Paclitaxel-induced neuropathy induces changes in oral cavity organs of rats
Abstract
The developmental mechanisms of pathological changes in the oral cavity organs, in particular, periodontal tissues and salivary glands, were elucidated in the model of paclitaxel-induced neuropathy. Experimental studies were performed on 41 white nonlinear rats of both sexes weighing 180–220 g. Toxic neuropathy was modeled by intraperitoneal injection of paclitaxel (Actavis Ltd; series 5GN5122) 2 mg/kg for 4 days (0, 2, 4 and 6). The presence of paclitaxel-induced peripheral neuropathy was confirmed by the Randall-Selitto tensoalgometric test to determine the threshold of pain sensitivity. The total proteolytic activity, total antitryptic activity, and the content of TBA-active products were determined in the homogenate of the rat submandibular and sublingual salivary glands and periodontal soft tissues, content of oxidatively modified proteins, content of average mass molecules and catalase activity; α-amylase activity was also determined in the salivary glands of animals, and the content of free fucose and glycosaminoglycans in periodontal tissues. Paclitaxel-induced neuropathy causes the development of pathological changes in the oral cavity, in particular in periodontal tissues and salivary glands of rats, as evidenced by impaired proteinase-inhibitory potential, intensification of carbonyl oxidative stress, inhibition of protein synthetic function in salivary glands and increased depolymerization of non-collagenous proteins in periodontal soft tissues.References
Areti, A., Yerra, V. G., Naidu, V., & Kumar, A. (2014). Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy. Redox Biology, 2, 289–295.
Boyette-Davis, J. A., Cata, J. P., Driver, L. C., Novy, D. M., Bruel, B. M., Mooring, D. L., Wendelschafer-Crabb, G., Kennedy, W. R., & Dougherty, P. M. (2012). Persistent chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine. Cancer Chemotherapy and Pharmacology, 71(3), 619–626.
Caraway, W. T. (1959). A stable starch substrate for the determination of amylase in serum and other body fluids. American Journal of Clinical Pathology, 32(1), 97–99.
Cavaletti, G. (2014). Chemotherapy-induced peripheral neurotoxicity (CIPN): What we need and what we know. Journal of the Peripheral Nervous System, 19(2), 66–76.
Chua, K. C., El‐Haj, N., Priotti, J., & Kroetz, D. L. (2021). Mechanistic insights into the pathogenesis of microtubule‐targeting agent‐induced peripheral neuropathy from pharmacogenetic and functional studies. Basic and Clinical Pharmacology and Toxicology, 130(S1), 60–74.
Cirrincione, A. M., Pellegrini, A. D., Dominy, J. R., Benjamin, M. E., Utkina-Sosunova, I., Lotti, F., Jergova, S., Sagen, J., & Rieger, S. (2020). Paclitaxel-induced peripheral neuropathy is caused by epidermal ROS and mitochondrial damage through conserved MMP-13 activation. Scientific Reports, 10, 3970.
Dougherty, P. M., Cata, J. P., Cordella, J. V., Burton, A., & Weng, H.-R. (2004). Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients. Pain, 109(1), 132–142.
Dubinina, E. E., Burmistrov, S. O., Khodov, D. A., & Porotov, I. G. (1995). Okislitel’naja modifikatsija belkov syvorotki krovi cheloveka, metod ee opredelenija [Oxidative modification of human serum proteins. A method of determining it]. Voprosy Meditsinskoj Khimii, 41(1), 24–26 (in Russian).
Duggett, N. A., Griffiths, L. A., & Flatters, S. J. L. (2017). Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons. Pain, 158(8), 1499–1508.
Duggett, N. A., Griffiths, L. A., McKenna, O. E., de Santis, V., Yongsanguanchai, N., Mokori, E. B., & Flatters, S. J. L. (2016). Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy. Neuroscience, 333, 13–26.
Eldridge, S., Guo, L., & Hamre, J. (2019). A comparative review of chemotherapy-induced peripheral neuropathy in in vivo and in vitro models. Toxicologic Pathology, 48(1), 190–201.
Flatters, S. J. L., Dougherty, P. M., & Colvin, L. A. (2017). Clinical and preclinical perspectives on chemotherapy-induced peripheral neuropathy (CIPN): A narrative review. British Journal of Anaesthesia, 119(4), 737–749.
Fukuda, Y., Li, Y., & Segal, R. A. (2017). A mechanistic understanding of axon degeneration in chemotherapy-induced peripheral neuropathy. Frontiers in Neuroscience, 11, 481.
Gordon-Williams, R., & Farquhar-Smith, P. (2020). Recent advances in understandding chemotherapy-induced peripheral neuropathy. F1000Research, 9, 177.
Gornstein, E. L., & Schwarz, T. L. (2017). Neurotoxic mechanisms of paclitaxel are local to the distal axon and independent of transport defects. Experimental Neurology, 288, 153–166.
Hershman, D. L., Lacchetti, C., Dworkin, R. H., Lavoie Smith, E. M., Bleeker, J., Cavaletti, G., Chauhan, C., Gavin, P., Lavino, A., Lustberg, M. B., Paice, J., Schneider, B., Smith, M. L., Smith, T., Terstriep, S., Wagner-Johnston, N., Bak, K., & Loprinzi, C. L. (2014). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology, 32(18), 1941–1967.
Ji, R.-R., Berta, T., & Nedergaard, M. (2013). Glia and pain: Is chronic pain a gliopathy? Pain, 154, S10–S28.
Kaidashev, I. P., (2003). Metody klinichnykh ta eksperymentalnykh doslidzhen’ v medytsyni [Methods of clinical and experimental research in medicine]. Polimet, Poltava (in Ukrainian).
Kapitein, L. C., & Hoogenraad, C. C. (2015). Building the neuronal microtubule cytoskeleton. Neuron, 87(3), 492–506.
Klein, I., & Lehmann, H. C. (2021). Pathomechanisms of paclitaxel-induced peripheral neuropathy. Toxics, 9(10), 229.
Koroliuk, M. A., Ivanova, L. I., Maĭorova, I. G., & Tokarev, V. E. (1988). Metod opredelenija aktivnosti katalazy [A method of determining catalase activity]. Laboratornoe Delo, 1, 16–19 (in Russian).
Brandolini, L., Benedetti, E., Ruffini, P. A., Russo, R., Cristiano, L., Antonosante, A., d’Angelo, M., Castelli, V., Giordano, A., Allegretti, M., & Cimini, A. C. (2017). CXCR1/2 pathways in paclitaxel-induced neuropathic pain. Oncotarget, 8(14), 23188–23201.
Lisse, T. S., Middleton, L. J., Pellegrini, A. D., Martin, P. B., Spaulding, E. L., Lopes, O., Brochu, E. A., Carter, E. V., Waldron, A., & Rieger, S. (2016). Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish. Proceedings of the National Academy of Sciences, 113(15), E2189–E2198.
McCormick, B., Lowes, D. A., Colvin, L., Torsney, C., & Galley, H. F. (2016). MitoVitE, a mitochondria-targeted antioxidant, limits paclitaxel-induced oxidative stress and mitochondrial damage in vitro, and paclitaxel-induced mechanical hypersensitivity in a rat pain model. British Journal of Anaesthesia, 117(5), 659–666.
Pachman, D. R., Qin, R., Seisler, D., Smith, E. M. L., Kaggal, S., Novotny, P., Ruddy, K. J., Lafky, J. M., Ta, L. E., Beutler, A. S., Wagner-Johnston, N. D., Staff, N. P., Grothey, A., Dougherty, P. M., Cavaletti, G., & Loprinzi, C. L. (2016). Comparison of oxaliplatin and paclitaxel-induced neuropathy (Alliance A151505). Supportive Care in Cancer, 24(12), 5059–5068.
Randall, L. O., & Selitto, J. J. (1957). A method for measurement of analgesic activity on inflammed tissue. Archives Internationales de Pharmacodynamie et de Therapie, 111, 409–419.
Santos-Nogueira, E., Redondo Castro, E., Mancuso, R., & Navarro, X. (2012). Randall-Selitto test: A new approach for the detection of neuropathic pain after spinal cord injury. Journal of Neurotrauma, 29(5), 898–904.
Seretny, M., Currie, G., Sena, E., Ramnarine, S., Grant, R., Macleod, M., Colvin, L., & Fallon, M. (2014). CN-16 incidence, prevalence and predictors of chemotherapy induced peripheral neuropathy: A systematic review and meta-analysis. Neuro-Oncology, 16(Suppl. 5), v49.
Sharaev, P. N., Pishkov, V. N., Soloveva, N. I., Shirokova, T. I., & Soloveva, T. V. (1987). Metod opredeleniia glikozaminoglikanov v biologicheskikh zhidkostiakh [Method of determining glycosaminoglycans in biological fluids]. Laboratornoe Delo, 5, 330–332.
Sharaev, P. N., Strelkov, R. R., & Kyldyiarova, A. A. (1997). Metod opredelenija fukozy, nesviazannoji z belkamy [Method for the determination of fucose not bound to proteins]. Klynycheskaja Laboratornaja Diahnostyka, 4, 17–18.
Shim, H. S., Bae, C., Wang, J., Lee, K.-H., Hankerd, K. M., Kim, H. K., Chung, J. M., & La, J.-H. (2019). Peripheral and central oxidative stress in chemotherapy-induced neuropathic pain. Molecular Pain, 15, 174480691984009.
Staff, N. P., Fehrenbacher, J. C., Caillaud, M., Damaj, M. I., Segal, R. A., & Rieger, S. (2020). Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems. Experimental Neurology, 324, 113121.
Stalnaya, I. D., & Garishvili, T. G. (1977). Metod opredelenija malonovogo dial’degida s pomoshchyu tiobarbiturovoj kisloty [Method for the determination of malondialdehyde using thiobarbituric acid]. Sovremennye Metody v Biokhimii, 1977, 66–68 (in Russian).
Tofthagen, C., McAllister, R. D., & Visovsky, C. (2013). Peripheral neuropathy caused by paclitaxel and docetaxel: An evaluation and comparison of symptoms. Journal of the Advanced Practitioner in Oncology, 4, 204–215.
Ugolev, A. M., Iezuitova, N. N., & Masevich, U. G. (1969). Issledovanie pishchevaritel’nogo apparata u cheloveka [Study of the human digestive system]. Nauka, Leningrad (in Russian).
Van den Bent, M. J., van Raaij-van den Aarssen, V. J. M., Verweij, J., Doorn, P. A. V., & Sillevis Smitt, P. A. E. (1997). Progression of paclitaxel-induced neuropathy following discontinuation of treatment. Muscle and Nerve, 20(6), 750–752.
Veremeenko, K. N., Goloborodko, O. P., & Kizim, A. I. (1988). Proteoliz v norme i pri patologii [Proteolysis in norm and pathology]. Zdorovya, Kiev (in Russian).
Zhang, H., Li, Y., de Carvalho-Barbosa, M., Kavelaars, A., Heijnen, C. J., Albrecht, P. J., & Dougherty, P. M. (2016). Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy-induced peripheral neuropathy. The Journal of Pain, 17(7), 775–786.

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