Attenuation of Thrombin-Induced Brain Edema by Cerebral Thrombin Preconditioning

Abstract

Background and Purpose-Edema formation after intracerebral hemorrhage has been linked to thrombin toxicity induced by the clot. However, thrombin at low concentrations actually protects neurons and astrocytes in culture from hypoglycemic and ischemic cell death. It is also known that a brief episode of brain ischemia increases neuronal tolerance to a subsequent severe ischemic episode. The objective of this study was to investigate whether pretreatment of the brain with low-dose thrombin induces tolerance to a subsequent large dose of thrombin injected into brain parenchyma. Methods-The rat brain was preconditioned with 1 U thrombin by direct infusion into the right caudate nucleus. After thrombin pretreatment, the effects of a large dose (5 U) of thrombin on brain edema formation were studied at different intervals. We examined whether heat-shock protein (HSP) 27, HSP32, and HSP70 were induced by Western blot analysis, immunocytochemistry, and immunofluorescent double staining. Results-Thrombin pretreatment significantly attenuated the brain edema that normally follows the infusion of a large dose of thrombin (79.2Ϯ0.4 versus 84.0Ϯ0.3; PϽ0.01). This effect was abolished by the thrombin inhibitor hirudin. Time course studies showed that the maximal effect of thrombin preconditioning (TPC) on brain edema formation was 7 days after pretreatment. This time course corresponded to marked upregulation of HSP27 in the ipsilateral brain. TPC also induced HSP32, but this effect occurred earlier than the effect on edema formation. TPC had no effect on HSP70.Immunocytochemistry and immunofluorescent double labeling showed that HSP27 and HSP32 were expressed in astrocytes after TPC. Conclusions-The phenomenon of thrombin-induced tolerance of the brain to edema formation may be related to HSP27 induction. (Stroke. 1999;30:1247-1255.)

Protective Role of Early Aquaporin 4 Induction against Postischemic Edema Formation

“…Using a preconditioning paradigm, we have studied the consequences of an early induction of the AQP4 expression, with the hypothesis that early upregulation of AQP4 expression is aimed at reducing edema formation. We and others have shown previously that exposure to a low dose of thrombin can protect the brain parenchyma against subsequent ischemia (Granziera et al, 2007;Masada et al, 2003;Xi et al, 1999). We chose to explore the effect of TPC both on early edema formation and AQP4 expression.…”

Hydrocephalus after Intraventricular Hemorrhage: The Role of Thrombin

“…First, rats received a 200-ml injection of saline (n ¼ 8), autologous blood (n ¼ 8), or heparinized blood (5 units heparin, n ¼ 6) into the right lateral ventricle over 15 minutes. Serial magnetic resonance imaging (MRI) scanning was performed at days 1,3,8,14, and 28. Rats were euthanized at day 28 after IVH.…”

The effect of thrombin on a 6-hydroxydopamine model of Parkinson's disease depends on timing

“…This concentration of thrombin was chosen because it has previously been found to be protective when administered prior to 6-OHDA [3]; it is, therefore, ideal to further elucidate the temporal effects of thrombin in the 6-OHDA model. Additionally, this dosage of thrombin (1 U/50 μL saline) does not produce brain edema [45]. To evaluate the effects of thrombin at an earlier time-point after 6-OHDA, additional animals were administered either saline (n = 4) or thrombin (n = 5) one day after 6-OHDA.…”

“…In contrast to the detrimental effects of high doses of thrombin, administration of a low dose thrombin several days prior to experimental stroke is highly protective, an effect termed thrombin preconditioning [29,45]. It is well established that a minor insult to the brain can activate cell survival mechanisms that can reduce or prevent tissue destruction normally expected from a severe insult several days later [15].…”