Biringer Roger Gregory
College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA.
Headache. 2025 Jun 18. doi: 10.1111/head.14980.
The sodium theory for migraine proposes that excessive sodium pumping into the cerebrospinal fluid (CSF) leads to sodium infiltration into the neural tissue, which can lead to activation and central sensitization of trigeminovascular neurons, predisposing individuals to migraine. Dysregulation of the Na, K-ATPase pump in the choroid plexus is likely to be the primary cause of elevated sodium in the CSF. The identity of intrinsic regulatory molecules that are inhibitors for this pump and their involvement in migraine have been the subject of numerous studies; however, data detailing the involvement of only a few of these regulatory molecules in migraine pathology are published. The regulation mechanisms and the path for these regulators are currently unknown.
This review aims to present data supporting the sodium theory for migraine and explore potential mechanisms for brain sodium dysregulation.
PubMed, Google Scholar, and UniProtKB/Swiss-Prot were searched for articles and corroborating information through March 2024. Search items for PubMed and Google Scholar included headache, migraine, Na, K-ATPase, cardiotonic steroids, ouabain, digoxin, bufalin, marinobufagenin, telocinobufagin, organic anion transporters, and ATP-binding cassette transporters. The Human Protein Atlas was used to obtain receptor and transporter expression levels.
Clinical and preclinical studies reveal that dysregulation of Na, K-ATPase in the choroid plexus results in excess CSF sodium that enhances central sensitization, predisposing individuals to migraine. Preclinical work also shows that the exogenous, plant-derived cardiotonic steroid ouabain can prevent and alleviate migraine by inhibiting Na, K-ATPase. Four additional exogenous cardiotonic steroids are also known to inhibit Na, K-ATPase in vitro, and all five have similar, if not identical, structures to molecules found in human tissues. The documented, evaluated, and potential mechanisms for the involvement of these endogenous cardiotonic steroids in regulating CSF sodium in humans and how these molecules reach the Na, K-ATPase are presented.
Thus far, only endogenous ouabain is known to regulate CSF sodium levels by regulating Na, K-ATPase in the choroid plexus epithelium. Four other endogenous regulators similar or identical in structure to digoxin, bufalin, marinobufagenin, and telocinobufagin also have the potential to regulate CSF sodium levels in this manner, but this has yet to be proven. The source for these endogenous regulators is most likely the hypothalamus through paracrine signaling to the choroid plexus; however, endocrine signaling from the hypothalamus or adrenal tissue through the bloodstream is also possible. Several mechanisms for transporting these regulators to the CSF and controlling their production and release have been proposed but have yet to be proven.
偏头痛的钠理论提出，过多的钠泵入脑脊液（CSF）会导致钠渗入神经组织，进而导致三叉神经血管神经元激活和中枢敏化，使个体易患偏头痛。脉络丛中钠钾ATP酶泵的失调很可能是脑脊液中钠升高的主要原因。作为该泵抑制剂的内源性调节分子的身份及其与偏头痛的关系一直是众多研究的主题；然而，仅详细阐述其中少数调节分子与偏头痛病理关系的数据已发表。目前尚不清楚这些调节因子的调节机制和途径。
本综述旨在展示支持偏头痛钠理论的数据，并探讨脑钠失调的潜在机制。
检索了PubMed、谷歌学术和UniProtKB/瑞士蛋白质数据库，以获取截至2024年3月的文章及确证信息。PubMed和谷歌学术的检索词包括头痛、偏头痛、钠钾ATP酶、强心甾类、哇巴因、地高辛、蟾毒灵、海蟾蜍精、端粒蟾蜍精、有机阴离子转运体和ATP结合盒转运体。利用人类蛋白质图谱获取受体和转运体的表达水平。
临床和临床前研究表明，脉络丛中钠钾ATP酶的失调导致脑脊液钠过多，增强中枢敏化，使个体易患偏头痛。临床前研究还表明，外源性植物源强心甾类哇巴因可通过抑制钠钾ATP酶预防和缓解偏头痛。已知另外四种外源性强心甾类在体外也能抑制钠钾ATP酶，且所有五种强心甾类与人体组织中发现的分子结构相似（即便不完全相同）。本文介绍了这些内源性强心甾类参与调节人体脑脊液钠的已记录、已评估和潜在机制，以及这些分子如何作用于钠钾ATP酶。
迄今为止，已知只有内源性哇巴因通过调节脉络丛上皮中的钠钾ATP酶来调节脑脊液钠水平。其他四种与地高辛、蟾毒灵、海蟾蜍精和端粒蟾蜍精结构相似或相同的内源性调节因子也有可能以这种方式调节脑脊液钠水平，但尚未得到证实。这些内源性调节因子的来源很可能是下丘脑，通过旁分泌信号作用于脉络丛；然而，下丘脑或肾上腺组织通过血液的内分泌信号传导也有可能。已经提出了几种将这些调节因子转运到脑脊液并控制其产生和释放的机制，但尚未得到证实。
