目的:肌萎缩侧索硬化症(ALS)的临床前研究表明,内源性大麻素(eCB)信号的改变可能与该疾病有关。人类研究的结果很少且尚无定论。这项研究的目的是确定eCBs或其同源物的血清水平之间的关联,所谓的内源性大麻素,以及ALS患者的疾病状态和活动。
方法:血清2-花生四酰基甘油和N-花生四酰基乙醇胺(AEA)的浓度,和AEA同源物棕榈酰乙醇胺(PEA),油酰乙醇胺(OEA),二十碳五烯酰乙醇胺(EPEA),在65名ALS患者的样品中测量了2-二十二碳六烯酰甘油(2-DHG)和二十二碳六烯酰乙醇胺(DHEA),32名健康对照(HCs)和16名神经系统疾病对照(NALS)。46名ALS患者的子集进行了纵向研究。疾病活动和进展与eCB和同源物水平相关。
结果:ALS中大多数循环介质高于HC(均p<0.001),但不是NALS。在整个临床阶段,ALS患者的PEA水平升高,OEA和EPEA(所有p<0.02),纵向研究证实了这一点(所有p<0.03)。血清PEA和OEA水平是生存的独立预测因子,而抱怨食欲不振的患者OEA水平较高。聚类分析显示与相应的疾病活动模式相关的循环介质的两个不同特征(严重与温和)。与NALS和HC相比,属于“严重”集群的患者显示出OEA和PEA水平明显较高,2-DHG水平较低。
结论:循环内源性大麻素组织谱是疾病活动的指示,因此可能为个性化铺平道路,而不是“一刀切”,针对内源性大麻素的治疗方法。
OBJECTIVE: Preclinical studies of amyotrophic lateral sclerosis (ALS) have shown altered
endocannabinoid (eCB) signalling that may contribute to the disease. Results from human studies are sparse and inconclusive. The aim of this study was to determine the association between serum levels of eCBs or their congeners, the so-called endocannabinoidome, and disease status and activity in ALS patients.
METHODS: Serum concentrations of 2-arachidonoylglycerol and N-arachidonoylethanolamine (AEA), and AEA congeners palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2-docosahexaenoylglycerol (2-DHG) and docosahexaenoylethanolamide (DHEA) were measured in samples from 65 ALS patients, 32 healthy controls (HCs) and 16 neurological disease controls (NALS). A subset of 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCB and congener levels.
RESULTS: Most circulating mediators were higher in ALS than HCs (all p < 0.001), but not NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA and EPEA (all p < 0.02), which were confirmed by the longitudinal study (all p < 0.03). Serum PEA and OEA levels were independent predictors of survival and OEA levels were higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating mediators associated with corresponding patterns of disease activity (severe vs. mild). Patients belonging to the \'severe\' cluster showed significantly higher levels of OEA and PEA and lower levels of 2-DHG compared to NALS and HCs.
CONCLUSIONS: Circulating endocannabinoidome profiles are indicative of disease activity, thus possibly paving the way to a personalized, rather than a \'one-fits-all\', therapeutic approach targeting the endocannabinoidome.