title: Thrombin and protein C pathway in peripheral nerve Schwann cells.
abstract: Thrombin and activated protein C (aPC) bound to the endothelial protein C receptor (EPCR) both activate protease-activated receptor 1 (PAR1) generating either harmful or protective signaling respectively. In the present study we examined the localization of PAR-1 and EPCR and thrombin activity in Schwann glial cells of normal and crushed peripheral nerve and in Schwannoma cell lines. In the sciatic crush model nerves were excised 1h, 1, 4, and 7days after the injury. Schwannoma cell lines produced high levels of prothrombin which is converted to active thrombin and expressed both EPCR and PAR-1 which co-localized. In the injured sciatic nerve thrombin levels were elevated as early as 1h after injury, reached their peak 1day after injury which was significantly higher (24.4±4.1mU/ml) compared to contralateral uninjured nerves (2.6±7mU/ml, t-test p<0.001) and declined linearly reaching baseline levels by day 7. EPCR was found to be located at the microvilli of Schwann cells at the node of Ranvier and in cytoplasm surrounding the nucleus. Four days after sciatic injury, EPCR levels increased significantly (57,785±16602AU versus 4790±1294AU in the contralateral uninjured nerves, p<0.001 by t-test) mainly distal to the site of injury, where axon degeneration is followed by proliferation of Schwann cells which are diffusely stained for EPCR. EPCR seems to be located to cytoplasmic component of Schwann cells and not to compact myelin component, and is highly increased following injury.
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Physical Therapy, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: ornagera@gmail.com.
authors: Orna
authors: O
authors: Gera
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel. Electronic address: efrat.shavit.stein@gmail.com.
authors: Efrat
authors: E
authors: Shavit-Stein
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: doron.bushi@gmail.com.
authors: Doron
authors: D
authors: Bushi
authors: Department of Neurosurgery, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: sharnof@gmail.com.
authors: Sagi
authors: S
authors: Harnof
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: elgart.marina@gmail.com.
authors: Marina Ben
authors: MB
authors: Shimon
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. Electronic address: ronenwe@gmail.com.
authors: Ronen
authors: R
authors: Weiss
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: valery.rodionov@gmail.com.
authors: Valery
authors: V
authors: Golderman
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel. Electronic address: amir.dori@gmail.com.
authors: Amir
authors: A
authors: Dori
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel; Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. Electronic address: nicmaggio@gmail.com.
authors: Nicola
authors: N
authors: Maggio
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: feingoldkate@gmail.com.
authors: Kate
authors: K
authors: Finegold
authors: Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Robert and Martha Harden Chair in Mental and Neurological Diseases, Sackler Faculty of Medicine, Tel Aviv University, Israel. Electronic address: jchapman@post.tau.ac.il.
authors: Joab
authors: J
authors: Chapman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007839:Functional Laterality; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism; D011486:Protein C / Q000378:metabolism*; D011516:Prothrombin / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism*; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism*; D018180:Thrombomodulin / Q000378:metabolism; D013997:Time Factors
chemical_list: D011486:Protein C; D044463:Receptor, PAR-1; D017466:Receptors, Endothelin; D018180:Thrombomodulin; D011516:Prothrombin; D013917:Thrombin
keywords: EPCR; PAR-1; Schwannoma; protein C pathway; sciatic nerve; sciatic nerve injury