Intrinsic activation of the coagulation pathway induces mouse sciatic nerve hypoexcitability

Shani Berkowitz; Valery Golderman; Zehavit Goldberg; Joab Chapman; Amir Dori; Nicola Maggio; Jérôme Joël Devaux; Efrat Shavit-Stein

doi:10.1016/j.neuropharm.2025.110569

Intrinsic activation of the coagulation pathway induces mouse sciatic nerve hypoexcitability

Neuropharmacology. 2025 Jun 21:278:110569. doi: 10.1016/j.neuropharm.2025.110569. Online ahead of print.

Authors

Shani Berkowitz¹, Valery Golderman², Zehavit Goldberg³, Joab Chapman⁴, Amir Dori⁵, Nicola Maggio⁶, Jérôme Joël Devaux⁷, Efrat Shavit-Stein⁸

Affiliations

¹ Department of Neurology and Neurosurgery, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan, 52626202, Israel. Electronic address: shanihberkowitz@gmail.com.
² Department of Neurology and Neurosurgery, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan, 52626202, Israel. Electronic address: valery.rodionov@gmail.com.
³ Department of Neurology and Neurosurgery, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan, 52626202, Israel. Electronic address: ze01buza@gmail.com.
⁴ Department of Neurology and Neurosurgery, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan, 52626202, Israel; Robert and Martha Harden Chair in Mental and Neurological Diseases, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel. Electronic address: joabchapman@gmail.com.
⁵ Department of Neurology and Neurosurgery, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan, 52626202, Israel; Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, Ramat Gan, Israel. Electronic address: Amir.Dori@sheba.health.gov.il.
⁶ Department of Neurology and Neurosurgery, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan, 52626202, Israel; Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, Ramat Gan, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel. Electronic address: nicmaggio@gmail.com.
⁷ Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France. Electronic address: jerome.devaux@igf.cnrs.fr.
⁸ Department of Neurology and Neurosurgery, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan, 52626202, Israel; The TELEM Rubin Excellence in Biomedical Research Program, The Chaim Sheba Medical Center, Ramat Gan, Israel. Electronic address: shavitef@tauex.tau.ac.il.

PMID: 40550465
DOI: 10.1016/j.neuropharm.2025.110569

Abstract

Background: Thrombin and its protease-activated receptor 1 (PAR1) modulate neuronal function in experimental settings, but the effects of activating intrinsic neuronal coagulation factors remain unclear. We investigated how activation of this pathway influences peripheral nerve function in an isolated mouse sciatic nerve model.

Methods: We used an ex vivo mouse sciatic nerve model to evaluate the effects of coagulation activation on neural excitability. Isolated nerves from male C57BL/6J mice were treated with Russell's viper venom factor X (FX) activator (RVV-X, 0.3 U/ml), FX inhibitor (apixaban, 1 μM), thrombin (200 U/ml), or a PAR1 antagonist (SCH 79797, 1 μM). Electrophysiological recordings assessed evoked neural responses. Thrombin and FX activity were quantified in tissue and artificial cerebrospinal fluid (aCSF). mRNA and immunofluorescence analyses localized coagulation-related components.

Results: RVV-X and thrombin treatments significantly attenuated neural responses to repeated stimulation (p < 0.0001), while apixaban and the PAR1 antagonist prevented these effects (p > 0.9999). RVV-X markedly increased thrombin activity in aCSF (p < 0.0001). mRNA and immunofluorescence analyses confirmed that coagulation-related components were primarily expressed in the paranodal region of the sciatic nerve.

Conclusions: The FX-thrombin pathway is intrinsically present and functionally active in sciatic nerves of mice. Activation of this pathway reduces neuronal excitability via PAR1, suggesting a finely tuned feedback mechanism between coagulation factors and neural function. These findings highlight the potential role of coagulation-mediated mechanisms in peripheral nerve pathologies, which may serve as biomarkers and therapeutic targets for neurological diseases.

Keywords: Electrophysiology; Factor X; Neuronal excitability; PAR1; Peripheral nerve pathology; Sciatic nerve; Thrombin.