Intrathecal Administration of Thrombin Inhibitor Ameliorates Cerebral Vasospasm

Kudo, Akira; Suzuki, Michiyasu; Kubo, Yoshitaka; Watanabe, Mikio; Yoshida, Kenji; Doi, Mamoru; Kuroda, Kazuo

doi:10.1159/000016102

Cited by 12 publications

(7 citation statements)

References 25 publications

(46 reference statements)

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“…11,12,34,35 Recently, it has been reported that intrathecal placement of collagen pellets releasing thrombin inhibitor prevented the development of canine vasospasm. 36 Although vascular endothelial and smooth muscle cells are capable of expressing thrombin receptor, 37 and thrombin causes the immediate contraction of smooth muscle cells via activated thrombin receptor, 38,39 the peak thrombinantithrombin III complex concentration in the CSF of SAH patients was apparently earlier (on days 2 to 5) than the development of human cerebral vasospasm, which indicated that thrombin activation and its vasoconstrictive effect were not a direct cause of cerebral vasospasm. 34,39 In the search for factors downstream to thrombin activation due to SAH, elevated immunoreactivity for PDGF-BB was first demonstrated in the endothelial and smooth muscle cells of the basilar artery after SAH.…”

Section: Discussionmentioning

confidence: 99%

Broad-Spectrum and Selective Serine Protease Inhibitors Prevent Expression of Platelet-Derived Growth Factor–BB and Cerebral Vasospasm After Subarachnoid Hemorrhage

Zhang

Nagata

Kikuchi

et al. 2001

Stroke

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Background and Purpose-Plasma serine protease cascade, including the complement system and thrombin, is activated in the subarachnoid space during the acute phase after subarachnoid hemorrhage (SAH). To examine the effect of protease cascade-based inflammation and subsequent vascular repair in the development of cerebral vasospasm, we examined the effect of 2 synthetic serine protease inhibitors-FUT-175, an inhibitor of thrombin and the complement system, and argatroban, a selective inhibitor of thrombin-on the development of cerebral vasospasm in a rabbit SAH model. Methods-One hundred Japanese White male rabbits were used in the study. The SAH was simulated by a single injection of autologous arterial blood into the cisterna magna. To evaluate the development of cerebral vasospasm, the caliber of the basilar artery was measured on x-ray film before and at 2 days after SAH. Nine groups of rabbits (nϭ6 each) were treated with continuous intravenous injection of FUT-175 (2.5, 5, 10, or 20 mg/d), argatroban (1.25, 2.5, or 5 mg/d), or the same amount of saline (vehicle) for 48 hours, starting 40 minutes after SAH. Two days after SAH, the expression of homodimer of platelet-derived growth factor-BB (PDGF-BB) in the basilar artery was examined with immunohistochemical techniques. In 20 normal rabbits, 5 g of recombinant PDGF-BB or vehicle was injected into the cisterna magna, and the basilar arteries were examined on angiograms for 48 hours. Results-Significant differences were observed in the caliber of the basilar arteries between the vehicle group and the groups with the 3 larger doses of FUT-175 (vehicle, 52Ϯ5.0%; 5 mg, 79Ϯ5.7%; 10 mg, 80Ϯ2.5%; 20 mg, 80Ϯ3.7%) and between the vehicle group and the groups with the 2 larger doses of argatroban (vehicle, 52Ϯ6.4%; 2.5 mg, 81Ϯ9.0%; 5 mg, 85Ϯ4.1%) (PϽ0.05). In the histological examination, administration of effective doses of FUT-175 or argatroban suppressed the expression of PDGF-BB in the endothelial and medial smooth muscle cell layers. Exogenous PDGF-BB caused delayed and prolonged vasoconstriction on normal basilar arteries. Conclusions-Activation

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Section: Discussionmentioning

confidence: 99%

Broad-Spectrum and Selective Serine Protease Inhibitors Prevent Expression of Platelet-Derived Growth Factor–BB and Cerebral Vasospasm After Subarachnoid Hemorrhage

Zhang

Nagata

Kikuchi

et al. 2001

Stroke

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“…However, its intrinsic influence on cerebral arteries after SAH remains unclear (190,191), despite some correlation of its presence with VS (189) or infarction (188) or outcome (191). Thrombin inhibitors seem to reduce VS (192,193). At least part of the action of thrombin may result from the induction of PDGF (ref.…”

Section: Thrombinmentioning

confidence: 99%

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Sercombe

Dinh

Gomis

2002

Japanese Journal of Pharmacology

182

140

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ABSTRACT-Aneurysmal subarachnoid hemorrhage frequently results in complications including intracranial hypertension, rebleeding and vasospasm. The extravasated blood is responsible for a cascade of reactions involving release of various vasoactive and pro-inflammatory factors (several of which are purported to induce vasospasm) from blood and vascular components in the subarachnoid space. The authors review the available evidence linking these factors to the development of inflammatory lesions of the cerebral vasculature, emphasizing: 1) neurogenic inflammation due to massive release of sensory nerve neuropeptides; 2) hemoglobin from lysed erythrocytes, which creates functional lesions of endothelial and smooth muscle cells; 3) activity, expression and metabolites of lipoxygenases cyclooxygenases and nitric oxide synthases; 4) the possible role of endothelin-1 as a pro-inflammatory agent; 5) serotonin, histamine and bradykinin which are especially involved in blood-brain barrier disruption; 6) the prothrombotic and pro-inflammatory action of complement and thrombin towards endothelium; 7) the multiple actions of activated platelets, including platelet-derived growth factor production; 8) the presence of perivascular and intramural macrophages and granulocytes and their interaction with adhesion molecules; 9) the evolution, origins, and effects of pro-inflammatory cytokines, especially IL-1, TNF-a and IL-6. Human and animal studies on the use of anti-inflammatory agents in subarachnoid hemorrhage include superoxide and other radical scavengers, lipid peroxidation inhibitors, iron chelators, NSAIDs, glucocorticoids, and serine protease inhibitors. Many animal studies claim reduced vasospasm, but these effects are not always confirmed in human trials, where symptomatic vasospasm and outcome are the major endpoints. Despite recent work on penetrating vessel constriction, there is a paucity of studies on inflammatory markers in the microcirculation.

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“…The diameter of the basilar artery on the angiograms was measured at three different points using a microscale loupe (×10; Peak, Tokyo), and the mean value was calculated. The mean diameter for each animal was used to calculate the percentage reduction in the diameter of the basilar artery, which was compared with the mean value of the pretreatment arteries [22, 23]. …”

Section: Methodsmentioning

confidence: 99%

“…Details of the method used for inducing SAH have been described elsewhere [22]. Briefly, the cisterna magna was atraumatically punctured with a 21-gauge spinal needle, autologous nonheparinized arterial blood (0.5 ml/kg) was carefully injected (day 0), and angiography was performed.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory Effects of Eicosapentaenoic Acid on Chronic Cerebral Vasospasm after Subarachnoid Hemorrhage: Possible Involvement of a Sphingosylphosphorylcholine-Rho-Kinase Pathway

Shirao¹,

Fujisawa²,

Kudo

et al. 2008

Cerebrovasc Dis

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Background and Purpose: Rho-kinase (ROK)-mediated Ca²⁺ sensitization of vascular smooth muscle (VSM) contraction plays a pivotal role in cerebral vasospasm (CV). We previously demonstrated that sphingosylphosphorylcholine (SPC) induces Ca²⁺ sensitization through sequential activation of the Src family protein tyrosine kinases (Src-PTKs) and ROK in vitro, and that Ca²⁺ sensitization is inhibited by eicosapentaenoic acid (EPA) through the selective inactivation of Src-PTK. In this study, we examined whether SPC induced CV in vivo, and, if it did, whether EPA would inhibit CV, as induced by SPC or in an in vivo model of subarachnoid hemorrhage (SAH). Methods: Changes in the diameter of the canine basilar artery were investigated by angiography after administering SPC into the cisterna magna. Then, Y27632, a specific Rho-kinase inhibitor, or EPA was injected intracisternally and the effects of both agents were investigated. In another experiment using a single-hemorrhage model, Y27632 or EPA was injected on day 7 after SAH and the changes in the diameter of the canine basilar artery were investigated. Results: At cerebrospinal fluid concentrations of 100 and 300 µmol/l, SPC induced severe vasoconstriction (maximum vasoconstriction by SPC (100 µmol/l): 61.8 ± 8.2%), which was markedly reversed by Y27632 (96.3 ± 4.4%) or EPA (92.6 ± 12.8%). SAH caused severe vasospasm on day 7 (67.6 ± 7.8%), which was significantly blocked by Y27632 (95.5 ± 10.6%) or EPA (90.0 ± 4.4%). Conclusions: SPC is a novel mediator of ROK-induced CV in vivo. The inhibition of CV induced by SPC or after SAH by EPA suggests beneficial roles of EPA in the treatment of CV. Our findings are compatible with the notion that the SPC-ROK pathway may be involved in CV.

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Intrathecal Administration of Thrombin Inhibitor Ameliorates Cerebral Vasospasm

Cited by 12 publications

References 25 publications

Broad-Spectrum and Selective Serine Protease Inhibitors Prevent Expression of Platelet-Derived Growth Factor–BB and Cerebral Vasospasm After Subarachnoid Hemorrhage

Broad-Spectrum and Selective Serine Protease Inhibitors Prevent Expression of Platelet-Derived Growth Factor–BB and Cerebral Vasospasm After Subarachnoid Hemorrhage

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Inhibitory Effects of Eicosapentaenoic Acid on Chronic Cerebral Vasospasm after Subarachnoid Hemorrhage: Possible Involvement of a Sphingosylphosphorylcholine-Rho-Kinase Pathway

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