Nervonic acid alleviates stroke and its associated poststroke depression behaviors

Fengrong Zhang^{¹^,^#}, Yong Fan^{²^,^#}, Nghi Van Phung^², Boyang Ji^³, Junmiao Chen^⁴, Xingyue Xu^{¹^,⁵}, Fuli Li^²(), Peifeng Ji^{¹^,⁶}(), Hongjun Yang^¹(), Xianyu Li^¹()

Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China

Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Shandong, China

BioInnovation Institute, BII, Copenhagen, Denmark

SCIEX China, Beijing, China

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangdong, China

Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China

^#The authors contributed equally to this work

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HIGHLIGHTS

● Nervonic Acid (NA) is a promising candidate for drug therapy in addressing stroke and associated poststroke depression (PSD)-like behaviors.

● NA was potentially upregulated the expression of brain-derived neurotrophic factor and myelin basic protein in rats.

● NA was potentially modified glutamate and phenylalanine metabolism in brain.

● NA also led to increased levels of Blautia and Sutterella in the gut microbiota.

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Abstract

Nervonic acid (NA) is an important long-chain monounsaturated fatty acid found in mammalian nervous tissue. It has recently garnered research attention due to its therapeutic potential in treating psychiatric and neurodegenerative disorders. In this study, we investigated the efficacy of NA in treating ischemia/reperfusion and poststroke events in a rat model. Specifically, there was significant reduction in the infarct area, cell death, and neuronal swelling after NA treatment, and the improvement in cerebral blood flow was also observed on day five after middle cerebral artery occlusion. Moreover, NA treatment led to the upregulation of brain-derived neurotrophic factors and myelin basic protein genes. NA displayed improved effects on depressive-like behavior of rats by three validated assays—the sucrose preference test, open-field test, and forced swim test. Regarding the mechanism of action, direct supplementation of NA in the brain was observed. We also observed the indirect effects of NA on the gut microbiota. Notably, the NA group gradually restored the bacterial diversity and the EGb group exhibited no impact based on observed-out analysis. We found an increase in the abundance of Blautia and Sutterella, which participated in phenylalanine metabolism. The metabolomics of plasma and brain samples revealed a decrease in the levels of phenylalanine-based amino acids, which alleviated the inhibitory effects on glutamine metabolism and promoted the recovery and signaling transmission of neurons after stroke. Altogether, our findings suggest that NA can be a viable treatment option for alleviating stroke and its associated poststroke depressive-like behaviors.

Keywords

nervonic acid poststroke depressive-like behaviors gut microbiota

References

[1]

Li Q, Chen J, Yu X, Gao JM. A mini review of nervonic acid: Source, production, and biological functions. Food Chem 2019;301:125286.