期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：30
DOI：10.1073/pnas.2122158119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Danish and Greenland Inuit epidemiologic studies in the 1970s reported that eicosapentaenoic acid (EPA) reduces the risk of death after myocardial infarction, and further clinical studies have indicated its analgesic, anti-(neuro)inflammatory, platelet aggregation inhibition, blood triglyceride and glucose decrease, and insulin resistance improvement properties. However, the molecular target of EPA remains unclear. In this study, we demonstrated that EPA is a potent physiological blocker of vesicular nucleotide transporter (VNUT) and potently alleviates neuropathic and inflammatory pain and insulin resistance with few side effects via VNUT inhibition. Thus, we identified VNUT as a molecular target of EPA. Our results can help develop unique nutrient-based treatment and prevention strategies by targeting purinergic chemical transmission for inflammatory, neurological, and metabolic diseases.
Eicosapentaenoic acid (EPA), an omega-3 (ω-3) polyunsaturated fatty acid, is an essential nutrient that exhibits antiinflammatory, neuroprotective, and cardiovascular-protective activities. Although EPA is used as a nutrient-based pharmaceutical agent or dietary supplement, its molecular target(s) is debatable. Here, we showed that EPA and its metabolites strongly and reversibly inhibit vesicular nucleotide transporter (VNUT), a key molecule for vesicular storage and release of adenosine triphosphate (ATP) in purinergic chemical transmission. In vitro analysis showed that EPA inhibits human VNUT-mediated ATP uptake at a half-maximal inhibitory concentration (IC
50) of 67 nM, acting as an allosteric modulator through competition with Cl
−. EPA impaired vesicular ATP release from neurons without affecting the vesicular release of other neurotransmitters. In vivo,
VNUT
−/−
mice showed a delay in the onset of neuropathic pain and resistance to both neuropathic and inflammatory pain. EPA potently attenuated neuropathic and inflammatory pain in wild-type mice but not in
VNUT
−/−
mice without affecting the basal nociception. The analgesic effect of EPA was canceled by the intrathecal injection of purinoceptor agonists and was stronger than that of existing drugs used for neuropathic pain treatment, with few side effects. Neuropathic pain impaired insulin sensitivity in previous studies, which was improved by EPA in the wild-type mice but not in the
VNUT
−/−
mice. Our results showed that VNUT is a molecular target of EPA that attenuates neuropathic and inflammatory pain and insulin resistance. EPA may represent a unique nutrient-based treatment and prevention strategy for neurological, immunological, and metabolic diseases by targeting purinergic chemical transmission.
关键词：eneicosapentaenoic acidomega-3 polyunsaturated fatty acidvesicular nucleotide transporterpurinergic chemical transmissionneuropathic pain
