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Da Chuanxiong extract modulates the Lands cycle to elicit spatially specific phospholipid remodeling against cerebral
Biqiong Qu1, Menghan Feng2, Lirong Liu2
1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China; Shanxi Key Laboratory of Traditional Herbal Medicines Processing, Shanxi University of Chinese Medicine, Jinzhong, Shanxi, 030600, China.
Ethnopharmacological Relevance:
Da Chuanxiong (DCX), composed of Ligusticum chuanxiong Hort. and Gastrodia elata Bl. (4:1), is a classical Chinese herbal formula, traditionally used for headache and vertigo caused by wind pathogen and blood stasis. Modern clinical practice has extended its application to ischemic stroke. However, whether DCX exerts neuroprotection through Lands cycle-mediated phospholipid remodeling, particularly in a spatially specific manner, remains unclear.
Aim Of The Study:
To demonstrate whether DCX elicits spatially specific phospholipid remodeling through Lands cycle activation, and to identify the brain-penetrating constituents responsible for this effect.
Materials And Methods:
Protective effects of DCX were evaluated in pMCAO rats, and those of its brain-penetrating constituents were assessed in OGD/R-induced HT22 cells. Glycerophospholipid composition and spatial distribution were analyzed by targeted lipidomics and AFADESI-QQQ-MSI-based spatial metabolomics. Lands cycle enzyme expression was measured by RT-qPCR and western blotting.
Results:
DCX dose-dependently reduced infarct volume and attenuated neuronal damage, accompanied by decreased ROS and MDA, elevated GSH, and preserved mitochondrial membrane integrity. Lipidomic analysis revealed that DCX shifted phospholipids from peroxidation-prone PUFA-PLs to oxidation-resistant SFA/MUFA-PLs in a spatially specific manner, reducing PUFA-PLs from 90.7% to 82.9% and increasing SFA/MUFA-PLs from 9.3% to 17.1%. SFA-PLs were region-selectively restored in hippocampus and thalamus, and MUFA-PLs in the corpus callosum and internal capsule. Mechanistically, DCX concurrently upregulated PLA2G6, ACSL3, MBOAT2, and LPCAT1, consistent with Lands cycle-mediated deacylation and reacylation. Five brain-penetrating constituents (senkyunolide A, butylphthalide, levistilide A, ferulic acid, and gastrodin) modulated these enzymes in vitro.
Conclusion:
This work provides the first evidence that DCX elicits spatially specific phospholipid remodeling toward oxidation-resistant species, an effect associated with Lands cycle activation and its brain-penetrating constituents. This remodeling may reduce peroxidation substrate availability and counteract lipid peroxidation in cerebral ischemia.