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5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT(3) receptors and monoamines

Vincristine is the drug of choice for Hodgkin’s lymphoma, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Despite its significant anticancer effects, it causes dose-dependent neuropathy, leading to compulsive dose reduction. The available drugs used for vincristine-induced neuropathic pain (...

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Autores principales: Usman, Muhammad, Malik, Hurmat, Tokhi, Ahmed, Arif, Mehreen, Huma, Zilli, Rauf, Khalid, Sewell, Robert D. E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619918/
https://www.ncbi.nlm.nih.gov/pubmed/37920212
http://dx.doi.org/10.3389/fphar.2023.1213763
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author Usman, Muhammad
Malik, Hurmat
Tokhi, Ahmed
Arif, Mehreen
Huma, Zilli
Rauf, Khalid
Sewell, Robert D. E.
author_facet Usman, Muhammad
Malik, Hurmat
Tokhi, Ahmed
Arif, Mehreen
Huma, Zilli
Rauf, Khalid
Sewell, Robert D. E.
author_sort Usman, Muhammad
collection PubMed
description Vincristine is the drug of choice for Hodgkin’s lymphoma, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Despite its significant anticancer effects, it causes dose-dependent neuropathy, leading to compulsive dose reduction. The available drugs used for vincristine-induced neuropathic pain (VINP) have a range of safety, efficacy, and tolerability issues prompting a search for new therapies. 5,7-Dimethoxycoumarin (5,7-DMC) also known as citropten, is a natural coumarin found in the essential oils of citrus plants such as lime, lemons, and bergamots, and it possesses both antidepressant and anti-inflammatory effects. This study was designed to investigate the possible analgesic and antiallodynic effects of 5,7-DMC in a murine model of VINP. Vincristine was administered to groups of BALB/c male mice (0.1 mg/kg intraperitoneally) once daily for 14 days to induce VINP. Thermal hyperalgesia and mechanical allodynia were quantified using the tail immersion test and von Frey filament application method. The levels of monoamine neurotransmitters and vitamin C in frontal cortical, striatal and hippocampal tissues, as well as the TNF-α level in plasma, were quantified using high performance liquid chromatography and ELISA respectively. On day 15 of the protocol, acute treatment with 5,7-DMC clearly reversed VINP thermal hyperalgesia, mechanical static allodynia, mechanical dynamic allodynia, and cold allodynia. The activity of 5,7-DMC against hyperalgesia and allodynia was inhibited by pretreatment with ondansetron but not naloxone, implicating a 5-HT(3) receptor involvement. VINP vitamin C levels were restored by 5,7-DMC in the frontal cortex, and changes in serotonin, dopamine, adenosine, inosine and hypoxanthine levels caused by vincristine were reversed either fully or partially. Additionally, the vincristine-induced rise in hippocampal serotonin, dopamine, inosine and striatal serotonin was appreciably reversed by 5,7-DMC. 5,7-DMC also reversed the vincristine-induced increase in the plasma level of TNF-α. In negating the changes in the levels of some neurotransmitters in the brain caused by vincristine, 5,7-DMC showed stronger effects than gabapentin. It was concluded that, there is a potential role of 5-HT3 receptors and monoamines in the amelioration of VINP induced by 5,7-DMC, and the use of this compound warrants further investigation.
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spelling pubmed-106199182023-11-02 5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT(3) receptors and monoamines Usman, Muhammad Malik, Hurmat Tokhi, Ahmed Arif, Mehreen Huma, Zilli Rauf, Khalid Sewell, Robert D. E. Front Pharmacol Pharmacology Vincristine is the drug of choice for Hodgkin’s lymphoma, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Despite its significant anticancer effects, it causes dose-dependent neuropathy, leading to compulsive dose reduction. The available drugs used for vincristine-induced neuropathic pain (VINP) have a range of safety, efficacy, and tolerability issues prompting a search for new therapies. 5,7-Dimethoxycoumarin (5,7-DMC) also known as citropten, is a natural coumarin found in the essential oils of citrus plants such as lime, lemons, and bergamots, and it possesses both antidepressant and anti-inflammatory effects. This study was designed to investigate the possible analgesic and antiallodynic effects of 5,7-DMC in a murine model of VINP. Vincristine was administered to groups of BALB/c male mice (0.1 mg/kg intraperitoneally) once daily for 14 days to induce VINP. Thermal hyperalgesia and mechanical allodynia were quantified using the tail immersion test and von Frey filament application method. The levels of monoamine neurotransmitters and vitamin C in frontal cortical, striatal and hippocampal tissues, as well as the TNF-α level in plasma, were quantified using high performance liquid chromatography and ELISA respectively. On day 15 of the protocol, acute treatment with 5,7-DMC clearly reversed VINP thermal hyperalgesia, mechanical static allodynia, mechanical dynamic allodynia, and cold allodynia. The activity of 5,7-DMC against hyperalgesia and allodynia was inhibited by pretreatment with ondansetron but not naloxone, implicating a 5-HT(3) receptor involvement. VINP vitamin C levels were restored by 5,7-DMC in the frontal cortex, and changes in serotonin, dopamine, adenosine, inosine and hypoxanthine levels caused by vincristine were reversed either fully or partially. Additionally, the vincristine-induced rise in hippocampal serotonin, dopamine, inosine and striatal serotonin was appreciably reversed by 5,7-DMC. 5,7-DMC also reversed the vincristine-induced increase in the plasma level of TNF-α. In negating the changes in the levels of some neurotransmitters in the brain caused by vincristine, 5,7-DMC showed stronger effects than gabapentin. It was concluded that, there is a potential role of 5-HT3 receptors and monoamines in the amelioration of VINP induced by 5,7-DMC, and the use of this compound warrants further investigation. Frontiers Media S.A. 2023-10-17 /pmc/articles/PMC10619918/ /pubmed/37920212 http://dx.doi.org/10.3389/fphar.2023.1213763 Text en Copyright © 2023 Usman, Malik, Tokhi, Arif, Huma, Rauf and Sewell. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Usman, Muhammad
Malik, Hurmat
Tokhi, Ahmed
Arif, Mehreen
Huma, Zilli
Rauf, Khalid
Sewell, Robert D. E.
5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT(3) receptors and monoamines
title 5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT(3) receptors and monoamines
title_full 5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT(3) receptors and monoamines
title_fullStr 5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT(3) receptors and monoamines
title_full_unstemmed 5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT(3) receptors and monoamines
title_short 5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT(3) receptors and monoamines
title_sort 5,7-dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5ht(3) receptors and monoamines
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619918/
https://www.ncbi.nlm.nih.gov/pubmed/37920212
http://dx.doi.org/10.3389/fphar.2023.1213763
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