MMP10 Promotes Efficient Thrombolysis After Ischemic Stroke in Mice with Induced Diabetes

Abstract

Diabetes is an important risk factor for ischemic stroke (IS). Tissue-type plasminogen activator (tPA) has been associated with less successful revascularization and poor functional outcome in diabetes. We assessed whether a new thrombolytic strategy based on MMP10 was more effective than tPA in a murine IS model of streptozotocin (STZ)-induced diabetes. Wild-type mice were administered a single dose of streptozotocin (STZ) (180 mg/kg) to develop STZ-induced diabetes mellitus. Two weeks later, IS was induced by thrombin injection into the middle cerebral artery and the effect of recombinant MMP10 (6.5 μg/kg), tPA (10 mg/kg) or tPA/MMP10 on brain damage and functional outcome were analysed. Motor activity was assessed using the open field test. Additionally, we studied plasminogen activator inhibitor-1 (PAI-1) and thrombin-antithrombin complex levels (TAT) by ELISA and oxidative stress and blood-brain barrier (BBB) integrity by immunohistochemistry and western blot. MMP10 treatment was more effective at reducing infarct size and neurodegeneration than tPA 24 h and 3 days after IS in diabetic mice. Locomotor activity was impaired by hyperglycemia and ischemic injury, but not by the thrombolytic treatments. Additionally, TAT, oxidative stress and BBB permeability were reduced by MMP10 treatment, whereas brain bleeding or PAI-1 expression did not differ between treatments. Thrombolytic treatment with MMP10 was more effective than tPA at reducing stroke and neurodegeneration in a diabetic murine model of IS, without increasing haemorrhage. Thus, we propose MMP10 as a potential candidate for the clinical treatment of IS in diabetic patients.

Rh-CSF1 Attenuates Oxidative Stress and Neuronal Apoptosis via the CSF1R/PLCG2/PKA/UCP2 Signaling Pathway in a Rat Model of Neonatal HIE

“…Western blot tests were performed as previously described [ 44 ]. After TTC staining and digitally photographing at 48 h after HI, the brain sections were divided into ipsilateral and contralateral hemispheres, snap frozen in the liquid nitrogen, and stored in a −80°C freezer until further tissue lysis.…”

CM-352 Efficacy in a Mouse Model of Anticoagulant-Associated Intracranial Hemorrhage

“…In addition, MMPs may play a role in thrombolysis, since the fibrinolytic system and MMPs cooperate in thrombus dissolution by directly targeting fibrin(ogen) or by collaborating with plasmin 20,21 . Specifically, our group described the fibrinolytic role of MMP-10 by preventing the activation of thrombin-activatable fibrinolysis inhibitor (TAFI) 22 in experimental models of stroke 23,24 . Based on these results, we developed a potent MMPs inhibitor, CM-352, which inhibits MMP-10 and MMP-3 and fibrinolysis 25 , and effectively reduces bleeding, hematoma expansion, and functional impairment in different experimental models of haemorrhage with no signs of thrombotic side effects 26,27 .…”

Major histocompatibility complex Class II-based therapy for stroke

“…[ 3 4 ] It is more difficult to develop a stroke treatment due to the limited therapeutic window that accompanies a stroke. [ 5 6 7 ] Many therapeutic treatments aim at improving the immune response, specifically weakening neuroinflammation. [ 8 9 ] Stroke is associated with both central and peripheral inflammatory responses, and the spleen contributes a major role in secondary cell death.…”