title: Effects of thrombin inhibitor on thrombin-related signal transduction and cerebral vasospasm in the rabbit subarachnoid hemorrhage model.
abstract: OBJECTIVE
  Thrombin is activated in the cerebrospinal fluid (CSF) after a subarachnoid hemorrhage (SAH). However, the relationship between thrombin and cerebral vasospasm has not yet been fully established. The aim of this study was to investigate the possibility of thrombin as a causative factor for cerebral vasospasm and to delineate the signal transduction mechanism that results in thrombin-inducing sustained vasoconstriction in cerebral vasospasm.
  
  
  METHODS
  In the SAH group, SAH was simulated by the 2-hemorrhage rabbit model. In the treatment group, antithrombin III (AT-III) was injected into the cisterna magna just before production of the SAH. CSF samples were obtained serially to measure d-dimer with latex photometric immunoassay. On day 4, the basilar artery was excised after perfusion-fixation. The degree of cerebral vasospasm was evaluated by measuring the cross-sectional area of each basilar arterial lumen, and the expression of mitogen-activated protein kinase (MAPK) in the vascular wall was examined with an immunohistochemical technique.
  
  
  RESULTS
  In the treatment group, the value of d-dimer on day 4 was 0.83+/-0.07 microg/mL, which was statistically significantly lower than that in the nontreated SAH group (2.49+/-0.09 microg/mL, P<0.01). The cross-sectional area of the arterial lumen in the treatment group was 3.67x10(5)+/-1.58x10(4) square pixels, which was statistically significantly larger than that in the nontreated SAH group (2.60x10(5)+/-2.29x10(4) square pixels; P<0.01). MAPK was detected diffusely in the vascular smooth muscle cell layer in the nontreated SAH group, but it was absent in the treatment group.
  
  
  CONCLUSIONS
  Inhibition of thrombin activity leads to amelioration of cerebral vasospasm and suppression of MAPK diphosphorylation. This suggests that thrombin and its related signal transduction, including the MAPK cascade, appear to play an important role in the pathogenesis of cerebral vasospasm after SAH.
authors.affiliation: Department of Neurosurgery, Hirosaki University, School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8216 Japan. hisamd@ca-3.so.net.jp
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Tsurutani
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohkuma
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000494:pharmacology*; D001488:Basilar Artery / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products / Q000134:cerebrospinal fluid; D007276:Injections, Intraventricular; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000502:physiology; D014654:Vascular Patency / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D015842:Serine Proteinase Inhibitors; C036309:fibrin fragment D; D000990:Antithrombin III; D020928:Mitogen-Activated Protein Kinases; D013917:Thrombin