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

• Published in: Journal of cachexia, sarcopenia and muscle sarcopenia and muscle, 2019-08, Vol.10 (4), p.844-859
• Main Authors: Brierley, Daniel I., Harman, Joe R., Giallourou, Natasha, Leishman, Emma, Roashan, Anna Emily, Mellows, Ben A.D., Bradshaw, Heather B., Swann, Jonathan R., Patel, Ketan, Whalley, Benjamin J., Williams, Claire M.
• Format: Article
• Language: English
• Subjects: Animals; Anorexia; Appetite; Cachexia; Cachexia - chemically induced; Cancer therapies; Cannabigerol; Cannabinoid; Cannabinoids - pharmacology; Cannabinoids - therapeutic use; Chemotherapy; Cisplatin; Clinical trials; Cytotoxicity; Disease Models, Animal; Experiments; Food; Humans; Hypothalamus - drug effects; Hypotheses; Laboratories; Lipoamine; Magnetic Resonance Spectroscopy - methods; Male; Metabolism; Mortality; Original; Pilot Projects; Plasma; Quality of life; Rats; Studies
• ISSN: 2190-5991; 2190-6009
• DOI: 10.1002/jcsm.12426

Background 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. Methods 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. Results CBG (120 mg/kg) modestly increased food intake, predominantly at 36‐60hrs (p