Thrombin contributes to the injury development and neurological deficit after acute subdural hemorrhage in rats only in collaboration with additional blood-derived factors

Abstract

BackgroundAcute subdural hemorrhage (ASDH) is a severe consequence of traumatic brain injury. The occurrence of subdural blood increases the lethality of these patients independent of the amount of blood or elevated intracranial pressure. Thrombin is one of the potential harmful blood components. Possible harmful effects of thrombin are mediated via the Protease-activated-receptor-1 (PAR1) and thus, translating the acute Thrombin release after ASDH into cell loss. The objectives of the present study were twofold, namely to examine (1) the impact of direct thrombin inhibition in the acute phase after hemorrhage on the long-term histological and functional deficits and (2) the early inhibition of PAR1 activation by thrombin with the selective antagonist SCH79797 on lesion volume at 14 days after ASDH. The effects of thrombin on the lesion size were investigated in two separate experiments via (1) direct thrombin inhibition in the subdural infused blood (Argatroban 600 µg) as well as by (2) intraventricular injection of the PAR-1 antagonist SCH79797 (1 µg or 5 µg). Lesion volume and behavior deficits using a neurological deficit score and a motor function test (beam balance test) were analyzed as outcome parameters at 14 days after injury.Results59 Male Sprague–Dawley rats received a subdural infusion of 300 µl autologous blood or sham operation. Lesion volume at 14 days after ASDH tended to be smaller in the Argatroban-treated group when compared to the vehicle group (8.1 ± 1.1 vs. 10.1 ± 2.3 mm2, n.s.). Motor deficits in the beam balance test were not significantly less severe in the Argatroban-treated group. Animals treated with SCH79797 also showed a trend towards dose-dependent decreased lesion volume in comparison to the vehicle-treated group (1 μg: 4.3 ± 0.7 mm3; 5 μg: 3.8 ± 1.1 mm3; vehicle: 6.5 ± 2.0 mm3, n.s).ConclusionsThrombin inhibition in the subdural blood and local cerebral blockade of PAR-1 cause a tendency towards reduced lesion volume or functional recovery. All results show a trend in favor of the acute treatment on the outcome parameters. Our results suggests that thrombin could be an important blood-derived factor during acute subdural hemorrhage that translates its deleterious effects in concert with other blood-induced factors.

Cerebral Blood Flow Disorder in Acute Subdural Hematoma and Acute Intraoperative Brain Bulge

“…These injuries may be caused not only by the pressure of the hematoma but also by the influence of blood components ( 15 ). Other studies have indeed found that thrombin in blood and some components in blood clots are factors causing brain swelling and other serious consequences ( 16 – 18 ). Therefore, studying the role of cerebral circulation in ASDH will be conducive to a comprehensive understanding of the pathophysiological changes after ASDH.…”

Imbalance of the hemocoagulation and fibrinolysis systems under conditions of diabetes mellitus complicated by acute circulatory disturbance in the pool of carotid arteries of rats

“…Thus, intracerebral infusion of a low dose of thrombin activates endogenous neuroprotective mechanisms and increases tolerance to cerebral ischemia. In case of a considerable increase thrombin intensifies edema and secondary lesion of the brain after ischemia and hemorrhages [8,14,15]. Instillation of thrombin іn vitro in nanomolar and micromolar concentrations induces death of the cells in the culture of the hippocampus and motor neurons [16].…”

High glucose upregulates PAR‐1 in SH‐SY5Y cells via deficiency of miR‐20a and miR‐190a

“…Thrombin, a serine protease and an essential component of the coagulation cascade, displays proinflammatory response in neurodegeneration [3–5]. Further studies indicate that protease‐activated receptors (PARs) mediate the toxic effects of thrombin on diseases in the central nervous system [6,7], and PAR‐1 is a high‐affinity receptor for thrombin in brain. Earlier reports indicate that an increase in PAR‐1 leads to neuronal damage caused by cerebral ischemia [8,9].…”