Levistilide A Exerts a Neuroprotective Effect by Suppressing Glucose Metabolism Reprogramming and Preventing Microglia Polarization Shift: Implications for Parkinson's Disease

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 4; p. 912
• Main Authors: Zhang, Mingjie, Duan, Congyan, Lin, Weifang, Wu, Honghua, Chen, Lu, Guo, Hong, Yu, Minyu, Liu, Qi, Nie, Yaling, Wang, Hong, Wang, Shaoxia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2024; MDPI
• Subjects: Acidification; AMP-Activated Protein Kinases - metabolism; Anti-Inflammatory Agents - therapeutic use; Brain; Cytokines; Development and progression; Dextrose; Disease; Flow cytometry; Glucose; Glucose - metabolism; Heterocyclic Compounds, Bridged-Ring; Humans; Inflammation; Levistilide A; Lipopolysaccharides - pharmacology; Medical research; Medicine, Experimental; Metabolic Reprogramming; Metabolism; Microglia; Microscopy; Nervous system; Neurons; Neuroprotective Agents - therapeutic use; NF-kappa B - metabolism; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson’s disease; Phosphorylation; Physiological aspects; Prevention; Prognosis; TOR Serine-Threonine Kinases - metabolism; Wang Hong; China; microglia; Parkinson’s disease; metabolic reprogramming; Levistilide A
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29040912

The microglia, displaying diverse phenotypes, play a significant regulatory role in the development, progression, and prognosis of Parkinson's disease. Research has established that glycolytic reprogramming serves as a critical regulator of inflammation initiation in pro-inflammatory macrophages. Furthermore, the modulation of glycolytic reprogramming has the potential to reverse the polarized state of these macrophages. Previous studies have shown that Levistilide A (LA), a phthalide component derived from Angelica sinensis, possesses a range of pharmacological effects, including anti-inflammatory, antioxidant, and neuroprotective properties. In our study, we have examined the impact of LA on inflammatory cytokines and glucose metabolism in microglia induced by lipopolysaccharide (LPS). Furthermore, we explored the effects of LA on the AMPK/mTOR pathway and assessed its neuroprotective potential both in vitro and in vivo. The findings revealed that LA notably diminished the expression of M1 pro-inflammatory factors induced by LPS in microglia, while leaving M2 anti-inflammatory factor expression unaltered. Additionally, it reduced ROS production and suppressed IκB-α phosphorylation levels as well as NF-κB p65 nuclear translocation. Notably, LA exhibited the ability to reverse microglial glucose metabolism reprogramming and modulate the phosphorylation levels of AMPK/mTOR. In vivo experiments further corroborated these findings, demonstrating that LA mitigated the death of TH-positive dopaminergic neurons and reduced microglia activation in the ventral SNpc brain region of the midbrain and the striatum. In summary, LA exhibited neuroprotective benefits by modulating the polarization state of microglia and altering glucose metabolism, highlighting its therapeutic potential.