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

Abstract

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

Up‐regulation of proteinase‐activated receptor 1 and increased contractile responses to thrombin after subarachnoid haemorrhage

“…Proteinase inhibitors including a thrombin inhibitor, argatroban, were reported to reduce the incidence of posthaemorrhagic vasospasm and to attenuate its severity (Yanamoto et al, 1992;Zhang et al, 2001). All these reports support the critical role of thrombin in the pathogenesis of post-haemorrhagic cerebral vasospasm after SAH.…”

“…The thrombin activity in the cerebrospinal fluid was shown to correlate with the development of vasospasm in SAH patients (Kasuya et al, 1998). An inhibition of the thrombin activity was reported to prevent the development of vasospasm in a rabbit SAH model (Zhang et al, 2001). It is thus conceivable that thrombin plays a crucial role in the development of post-haemorrhagic vasospasm.…”

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

“…At least part of the action of thrombin may result from the induction of PDGF (ref. 193, see next section).…”

“…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.…”

“…Apart from its marked contractile activity on vascular SMCs (193), PDGF stimulates SMCs from aorta to express and secrete the MCP-1 (202, 203) with a certain specificity, acting via the JE promotor, an immediate early gene. This induction was blocked by dexamethasone, suggesting it to to be a regulatable and specific event involved in inflammation.…”