Patrick Lyden, Benedict Pereira, Bo Chen, Lifu Zhao, Jessica Lamb, I-farn Lei, et al. Direct Thrombin Inhibitor Argatroban Reduces Stroke Damage in 2 Different Models. Stroke. 2014
A pilot study on acute stroke patients testing the direct thrombin inhibitor Argatroban in combination with IV-TPA led to increased recanalization rates and similar rates of symptomatic ICH compared to historical studies of IV-TPA alone. In addition to synergizing recanalization with IV-TPA, however, Argatroban may have neuroprotective properties. Thrombin injures neurons through protease activated receptors. A direct thrombin inhibitor like Argatroban may therefore benefit patients regardless of recanalization status. Lyden and colleagues sought to test the neuroprotective qualities of Argatroban in a rat model of stroke.
The authors performed 2 separate experiments. In the first experiment, 64 rats were randomized to Argatroban, thrombin, or saline infusion administered over 2 hrs during MCA occlusion. Behavioral measures of learning and memory were assessed several weeks later. In the second experiment, 272 rats were randomized to 2 separate doses of Argatroban administered at different time delays post-MCA occlusion. The rats treated with Argatroban demonstrated improved learning curves (P < 0.05), spatial memory (P < 0.05), and searching behavior (P = 0.03). Argatroban was beneficial when administered from 0-3 hrs post-MCA occlusion, but not at 4 hrs. Argatroban administered 0-1 hr post-MCA occlusion significantly reduced the histological size of the lesion.
The goals of this study were to demonstrate the neuroprotective effects of Argatroban using more robust behavioral endpoints and to identify an appropriate time window for administration. Both goals were achieved. Certain aspects of the methodology, however, raise questions as to how well these results translate to human subjects. The rats engaged in the behavioral experiment received Argatroban at the time of MCA occlusion. Delivering Argatroban 3 hrs post-MCA occlusion – a time window more realistic in humans – may possibly negate the benefits to learning and memory. One also wonders if 2 hrs of MCA occlusion is sufficient to simulate human stroke. The percentage of stroke patients who spontaneously recanalize by 2 hrs is likely quite low. These caveats aside, the authors clearly show that Argatroban has neuroprotective properties. They raise the possibility of testing other thrombin inhibitors in the future, which would help to validate the proposed mechanism of benefit. An additional avenue of research may be to identify an Argatroban dose that is optimal both for neuroprotection and increasing recanalization rates in combination with IV-TPA.