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Chemotherapy-induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol.

  • Brierley, Daniel I1, 2, 3
  • Harman, Joe R4
  • Giallourou, Natasha5
  • Leishman, Emma6
  • Roashan, Anna Emily2
  • Mellows, Ben A D4
  • Bradshaw, Heather B6
  • Swann, Jonathan R7
  • Patel, Ketan4
  • Whalley, Benjamin J2
  • Williams, Claire M1
  • 1 School of Psychology and Clinical Language Sciences, University of Reading, Berkshire, UK.
  • 2 School of Pharmacy, University of Reading, Berkshire, UK.
  • 3 Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
  • 4 School of Biological Sciences, University of Reading, Berkshire, UK.
  • 5 School of Food and Nutritional Sciences, University of Reading, Berkshire, UK.
  • 6 Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA. , (India)
  • 7 Division of Computational and Systems Medicine, Imperial College London, London, UK.
Published Article
Journal of cachexia, sarcopenia and muscle
Publication Date
Aug 01, 2019
DOI: 10.1002/jcsm.12426
PMID: 31035309


Muscle wasting, anorexia, and metabolic dysregulation are common side-effects of cytotoxic chemotherapy, having a dose-limiting effect on treatment efficacy, and compromising quality of life and mortality. Extracts of Cannabis sativa, and analogues of the major phytocannabinoid Δ9-tetrahydrocannabinol, have been used to ameliorate chemotherapy-induced appetite loss and nausea for decades. However, psychoactive side-effects limit their clinical utility, and they have little efficacy against weight loss. We recently established that the non-psychoactive phytocannabinoid cannabigerol (CBG) stimulates appetite in healthy rats, without neuromotor side-effects. The present study assessed whether CBG attenuates anorexia and/or other cachectic effects induced by the broad-spectrum chemotherapy agent cisplatin. An acute cachectic phenotype was induced in adult male Lister-hooded rats by 6 mg/kg (i.p.) cisplatin. In total 66 rats were randomly allocated to groups receiving vehicle only, cisplatin only, or cisplatin and 60 or 120 mg/kg CBG (po, b.i.d.). Feeding behavior, bodyweight and locomotor activity were recorded for 72 hours, at which point rats were sacrificed for post-mortem analyses. Myofibre atrophy, protein synthesis and autophagy dysregulation were assessed in skeletal muscle, plasma metabolic profiles were obtained by untargeted 1H-NMR metabonomics, and levels of endocannabinoid-like lipoamines quantified in plasma and hypothalami by targeted HPLC-MS/MS lipidomics. CBG (120 mg/kg) modestly increased food intake, predominantly at 36-60hrs (p<0.05), and robustly attenuated cisplatin-induced weight loss from 6.3% to 2.6% at 72hrs (p<0.01). Cisplatin-induced skeletal muscle atrophy was associated with elevated plasma corticosterone (3.7 vs 13.1ng/ml, p<0.01), observed selectively in MHC type IIx (p<0.05) and IIb (p<0.0005) fibres, and was reversed by pharmacological rescue of dysregulated Akt/S6-mediated protein synthesis and autophagy processes. Plasma metabonomic analysis revealed cisplatin administration produced a wide-ranging aberrant metabolic phenotype (Q2Ŷ=0.5380, p=0.001), involving alterations to glucose, amino acid, choline and lipid metabolism, citrate cycle, gut microbiome function, and nephrotoxicity, which were partially normalized by CBG treatment (Q2Ŷ=0.2345, p=0.01). Lipidomic analysis of hypothalami and plasma revealed extensive cisplatin-induced dysregulation of central and peripheral lipoamines (29/79 and 11/26 screened, respectively), including reversible elevations in systemic N-acyl glycine concentrations which were negatively associated with the anti-cachectic effects of CBG treatment. Endocannabinoid-like lipoamines may have hitherto unrecognized roles in the metabolic side-effects associated with chemotherapy, with the N-acyl glycine subfamily in particular identified as a potential therapeutic target and/or biomarker of anabolic interventions. CBG-based treatments may represent a novel therapeutic option for chemotherapy-induced cachexia, warranting investigation in tumour-bearing cachexia models. © 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

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