Gentili Valentina, Schiuma Giovanna, Dilliraj Latha Nagamani, Beltrami Silvia, Rizzo Sabrina, Lara Djidjell, Giovannini Pier Paolo, Marti Matteo, Bortolotti Daria, Trapella Claudio, Narducci Marco, Rizzo Roberta
Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy.
Department of Chemical, Pharmaceutical, Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy.
Nutrients. 2024 Dec 31;17(1):149. doi: 10.3390/nu17010149.
A neuroinflammatory disease such as Alzheimer's disease, presents a significant challenge in neurotherapeutics, particularly due to the complex etiology and allostatic factors, referred to as CNS stressors, that accelerate the development and progression of the disease. These CNS stressors include cerebral hypo-glucose metabolism, hyperinsulinemia, mitochondrial dysfunction, oxidative stress, impairment of neuronal autophagy, hypoxic insults and neuroinflammation. This study aims to explore the efficacy and safety of DAG-MAG-ΒHB, a novel ketone diester, in mitigating these risk factors by sustaining therapeutic ketosis, independent of conventional metabolic pathways.
We evaluated the intestinal absorption of DAG-MAG-ΒHB and the metabolic impact in human microglial cells. Utilizing the HMC3 human microglia cell line, we examined the compound's effect on cellular viability, Acetyl-CoA and ATP levels, and key metabolic enzymes under hypoglycemia. Additionally, we assessed the impact of DAG-AG-ΒHB on inflammasome activation, mitochondrial activity, ROS levels, inflammation and phagocytic rates.
DAG-MAG-ΒHB showed a high rate of intestinal absorption and no cytotoxic effect. In vitro, DAG-MAG-ΒHB enhanced cell viability, preserved morphological integrity, and maintained elevated Acetyl-CoA and ATP levels under hypoglycemic conditions. DAG-MAG-ΒHB increased the activity of BDH1 and SCOT, indicating ATP production via a ketolytic pathway. DAG-MAG-ΒHB showed remarkable resilience against low glucose condition by inhibiting NLRP3 inflammasome activation.
In summary, DAG-MAG-ΒHB emerges as a promising treatment for neuroinflammatory conditions. It enhances cellular health under varying metabolic states and exhibits neuroprotective properties against low glucose conditions. These attributes indicate its potential as an effective component in managing neuroinflammatory diseases, addressing their complex progression.
诸如阿尔茨海默病之类的神经炎症性疾病在神经治疗领域带来了重大挑战，尤其是由于其病因复杂以及存在加速疾病发展和进程的稳态应变因素（称为中枢神经系统应激源）。这些中枢神经系统应激源包括脑葡萄糖代谢低下、高胰岛素血症、线粒体功能障碍、氧化应激、神经元自噬受损、低氧损伤和神经炎症。本研究旨在探索新型酮二酯DAG-MAG-ΒHB通过维持治疗性酮症来减轻这些风险因素的疗效和安全性，且不依赖于传统代谢途径。
我们评估了DAG-MAG-ΒHB的肠道吸收情况及其对人小胶质细胞的代谢影响。利用HMC3人小胶质细胞系，我们检测了该化合物在低血糖条件下对细胞活力、乙酰辅酶A和ATP水平以及关键代谢酶的影响。此外，我们评估了DAG-AG-ΒHB对炎性小体激活、线粒体活性、活性氧水平、炎症和吞噬率的影响。
DAG-MAG-ΒHB显示出高肠道吸收率且无细胞毒性作用。在体外，DAG-MAG-ΒHB增强了细胞活力，保持了形态完整性，并在低血糖条件下维持了升高的乙酰辅酶A和ATP水平。DAG-MAG-ΒHB增加了BDH1和SCOT的活性，表明通过酮解途径产生ATP。DAG-MAG-ΒHB通过抑制NLRP3炎性小体激活，对低葡萄糖条件表现出显著的耐受性。
总之，DAG-MAG-ΒHB有望成为神经炎症性疾病的治疗方法。它在不同代谢状态下增强细胞健康，并对低葡萄糖条件表现出神经保护特性。这些特性表明其作为治疗神经炎症性疾病、应对其复杂病程的有效成分的潜力。
