Vesicular nucleotide transporter is a molecular target of eicosapentaenoic acid for neuropathic and inflammatory pain treatment.
Vesicular nucleotide transporter is a molecular target of eicosapentaenoic acid for neuropathic and inflammatory pain treatment.
复制标题
DOI：
10.1073/pnas.2122158119
复制
发表时间：
2022-07-26
影响因子：
11.1
通讯作者：
Miyaji, Takaaki
中科院分区：
文献类型：
--
作者：
Kato, Yuri;Ohsugi, Kengo;Fukuno, Yuto;Iwatsuki, Ken;Harada, Yuika;Miyaji, Takaaki
关键词：
丹麦和格陵兰20世纪70年代的因纽特流行病学研究报告称，二十碳五烯酸(EPA)可降低心肌梗死后的死亡风险，进一步的临床研究表明，EPA具有止痛、抗(神经)炎症、抑制血小板聚集、降低血甘油三酯和血糖以及改善胰岛素抵抗的特性。然而，EPA的分子靶标仍不清楚。在这项研究中，我们证明了EPA是一种有效的囊泡核苷酸转运体(VNUT)的生理学阻滞剂，并通过抑制VNUT有效地缓解神经病理性和炎症性疼痛和胰岛素抵抗，且副作用很少。因此，我们确定VNUT是EPA的一个分子靶点。我们的结果可以通过针对炎症性、神经系统和代谢性疾病的嘌呤能化学传递来帮助开发独特的基于营养的治疗和预防策略。二十碳五烯酸是一种omega-3(ω-3)多不饱和脂肪酸，是一种具有抗炎、神经保护和心血管保护活性的必需营养物质。虽然环保局被用作营养型药剂或膳食补充剂，但其分子靶标(S)仍有争议。在这里，我们展示了EPA及其代谢产物强烈且可逆地抑制囊泡核苷酸转运体(VNUT)，在嘌呤能化学传递中，囊泡核苷酸转运体(VNUT)是囊泡储存和释放三磷酸腺苷(ATP)的关键分子。体外分析表明，EPA通过与Cl-−竞争，以变构调节剂的形式抑制人vnUT介导的三磷酸腺苷摄取，半数抑制浓度为67 nM。EPA可抑制神经元囊泡性ATP的释放，但不影响其他神经递质的囊泡性释放。在体内，VNUT−/−小鼠表现出神经病理性疼痛的延迟以及对神经病理性疼痛和炎症性疼痛的抵抗。EPA有效地减轻了野生型小鼠的神经病理性和炎症性疼痛，但对VNUT−/−小鼠没有影响，而不影响基本的伤害性感受。鞘内注射嘌呤受体激动剂可取消EPA的镇痛作用，其作用强于现有的治疗神经病理性疼痛的药物，且副作用少。在以前的研究中，神经病理性疼痛损害了胰岛素敏感性，这一点在野生型小鼠中得到改善，但在VNUT−/−小鼠中却没有。我们的结果表明，VNUT是EPA的一个分子靶点，可以减轻神经病理性和炎症性疼痛以及胰岛素抵抗。EPA可能代表了一种独特的以营养为基础的治疗和预防策略，通过靶向嘌呤能化学传递来治疗和预防神经、免疫和代谢疾病。
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 (IC50) 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.
登录
查看更多内容
影响因子：
2.5
作者：
Hiasa M;Togawa N;Miyaji T;Omote H;Yamamoto A;Moriyama Y
通讯作者：
Moriyama Y
影响因子：
7.1
作者：
BANG, HO;DYERBERG, J;SINCLAIR, HM
通讯作者：
SINCLAIR, HM
影响因子：
4.3
作者：
Grote CW;Wright DE
通讯作者：
Wright DE
影响因子：
2.9
作者：
Ko, Gordon D.;Nowacki, Nathaniel Benjamin;Hum, Annie
通讯作者：
Hum, Annie
影响因子：
4.4
作者：
Arita, Makoto;Ohira, Taisuke;Serhan, Charles N.
通讯作者：
Serhan, Charles N.