New thrombolytic strategy providing neuroprotection in experimental ischemic stroke: MMP10 alone or in combination with tissue-type plasminogen activator

Roncal, Carmen; Lizarrondo, Sara Martínez de; Salicio, Agustina; Chevilley, Arnaud; Rodríguez, J.A.; Rosell, Anna; Couraud, Pierre‐Olivier; Weksler, Babette B.; Montaner, Joan; Vivien, Denis; Páramo, José A.; Orbe, Josune

doi:10.1093/cvr/cvx069

Cited by 16 publications

(11 citation statements)

References 39 publications

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“…Broad-spectrum MMP inhibitor-tPA combination has also showed protective effects in reducing IV tPA-related hemorrhagic complication [121]. Very interestingly, besides MMP inhibitor, combination of MMP-10 plus tPA exhibited effects of BBB protection, neuronal excitotoxicity reduction, and calcium overload mitigation [122]. Molecules targeting coagulation pathway have also been included as a potential adjunct of IV tPA therapy.…”

Section: Combination Therapy For IV Tpa Thrombolysismentioning

confidence: 99%

Diabetes Mellitus/Poststroke Hyperglycemia: a Detrimental Factor for tPA Thrombolytic Stroke Therapy

Jiang

Liu

Han

et al. 2020

Transl. Stroke Res.

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Intravenous administration of tissue-type plasminogen activator (IV tPA) therapy has long been considered a mainstay in ischemic stroke management. However, patients respond to IV tPA therapy unequally with some subsets of patients having worsened outcomes after treatment. In particular, diabetes mellitus (DM) is recognized as a clinically important vascular comorbidity that leads to lower recanalization rates and increased risks of hemorrhagic transformation (HT). In this short-review, we summarize the recent advances in understanding of the underlying mechanisms involved in post-IV tPA worsening of outcome in diabetic stroke. Potential pathologic factors that are related to the suboptimal tPA recanalization in diabetic stroke include higher plasma plasminogen activator inhibitor (PAI)-1 level, diabetic atherogenic vascular damage, glycation of the tPA receptor annexin A2, and alterations in fibrin clot density. While factors contributing to the exacerbation of HT in diabetic stroke include hyperglycemia, vascular oxidative stress, and inflammation, tPA neurovascular toxicity and imbalance in extracellular proteolysis are discussed. Besides, impaired collaterals in DM also compromise the efficacy of IV tPA therapy. Additionally, several tPA combination approaches developed from experimental studies that may help to optimize IV tPA therapy are also briefly summarized. In summary, more research efforts are needed to improve the safety and efficacy of IV tPA therapy in ischemic stroke patients with DM/poststroke hyperglycemia.

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Section: Combination Therapy For IV Tpa Thrombolysismentioning

confidence: 99%

Diabetes Mellitus/Poststroke Hyperglycemia: a Detrimental Factor for tPA Thrombolytic Stroke Therapy

Jiang

Liu

Han

et al. 2020

Transl. Stroke Res.

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“…In the same thromboembolic stroke model, administration of MMP-10 in combination with tissue-type plasminogen activator (tPA) significantly reduced the infarct size as compared with tPA alone. 14 In contrast to animal studies, increased MMP-10 protein levels were reported in human ischaemic brain. 8 …”

Section: Discussionmentioning

confidence: 85%

Post-stroke mRNA expression profile of MMPs: effect of genetic deletion of MMP-12

et al. 2018

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Background and purposeRecent reports from our laboratory demonstrated the post-ischaemic expression profile of various matrix metalloproteinases (MMPs) in rats and the detrimental role of MMP-12 in post-stroke brain damage. We hypothesise that the post-stroke dysregulation of MMPs is similar across species and that genetic deletion of MMP-12 would not affect the post-stroke expression of other MMPs. We tested our hypothesis by determining the pre-ischaemic and post-ischaemic expression profile of MMPs in wild-type and MMP-12 knockout mice.MethodsFocal cerebral ischaemia was induced in wild-type and MMP-12 knockout mice by middle cerebral artery occlusion procedure by insertion of a monofilament suture. One hour after ischaemia, reperfusion was initiated by removing the monofilament. One day after reperfusion, ischaemic brain tissues from various groups of mice were collected, and total RNA was isolated and subjected to cDNA synthesis followed by PCR analysis.ResultsAlthough the post-stroke expression profile of MMPs in the ischaemic brain of mice is different from rats, there is a clear species similarity in the expression of MMP-12, which was found to be predominantly upregulated in both species. Further, the post-stroke induction or inhibition of various MMPs in MMP-12 knockout mice is different from their respective expression profile in wild-type mice. Moreover, the brain mRNA expression profile of various MMPs in MMP-12 knockout mice under normal conditions is also different to their expression in wild-type mice.ConclusionsIn the ischaemic brain, MMP-12 upregulates several fold higher than any other MMP. Mice derived with the genetic deletion of MMP-12 are constitutive and have altered MMP expression profile both under normal and ischaemic conditions.

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“…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 .…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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

et al. 2022

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Background: Intracranial haemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinases (MMPs) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives: We evaluated the effects of CM-352 (MMPs-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin concentrate complex (PCC). Methods: ICH was induced by collagenase injection into the striatum of WT (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24h later by diaminobenzidine staining and different behavioural test. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays. Results: Only PCC reduced haemorrhage volume and improved functional outcome in warfarin-ICH, but both, PCC and CM-352 treatments, diminished haemorrhage volume (46%, p<0.01 and 64%, p<0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC decreased neutrophil infiltration in the haemorrhage area at 24h. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10-/- mice showed lower haemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation. Conclusions: CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihaemorrhagic strategy for rivaroxaban-associated ICH.

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New thrombolytic strategy providing neuroprotection in experimental ischemic stroke: MMP10 alone or in combination with tissue-type plasminogen activator

Abstract: These results show that MMP10, either alone or in combination with tPA, might represent a new strategy for thrombolysis in ischemic stroke, providing higher protection against cerebrovascular damage.

Cited by 16 publications

References 39 publications

Diabetes Mellitus/Poststroke Hyperglycemia: a Detrimental Factor for tPA Thrombolytic Stroke Therapy

Diabetes Mellitus/Poststroke Hyperglycemia: a Detrimental Factor for tPA Thrombolytic Stroke Therapy

Post-stroke mRNA expression profile of MMPs: effect of genetic deletion of MMP-12

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

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