Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies

Abstract

<jats:sec> <jats:title>Background:</jats:title> <jats:p> Painful peripheral neuropathy is a dose-limiting adverse effect of the antitumor drug oxaliplatin. The main symptoms of neuropathy: tactile allodynia and cold hyperalgesia, appear in more than 80% of patients on oxaliplatin therapy and are due to the overexpression of neuronal sodium channels (Navs) and neuroinflammation.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p> This study assessed antiallodynic and antihyperalgesic properties of two repurposed drugs with antiinflammatory and Nav-blocking properties (bromhexine and its pharmacologically active metabolite - ambroxol) in a mouse model of neuropathic pain induced by oxaliplatin. Using molecular docking techniques, we predicted targets implicated in the observed in vivo activity of bromhexine.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Oxaliplatin (a single intraperitoneal dose of 10 mg/kg) induced tactile allodynia and cold hyperalgesia in CD-1 mice and the effectiveness of single-dose or repeated-dose bromhexine and ambroxol to attenuate pain hypersensitivity was assessed in von Frey and cold plate tests. Additionally, Veber analysis and molecular docking experiments of bromhexine to mouse (m) and human (h) Nav1.6-1.9 were carried out. Results: At the corresponding doses ambroxol was more effective than bromhexine as an antiallodynic agent. However, at the dose of 150 mg/kg ambroxol induced motor impairments in mice. Repeated-dose bromhexine and ambroxol partially attenuated the development of late-phase tactile allodynia in oxaliplatin-treated mice. Only 7-day administration of bromhexine attenuated the development of late-phase cold hyperalgesia. Bromhexine was predicted to be a strong inhibitor of mNav1.6, mNav1.7, mNav1.9, and hNav1.7 - hNav1.9.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>The conversion of bromhexine to other than ambroxol active metabolites should be considered when interpreting some of its in vivo effects. Nav-blocking properties of bromhexine (and previously also predicted for ambroxol) might underlie their ability to attenuate pain caused by oxaliplatin.</jats:p> </jats:sec>

The Microglial Activation Inhibitor Minocycline, Used Alone and in Combination with Duloxetine, Attenuates Pain Caused by Oxaliplatin in Mice

“…In the von Frey test, significant differences were noted between the pre-drug paw withdrawal threshold in the early phase of the study and the pre-drug paw withdrawal threshold in the late phase of the study (day 7 after oxaliplatin) for repeated-dose ambroxol (90 mg/kg). This finding indicated that the repeated administration of this drug partially attenuated the tactile allodynia caused by oxaliplatin [41].…”

“…In our recent study [41], we demonstrated that intraperitoneal ambroxol (90 mg/kg) used as a single or repeated dose attenuated tactile allodynia in oxaliplatin-treated mice. In the von Frey test, significant differences were noted between the pre-drug paw withdrawal threshold in the early phase of the study and the pre-drug paw withdrawal threshold in the late phase of the study (day 7 after oxaliplatin) for repeated-dose ambroxol (90 mg/kg).…”

“…Our previous study showed that intraperitoneal ambroxol (90 mg/kg) used alone did not increase the cold pain threshold of oxaliplatin-treated mice [41].…”

Platinum-Induced Peripheral Neuropathy (PIPN): ROS-Related Mechanism, Therapeutic Agents, and Nanosystems

“…ROS also induce the release of Ca 2+ by activating inositol 1,4,5-trisphosphate receptors (IP3R) to open the permeability transition pore, thereby changing the permeability of mitochondria to further release more ROS as a vicious cycle ( Csordas and Hajnoczky, 2009 ; Kiselyov and Muallem, 2016 ). Moreover, voltage-gated sodium (NaV) channels play a role in initiating action potentials in DRG neurons, whose surface modification affects neuronal electrical excitability and participate in the development of cold abnormal pain ( Furgala-Wojas et al, 2020 ). For example, Pt drugs prolong Nav1.6 open times and increase persistent current in DRG neurons, which aggravate cold abnormal pain ( Sittl et al, 2012 ).…”

Assessment of Paroxetine Molecular Interactions with Selected Monoamine and γ-Aminobutyric Acid Transporters

“…The calculation procedures applied in the study are typical for processing of docking studies [63,[89][90][91].…”