum, A. Alcohol's Effects on the Brain: Neuroimaging Results in Humans and Animal Models. Alcohol research : current reviews 38, 183-206 (2017).

[7]. Iqbal, J. et al. Ursolic acid a promising candidate in the therapeutics of breast cancer: Current status and future implications. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 108, 752-756, doi:10.1016/j.biopha.2018.09.096 (2018).

[8]. Ku, C. M. & Lin, J. Y. Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes. Food chemistry 141, 1104-1113, doi:10.1016/j.foodchem.2013.04.044 (2013).

[9]. Tan, J., Huang, W., Chen, S. L. & Yue, Y. [Synthesis and anti-inflammatory activity of ursolic acid derivative-chalcone conjugates]. Yao xue xue bao = Acta pharmaceutica Sinica 51, 938-946 (2016).

[10]. Cargnin, S. T. & Gnoatto, S. B. Ursolic acid from apple pomace and traditional plants: A valuable triterpenoid with functional properties. Food chemistry 220, 477-489, doi:10.1016/j.foodchem.2016.10.029 (2017).

[11]. Rai, S. N. et al. Anti-inflammatory Activity of Ursolic Acid in MPTP-Induced Parkinsonian Mouse Model. Neurotoxicity research 36, 452-462, doi:10.1007/s12640-019-00038-6 (2019).

[12]. Iannuzzo, F. et al. Therapeutic Effect of an Ursolic Acid-Based Nutraceutical on Neuronal Regeneration after Sciatic Nerve Injury. International journal of molecular sciences 25, doi:10.3390/ijms25020902 (2024).

[13]. Kalueff, A. V., Stewart, A. M. & Gerlai, R. Zebrafish as an emerging model for studying complex brain disorders. Trends in pharmacological sciences 35, 63-75, doi:10.1016/j.tips.2013.12.002 (2014).

[14]. Cuoghi, B. & Mola, L. Microglia of teleosts: facing a challenge in neurobiology. European journal of histochemistry : EJH 51, 231-240 (2007).

[15]. Wager, K. & Russell, C. Mitophagy and neurodegeneration: the zebrafish model system. Autophagy 9, 1693-1709, doi:10.4161/auto.25082 (2013).

[16]. Bretaud, S., MacRaild, S., Ingham, P. W. & Bandmann, O. The influence of the zebrafish genetic background on Parkinson's disease-related aspects. Zebrafish 8, 103-108, doi:10.1089/zeb.2011.0697 (2011).

[17]. Vinciguerra, P., Iglesias, N., Camblong, J., Zenklusen, D. & Stutz, F. Perinuclear Mlp proteins downregulate gene expression in response to a defect in mRNA export. The EMBO journal 24, 813-823, doi:10.1038/sj.emboj.7600527 (2005).

[18]. Kimmel, C. B., Ballard, W. W., Kimmel, S. R., Ullmann, B. & Schilling, T. F. Stages of embryonic development of the zebrafish. Developmental dynamics : an official publication of the American Association of Anatomists 203, 253-310, doi:10.1002/aja.1002030302 (1995).

[19]. Dasgupta, T., Manickam, V. & Tamizhselvi, R. Benzydamine rescues ethanol-induced teratogenesis in zebrafish FASD model. Scientific reports 15, 9066, doi:10.1038/s41598-025-93539-8 (2025).

[20]. Bernardo, H. T. et al. Naltrexone Alters Neurochemical and Behavioral Parameters in a Zebrafish Model of Repeated Alcohol Exposure. Neurochemical research 50, 97, doi:10.1007/s11064-025-04349-3 (2025).

[21]. Sahu, S., Li, R., Kadeyala, P. K., Liu, S. & Schachner, M. The human natural killer-1 (HNK-1) glycan mimetic ursolic acid promotes functional recovery after spinal cord injury in mouse. The Journal of nutritional biochemistry 55, 219-228, doi:10.1016/j.jnutbio.2018.01.016 (2018).

[22]. Qiu, L. et al. Ursolic Acid Ameliorated Neuronal Damage by Restoring Microglia-Activated MMP/TIMP Imbalance in vitro. Drug design, development and therapy 17, 2481-2493, doi:10.2147/DDDT.S411408 (2023).

[23]. Wang, Y., He, Z. & Deng, S. Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury. Drug design, development and therapy 10, 1663-1674, doi:10.2147/DDDT.S103829 (2016).

[24]. Lei, P. et al. Ursolic Acid Alleviates Neuroinflammation after Intracerebral Hemorrhage by Mediating Microglial Pyroptosis via the NF-kappaB/NLRP3/GSDMD Pathway. International journal of molecular sciences 24, doi:10.3390/ijms241914771 (2023).

[25]. Wang, Y., Li, L., Deng, S., Liu, F. & He, Z. Ursolic Acid Ameliorates Inflammation in Cerebral Ischemia and Reperfusion Injury Possibly via High Mobility Group Box 1/Toll-Like Receptor 4/NFkappaB Pathway. Frontiers in neurology 9, 253, doi:10.3389/fneur.2018.00253 (2018).