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Effect of argatroban on microthrombi formation and brain damage in the rat middle cerebral artery thrombosis model
H Kawai1, K Umemura, M Nakashima
1Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
Abstract:
Ischemic cerebral infarcts induce hypercoagulation and microthrombosis in the surrounding region, thus leading to vascular occlusion. We determined whether microthrombi contribute to the spreading of ischemic lesions following thrombotic middle cerebral artery (MCA) occlusion and also determined whether argatroban, a selective thrombin inhibitor, reduces the formation of the microthrombi and the area of the ischemic lesions. The rat left MCA was occluded by a platelet-rich thrombus formed following the photochemical reaction between rose bengal and green light. Microthrombi were histologically identified in the left hemisphere. The extent of ischemic lesions and microthrombi containing fibrin increased in a time-dependent manner after MCA occlusion. Argatroban inhibited the formation of microthrombi up to 3 hr after MCA occlusion; beyond 3 hr, it was ineffective. Argatroban also significantly (P < 0.01) reduced the size of ischemic cerebral lesions at 6 hr after MCA occlusion. It is concluded that the formation of microthrombi contributes to the progression of ischemic lesions in the early stage. It is likely that thrombin generated following thrombotic MCA occlusion contributes to the progression of ischemic lesions by promoting the formation of microthrombi. Argatroban can reduce the formation of microthrombi and ischemic lesions in the early stage.
Insights
Microthrombi formation contributes to ischemic lesion spread after middle cerebral artery (MCA) occlusion. Early administration of argatroban, a thrombin inhibitor, reduced microthrombi and lesion size in rats.
Area of Science:
- Neuroscience
- Cerebrovascular Research
- Thrombosis and Hemostasis
Background:
- Ischemic cerebral infarcts cause hypercoagulation and microthrombosis, leading to vascular occlusion.
- Microthrombi formation is implicated in the progression of ischemic brain lesions.
- Understanding the role of microthrombi and potential interventions is crucial for stroke treatment.
Purpose of the Study:
- To investigate the contribution of microthrombi to the spreading of ischemic lesions following middle cerebral artery (MCA) occlusion.
- To evaluate the efficacy of argatroban, a selective thrombin inhibitor, in reducing microthrombi formation and ischemic lesion size.
Main Methods:
- Middle cerebral artery (MCA) occlusion was induced in rats using a photochemical method with rose bengal and green light.
- Microthrombi were identified histologically in the affected hemisphere.
- The time-dependent changes in ischemic lesion extent and microthrombi were assessed.
- The effect of argatroban administration on microthrombi formation and lesion size was evaluated at different time points.
Main Results:
- Microthrombi, containing fibrin, increased in extent over time after MCA occlusion.
- Argatroban effectively inhibited microthrombi formation within the first 3 hours post-occlusion but was ineffective thereafter.
- Argatroban significantly reduced the size of ischemic cerebral lesions at 6 hours after MCA occlusion.
Conclusions:
- Microthrombi formation plays a significant role in the early progression of ischemic brain lesions.
- Thrombin generation following MCA occlusion likely promotes microthrombi formation, contributing to lesion expansion.
- Early intervention with argatroban can mitigate microthrombi and reduce ischemic lesion size in the acute phase of stroke.