Gaberel Thomas, Montagne Axel, Lesept Flavie, Gauberti Maxime, Lemarchand Eloïse, Orset Cyrille, Goulay Romain, Bertrand Thomas, Emery Evelyne, Vivien Denis
Department of Neurosurgery, Caen University Hospital, Avenue de la côte de Nacre, 14000 Caen, France; Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Neuropharmacology. 2014 Oct;85:158-65. doi: 10.1016/j.neuropharm.2014.05.001. Epub 2014 May 15.
Intraventricular hemorrhage (IVH) is the most severe form of stroke with intraventricular fibrinolysis (IVF) as a hopeful treatment. Urokinase (uPA) and tissue-type plasminogen activator (tPA) are used for IVF in Human. No clinical trial has evaluated the differential impact of these two fibrinolytics for IVF. Thus, we decided here to compare the use of these two fibrinolytics in a pre-clinical study. IVH was induced in rats by injection of collagenase type VII within the brain parenchyma followed by an IVF. Rats were randomized to receive uPA, tPA or saline within the ventricle, and cerebrospinal fluid was aspirated. Hematoma and ventricular volumes, brain water contents, inflammation and neurological deficits were measured at day three post-treatments. We also performed in vitro studies, in which neuronal cultures were subjected to an excitotoxic paradigm in the presence of either uPA or tPA. In the IVH model, we showed that although both uPA and tPA led to reduced ventricular volumes, only uPA significantly improved functional recovery. These results could be explained by the fact that uPA, in contrast of tPA, fails to promote inflammatory processes and neurotoxicity. Our study provides evidence supporting the use of uPA for fibrinolysis of IVH. A clinical trial could be warranted if tPA failed to improve outcomes in human IVH.
脑室内出血（IVH）是最严重的中风形式，脑室内纤维蛋白溶解术（IVF）是一种有前景的治疗方法。尿激酶（uPA）和组织型纤溶酶原激活剂（tPA）用于人类的IVF。尚无临床试验评估这两种纤溶剂对IVF的不同影响。因此，我们在此决定在一项临床前研究中比较这两种纤溶剂的使用情况。通过在脑实质内注射VII型胶原酶诱导大鼠发生IVH，随后进行IVF。将大鼠随机分为在脑室内接受uPA、tPA或生理盐水的组，并抽取脑脊液。在治疗后第3天测量血肿和脑室体积、脑含水量、炎症和神经功能缺损。我们还进行了体外研究，其中神经元培养物在存在uPA或tPA的情况下接受兴奋性毒性模型。在IVH模型中，我们表明尽管uPA和tPA都导致脑室体积减小，但只有uPA显著改善了功能恢复。这些结果可以用以下事实来解释：与tPA不同，uPA不会促进炎症过程和神经毒性。我们的研究提供了支持使用uPA进行IVH纤维蛋白溶解的证据。如果tPA不能改善人类IVH的预后，可能有必要进行临床试验。
