Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, Bern, 3012, Switzerland.
Synendos Therapeutics AG, Barfuesserplatz 3, Basel, 4051, Switzerland.
Acta Neuropathol Commun. 2024 Oct 10;12(1):160. doi: 10.1186/s40478-024-01864-2.
Multiple sclerosis (MS) is a complex chronic neuroinflammatory disease characterized by demyelination leading to neuronal dysfunction and neurodegeneration manifested by various neurological impairments. The endocannabinoid system (ECS) is a lipid signalling network, which plays multiple roles in the central nervous system and the periphery, including synaptic signal transmission and modulation of inflammation. The ECS has been identified as a potential target for the development of novel therapeutic interventions in MS patients. It remains unclear whether ECS-associated metabolites are changed in MS and could serve as biomarkers in blood or cerebrospinal fluid (CSF). In this retrospective study we applied targeted lipidomics to matching CSF and serum samples of 74 MS and 80 non-neuroinflammatory control patients. We found that MS-associated lipidomic changes overall did not coincide between CSF and serum. While glucocorticoids correlated positively, only the endocannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) showed a weak positive correlation (r = 0.3, p < 0.05) between CSF and serum. Peptide endocannabinoids could be quantified for the first time in CSF but did not differ between MS and controls. MS patients showed elevated levels of prostaglandin E2 and steaorylethanolamide in serum, and 2-oleoylglycerol and cortisol in CSF. Sex-specific differences were found in CSF of MS patients showing increased levels of 2-AG and glucocorticoids in males only. Overall, arachidonic acid was elevated in CSF of males. Interestingly, CSF eCBs correlated positively with age only in the control patients due to the increased levels of eCBs in young relapsing-remitting MS patients. Our findings reveal significant discrepancies between CSF and serum, underscoring that measuring eCBs in blood matrices is not optimal for detecting MS-associated changes in the central nervous system. The identified sex and age-specific changes of analytes of the stress axis and ECS specifically in the CSF of MS patients supports the role of the ECS in MS and may be relevant for drug development strategies.
多发性硬化症（MS）是一种复杂的慢性神经炎症性疾病，其特征是脱髓鞘导致神经元功能障碍和神经退行性变，表现为各种神经功能障碍。内源性大麻素系统（ECS）是一种脂质信号网络，在中枢神经系统和外周组织中发挥多种作用，包括突触信号传递和炎症调节。ECS 已被确定为开发 MS 患者新型治疗干预措施的潜在靶点。目前尚不清楚 MS 患者的 ECS 相关代谢物是否发生变化，以及它们是否可以作为血液或脑脊液（CSF）中的生物标志物。在这项回顾性研究中，我们应用靶向脂质组学分析了 74 例 MS 患者和 80 例非神经炎症性对照患者的匹配 CSF 和血清样本。我们发现，MS 相关的脂质组学变化在 CSF 和血清之间并不完全一致。虽然糖皮质激素呈正相关，但只有内源性大麻素（eCB）2-花生四烯酸甘油（2-AG）在 CSF 和血清之间显示出微弱的正相关（r=0.3，p<0.05）。肽内源性大麻素首次在 CSF 中被定量，但在 MS 和对照组之间没有差异。MS 患者的血清中前列腺素 E2 和硬脂酰乙醇酰胺水平升高，CSF 中 2-油酰甘油和皮质醇水平升高。MS 患者的 CSF 中还发现了性别特异性差异，仅在男性中，2-AG 和糖皮质激素水平升高。总的来说，CSF 中花生四烯酸水平升高。有趣的是，由于年轻的复发性缓解型 MS 患者 eCB 水平升高，仅在对照组患者的 CSF 中，eCB 与年龄呈正相关。我们的研究结果揭示了 CSF 和血清之间的显著差异，这表明在血液基质中测量 eCB 并不能优化检测中枢神经系统中与 MS 相关的变化。MS 患者 CSF 中应激轴和 ECS 分析物的性别和年龄特异性变化支持 ECS 在 MS 中的作用，并且可能与药物开发策略相关。
