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

Background Muscle wasting, anorexia, and metabolic dysregulation are common side-effects of cytotoxic chemotherapy, which have a dose-limiting effect on treatment efficacy, and compromise 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 demonstrated little efficacy against weight loss. We have recently shown that the non-psychoactive phytocannabinoid cannabigerol (CBG) stimulates appetite in healthy rats, without neuromotor side-effects. The present study was thus designed to test whether CBG could attenuate anorexia and/or any 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 administration of 6 mg/kg (i.p.) cisplatin. A total of 66 rats were randomly allocated to groups receiving vehicle only, cisplatin only, or cisplatin and either 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 plasma and hypothalamic levels of endocannabinoid-like lipoamines were quantified by targeted HPLC-MS/MS lipidomics. Results 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 and observed selectively in MHC type IIx and IIb fibres, which was reversed by pharmacological rescue of dysregulated Akt/S6-mediated protein synthesis and autophagy processes. Plasma metabonomic analysis revealed cisplatin-induced cachexia was associated with a wide-ranging aberrant metabolic phenotype, involving alterations to glucose, amino acid, choline and lipid metabolism, citrate cycle, gut microbiome function, and nephrotoxicity, which were partially normalized by CBG treatment. Lipidomic analysis of hypothalami and plasma revealed extensive cisplatin-induced dysregulation of central and peripheral lipoamines, including reversible elevations in systemic N-acyl glycine concentrations which were negatively associated with the anti-cachectic effects of CBG treatment. Conclusions 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

Understanding communication pathways to foster community engagement for health improvement in North West Pakistan

Background: This paper describes the community engagement process undertaken to ascertain the focus, development and implementation of an intervention to improve iodised salt consumption in rural communities in North West Pakistan. The Jirga is a traditional informal structure, which gathers men respected within their community and acts in a governing and decision making capacity in the Pukhtoon culture. The Jirga system had a dual purpose for the study; to access men from the community to discuss the importance of iodised salt, and as an engagement process for the intervention. Methods: A number of qualitative data collection activities were undertaken, with Jirga members and their wives, male and female outreach workers and two groups of women, under and over forty years old. The aim of these were to highlight the communication channels and levers of influence on health behaviour, which were multiple and complex and all needed to be taken into consideration in order to ensure successful and locally sensitive community engagement. Results: Communication channels are described within local families and the communities around them. The key influential role of the Jirga is highlighted as linked both to the standing of its members and the community cohesion ethos that it embodies. Engaging Jirga members in discussions about iodised salt was key in designing an intervention that would activate the most influential levers to decision making in the community. Gendered decision making-processes within the household have been highlighted as restricting women’s autonomy. Whilst in one respect our data confirm this, a more complex hierarchy of decisional power has been highlighted, whereby the concept of ‘wisdom’, an amalgamation of age, experience and education, presents important possibilities. Community members with the least autonomy are the youngest uneducated females, who rely on a web of socially and culturally determined ways to influence decision-making. Conclusions: The major lines of communication and influence in the local community described are placed within the wider literature on community engagement in health improvement. The process of maximisation of local cultural knowledge as part of a community engagement effort is one that has application well beyond the particular setting of this study

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

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<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. Conclusions: 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