Submission
| Title: | Peripherally Restricted Inhibitor of Monoacylglycerol Lipase LEI-515 Suppresses Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model Through a CB2-Mediated Mechanism of Action |
| Authors: |
Wirt, Jonah, Department of Psychological and Brain Sciences, Program in Neuroscience, Gill Center for Biomolecular Science, Indiana University Bloomington; M. Jiang, Department of Molecular Physiology, Leiden University and Oncode Institute, Netherlands; M. Huizenga, Department of Molecular Physiology, Leiden University and Oncode Institute, Netherlands; A. Makriyannis, Department of Pharmaceutical Sciences, Northeastern University; M. Van Der Stelt, Department of Molecular Physiology, Leiden University and Oncode Institute, Netherlands; A.G. Hohmann, Department of Psychological and Brain Sciences, Program in Neuroscience, Gill Center for Biomolecular Science, Indiana University Bloomington |
Abstract
Background/Significance/Rationale: Monoacylglycerol lipase (MAGL) is the major enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Inhibitors of endocannabinoid deactivation show therapeutic potential for suppressing pathological pain.
Methods: In these studies, we used LEI-515, a first-in-class peripherally restricted MAGL inhibitor, to validate the therapeutic potential of inhibiting MAGL selectively outside the central nervous system (CNS) in a chemotherapy-induced peripheral neuropathy model using the taxane chemotherapeutic agent paclitaxel in mice of both sexes.
Results/Findings: LEI-515 suppressed established mechanical allodynia following intraperitoneal and oral administration. Anti-allodynic efficacy of LEI-515 was sustained for at least 24 h following acute administration. Anti-allodynic efficacy of LEI-515, administered intraperitoneally and orally, was preserved following repeated dosing over 10 consecutive days, whereas the brain penetrant MAGL inhibitor JZL184 produced tolerance in the same model (Slivicki et al, 2018). LEI-515 similarly suppressed cold allodynia in paclitaxel-treated mice. LEI-515 did not alter mechanical thresholds or cold allodynia in control mice that received the cremophor vehicle in lieu of paclitaxel. Pharmacological specificity of LEI-515 efficacy was assessed in paclitaxel-treated mice using CB1 (AM251 and AM6545) and CB2 (AM630 and SR144528) antagonists that differ in their ability to penetrate the CNS. Anti-allodynic efficacy of LEI-515 was attenuated by either CNS penetrant (AM630) or peripherally-restricted (SR144528) CB2 antagonists but not by CNS penetrant (AM251) or peripherally restricted (AM6545) CB1 antagonists. LEI-515 did not produce cardinal signs of CB1 activation. Challenge with the CB1 antagonist rimonabant produced signs of physical dependence in mice treated chronically with the orthosteric agonist WIN55,212-2 and the brain penetrant MAGL inhibitor JZL184, but not LEI-515.
Conclusions/Discussion: These observations further suggest that the therapeutic profile of LEI-515 is mediated by a peripheral CB2 mechanism.
Translational/Human Health Impact: Our studies suggest that LEI-515 shows promise as a therapeutic strategy for suppressing chemotherapy-induced neuropathic pain in patients without producing unwanted pharmacological effects associated with direct CB1 activation.
