Antihyperalgesic Activity of Propoxazepam in the Oxaliplatin-Induced Cold Allodynia in Rats
DOI:
https://doi.org/10.20535/ibb.2025.9.3.334984Keywords:
oxaliplatin-induced peripheral neuropathy, chemotherapy-induced neuropathic pain, propoxazepam, allodynia, GABAergic modulation, anti-inflammatory action, preclinical modelAbstract
Background. Oxaliplatin (OXP), a third-generation chemotherapeutic platinum compound, is widely used in treating metastatic colorectal cancer. However, its clinical utility is limited by oxaliplatin-induced peripheral neuropathy (OIPN), a dose-dependent and often persistent adverse effect characterized by sensory dysfunction such as cold allodynia. Current pharmacological options for OIPN management are limited, with duloxetine being the only drug recommended with moderate confidence by clinical guidelines. Novel analgesics with alternative mechanisms of action are urgently needed.
Objective. This study aimed to evaluate the antihyperalgesic (analgesic) effect of propoxazepam, a novel benzodiazepine derivative with known GABAergic and glycinergic activity, in a rat model of OXP-induced peripheral neuropathy.
Methods. Chronic peripheral neuropathy was induced in male Sprague–Dawley rats via repeated intraperitoneal injections of OXP (4 mg/kg, twice weekly for 3 weeks). Cold allodynia was assessed using the paw immersion test at 10 °C. Rats received a single oral dose of propoxazepam (0.5–8 mg/kg) or duloxetine (100 mg/kg) on days 4, 11, and 18, with paw withdrawal latency (PWL) measured at 60, 120, and 180 minutes post-administration. Data were analyzed using Student's t-test with p £ 0.05 as the threshold for statistical significance.
Results. OXP administration significantly reduced PWL, indicating development of cold allodynia. Propoxazepam demonstrated a dose-dependent analgesic effect starting as early as Day 4. Significant increases in PWL were observed at doses of 4 and 8 mg/kg, with maximal effects on Day 11 (up to 62% relative to the control). While duloxetine induced a stronger initial effect (~70–75%), it diminished rapidly to 19% by 180 minutes. Lower doses (0.5–2 mg/kg) of propoxazepam did not show statistically significant effects. The analgesic effect of propoxazepam peaked at 120 minutes post-administration and declined by 180 minutes.
Conclusions. Propoxazepam effectively reduces cold allodynia in a rat model of OIPN in a dose- and time-dependent manner. Its analgesic efficacy, mediated through GABAergic and glycinergic modulation and supported by anti-inflammatory properties, positions it as a promising candidate for treating chemotherapy-induced neuropathic pain. Given its favorable safety profile and novel mechanism, propoxazepam warrants further investigation in clinical trials.
Objective. This study aimed to evaluate the antihyperalgesic (analgesic) effect of propoxazepam, a novel benzodiazepine derivative with known GABAergic and glycinergic activity, in a rat model of OXP-induced peripheral neuropathy.
Methods: Chronic peripheral neuropathy was induced in male Sprague-Dawley rats via repeated intraperitoneal injections of OXP (4 mg/kg, twice weekly for 3 weeks). Cold allodynia was assessed using the paw immersion test at 10°C. Rats received a single oral dose of propoxazepam (0.5–8 mg/kg) or duloxetine (100 mg/kg) on days 4, 11, and 18, with paw withdrawal latency (PWL) measured at 60, 120, and 180 minutes post-administration. Data were analyzed using Student's t-test with p ≤ 0.05 as the threshold for statistical significance.
Results. OXP administration significantly reduced PWL, indicating development of cold allodynia. Propoxazepam demonstrated a dose-dependent analgesic effect starting as early as Day 4. Significant increases in PWL were observed at doses of 4 and 8 mg/kg, with maximal effects on Day 11 (up to 62% relative to the control). While duloxetine induced a stronger initial effect (~70–75%), it diminished rapidly to 19% by 180 minutes. Lower doses (0.5–2 mg/kg) of propoxazepam did not show statistically significant effects. The analgesic effect of propoxazepam peaked at 120 minutes post-administration and declined by 180 minutes.
Conclusion. Propoxazepam effectively reduces cold allodynia in a rat model of OIPN in a dose- and time-dependent manner. Its analgesic efficacy, mediated through GABAergic and glycinergic modulation and supported by anti-inflammatory properties, positions it as a promising candidate for treating chemotherapy-induced neuropathic pain. Given its favorable safety profile and novel mechanism, propoxazepam warrants further investigation in clinical trials.
References
McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity pharmacogenetics. Molecular Cancer Therapeutics. 2009;8(1):10-6. DOI: 10.1158/1535-7163.MCT-08-0840
Burgess J, Ferdousi M, Gosal D, Boon C, Matsumoto K, Marshall A, et al. Chemotherapy-Induced Peripheral Neuropathy: Epidemiology, Pathomechanisms and Treatment. Oncology and Therapy. 2021;9(2):385-450. DOI: 10.1007/s40487-021-00168-y
Pasetto LM, D'Andrea MR, Rossi E, Monfardini S. Oxaliplatin-related neurotoxicity: How and why? Critical Reviews in Oncology/Hematology. 2006;59(2):159-68. DOI: 10.1016/j.critrevonc.2006.01.001
Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer. New England Journal of Medicine. 2004;350(23):2343–51. DOI: 10.1056/NEJMoa032709
Agnes JP, dos Santos VW, das Neves RN, Gonçalves RM, Delgobo M, Girardi CS, et al. Antioxidants Improve Oxaliplatin-Induced Peripheral Neuropathy in Tumor-Bearing Mice Model: Role of Spinal Cord Oxidative Stress and Inflammation. The Journal of Pain. 2021;22(8):996-1013. DOI: 10.1016/j.jpain.2021.03.142
Mariani G, Garrone O, Granetto C, Numico G, LaCiura P, Grecchi G, et al. Oxaliplatin-induced neuropathy: could gabapentin be the answer? Proceedings of the American Society of Clinical Oncology. 2000;19:2397.
Serpell MG, Neuropathic Pain Study Group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002;99(3):557-66. DOI: 10.1016/S0304-3959(02)00255-5
Golovenko NYa, Larionov VB, Reder AS, Valivodz' IP. An effector analysis of the interaction of propoxazepam with antagonists of GABA and glycine receptors. Neurochemical Journal. 2017;11(4):302-8. DOI: 10.1134/S1819712417040043
Golovenko MYa, Larionov VB, Reder AS, Andronati SA, Valivodz’ IP, Yurpalova TO. Pharmacodynamics of Interaction between Propoxazepam and a GABA-Benzodiazepine Receptor-Ionofor Complex. Neurophysiology. 2018;50(1):2-10. DOI: 10.1007/s11062-018-9711-9
Golovenko M, Reder A, Andronati S, Larionov V. Evidence for the involvement of the GABA-ergic pathway in the anticonvulsant and antinociception activity of Propoxazepam in mice and rats. Journal of Pre-Clinical and Clinical Research. 2019;13(3):99-105. DOI: 10.26444/jpccr/110430
Golovenko NYa, Voloshchuk NI, Andronati SA, Taran IV, Reder AS, Pashynska OS, Larionov VB. Antinociception induced by a novel benzodiazepine receptor agonist and bradykinin receptor antagonist in rodent acute and chronic pain models. European Journal of Biomedical and Pharmaceutical Sciences. 2018;5(12):79-88.
Golovenko M, Reder A, Zupanets I, Bezugla N, Larionov V, Valivodz` I. A Phase I study evaluating the pharmacokinetic profile of a novel oral analgesic propoxazepam. Journal of Pre-Clinical and Clinical Research. 2023;17(3):138-44. DOI: 10.26444/jpccr/169426
Reder AS, Andronati SA, Golovenko MYa, Pavlovskiy VI, Kabanova TA, Khalimova OI, et al. Use of 7-bromo-5-(O-chlorophenyl)-3-propoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one for inhibition of neuropathic pain and seizures of different etiology. Patent of United States US11304956B2, published 19.04.2022.
Andronati S, Semenishyna E, Pavlovsky V, Simonov Y, Makan S, Boyko I, et al. Synthesis, structure and affinity of novel 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones for CNS central and peripheral benzodiazepine receptors. European Journal of Medicinal Chemistry. 2010;45(4):1346-51. DOI: 10.1016/j.ejmech.2009.12.027
Xiao WH, Zheng H, Bennett GJ. Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel. Neuroscience. 2012;203:194-206. DOI: 10.1016/j.neuroscience.2011.12.023
Hu S, Huang KM, Adams EJ, Loprinzi CL, Lustberg MB. Recent Developments of Novel Pharmacologic Therapeutics for Prevention of Chemotherapy-Induced Peripheral Neuropathy. Clinical Cancer Research. 2019;25(21):6295-301. DOI: 10.1158/1078-0432.CCR-18-2152
Eldridge S, Guo L, Hamre J. A Comparative Review of Chemotherapy-Induced Peripheral Neuropathy in In Vivo and In Vitro Models. Toxicologic Pathology. 2020;48(1):190-201. DOI: 10.1177/0192623319861937
Smith EML, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, et al. Effect of Duloxetine on Pain, Function, and Quality of Life Among Patients With Chemotherapy-Induced Painful Peripheral Neuropathy: A Randomized Clinical Trial. JAMA. 2013;309(13):1359-67. DOI: 10.1001/jama.2013.2813
Wang C, Chen S, Jiang W. Treatment for chemotherapy-induced peripheral neuropathy: A systematic review of randomized control trials. Frontiers in Pharmacology. 2022;13:1080888. DOI: 10.3389/fphar.2022.1080888
Chang TW, Yang F-Y, Liu Y-C, Hung C-H. Gabapentinoids for chemotherapy-induced peripheral neuropathy: systematic review and meta-analysis. BMJ Supportive & Palliative Care. 2024;14(3):269-78. DOI: 10.1136/spcare-2023-004362
Golovenko MYa, Valivodz IP, Reder AS, Larionov VB. Antiallodynic effect of propoxazepam at monoiodoacetate-induced osteoarthritis in rats. Pain, Joints, Spine. 2024;14(4):199-204. DOI: 10.22141/pjs.14.4.2024.438
Golovenko NYa, Kabanova TA, Andronati SA, Halimova OI, Larionov VB, Reder AS. Anti-inflammatory effects of propoxazepam on different models of inflammation. International Journal of Medicine and Medical Research. 2019;5(2):105-12. DOI: 10.11603/ijmmr.2413-6077.2019.2.10900
Egashira N. Pathological Mechanisms and Preventive Strategies of Oxaliplatin-Induced Peripheral Neuropathy. Frontiers in Pain Research. 2021;2:804260. DOI: 10.3389/fpain.2021.804260
Golovenko MYa, Reder AS, Larionov VB, Valivodz` IP. The effect of propoxazepam on development of thiosemicarbazide-induced GABA-deficient seizures in mice. Clinical Pharmacy. 2017;21(2):34-40. DOI: 10.24959/cphj.17.1419
Castro-Lopes JM, Tavares I, Coimbra A. GABA decreases in the spinal cord dorsal horn after peripheral neurectomy. Brain Research. 1993;620(2):287-91. DOI: 10.1016/0006-8993(93)90167-L
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