Regulation of Na+, K+-ATPase by cardiotonic steroids: Participation in the sodium theory for migraine

Abstract

Background: 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.

Objective: This review aims to present data supporting the sodium theory for migraine and explore potential mechanisms for brain sodium dysregulation.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: ATPase; headache; migraine; nociception; sodium.