Thrombolytic therapies for ischemic stroke: Triumphs and future challenges

Moussaddy, Aimen; Demchuk, Andrew M.; Hill, Michael D.

doi:10.1016/j.neuropharm.2017.11.010

Cited by 68 publications

(48 citation statements)

References 55 publications

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“…Stroke is the third leading cause of death in developed countries [1], the principal cause of severe long-term disability worldwide [2], and the largest contributor to global neurological disability-adjusted life-years [3]. Advances such as thrombolytic therapy and angioplasty have revolutionized acute management [4,5]; however, this obligatory revascularization induces further injury through reperfusion. This reperfusion injury is this methodology is available elsewhere [25].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke

Mendonça¹,

Cardoso²,

Michels³

et al. 2020

ICMx

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Background: Several therapeutic strategies to rescue the brain from ischemic injury have improved outcomes after stroke; however, there is no treatment as yet for reperfusion injury, the secondary damage caused by necessary revascularization. Recently we characterized ammonium tetrathiomolybdate (ATTM), a drug used as a copper chelator over many decades in humans, as a new class of sulfide donor that shows efficacy in preclinical injury models. We hypothesized that ATTM could confer neuroprotection in a relevant rodent model of regional stroke.Methods and results: Brain ischemia was induced by transient (90-min) middle cerebral artery occlusion (tMCAO) in anesthetized Wistar rats. To mimic a clinical scenario, ATTM (or saline) was administered intravenously just prior to reperfusion. At 24 h or 7 days post-reperfusion, rats were assessed using functional (rotarod test, spontaneous locomotor activity), histological (infarct size), and molecular (antioxidant enzyme capacity, oxidative damage, and inflammation) outcome measurements. ATTM-treated animals showed improved functional activity at both 24 h and 7-days post-reperfusion, in parallel with a significant reduction in infarct size. These effects were additionally associated with increased brain antioxidant enzyme capacity, decreased oxidative damage, and a late (7-day) effect on proinflammatory cytokine levels and nitric oxide products.Conclusion: ATTM confers significant neuroprotection that, along with its known safety profile in humans, provides encouragement for its development as a novel adjunct therapy for revascularization following stroke.

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Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke

Mendonça¹,

Cardoso²,

Michels³

et al. 2020

ICMx

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“…Furthermore, the narrow therapeutic time window of 4.5 h post ischemic injury and serious complications such as fatal intracerebral hemorrhage hinder its clinical use ( Jauch et al, 2013 ). As for mechanical thrombolysis, the requirements of rapid cerebral angiography in experienced stroke centers and qualified neurointerventional physicians largely impose restrictions on its clinical use ( Moussaddy et al, 2018 ). In addition, most patients treated with thrombolytic therapy are still found to have neurological dysfunction after treatments ( Moussaddy et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…As for mechanical thrombolysis, the requirements of rapid cerebral angiography in experienced stroke centers and qualified neurointerventional physicians largely impose restrictions on its clinical use ( Moussaddy et al, 2018 ). In addition, most patients treated with thrombolytic therapy are still found to have neurological dysfunction after treatments ( Moussaddy et al, 2018 ). Thus, it is particularly necessary to seek alternative therapeutic approaches for AIS patients.…”

Section: Introductionmentioning

confidence: 99%

Combined Use of Emodin and Ginsenoside Rb1 Exerts Synergistic Neuroprotection in Cerebral Ischemia/Reperfusion Rats

Shan

et al. 2018

Front. Pharmacol.

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Acute ischemic stroke (AIS) generally causes neurological dysfunction and poses a serious threat to public health. Here, we aimed to assess the independent and combined effects of ginsenoside Rb1 (GRb1) and Emodin on neuroprotection through regulating Connexin 43 (Cx43) and Aquaporin 4 (AQP4) expression in cerebral ischemia/reperfusion (I/R) model rats. Adult male Sprague-Dawley (SD) rats were randomly divided into five groups: sham group, I/R group, Emodin group, GRb1 group and Emodin+GRb1 group. They were further allocated to four subgroups according to the 6h, 1d, 3d, and 7d time points except the sham group. Based on the modified Longa suture method, the focal cerebral I/R model was established by middle cerebral artery occlusion (MCAO). The neurological deficit scores (NDS), blood brain barrier (BBB) permeability and cerebral infarction area were assessed at each corresponding time point. Cx43 and AQP4 levels were assessed by Real-time PCR and Immunofluorescence. Compared with I/R group, both the independent and combined use of GRb1 and Emodin could alleviate NDS, reduce the BBB permeability, reduce the infarction area and down-regulate Cx43 and AQP4 expression at 6h, 1d, 3d, and 7d after I/R (P < 0.05). The Emodin+GRb1 group had more significant effects than Emodin group and GRb1 group (P < 0.05). In conclusion, the combination of Emodin and GRb1 exerts synergistically neuroprotective functions through regulating AQP4 and Cx43 after I/R.

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“…Thrombolytic therapy is a powerful means to treat ischemic stroke . Currently, the standard method is the use of the enzyme tissue‐type plasminogen activator (t‐PA), which specifically cleaves plasminogen, converting it to the active thrombolytic enzyme plasmin .…”

Section: Introductionmentioning

confidence: 99%

Efficacy of SMTP‐7, a small‐molecule anti‐inflammatory thrombolytic, in embolic stroke in monkeys

Suzuki

Nishimura²,

Yoshikawa

et al. 2018

Pharmacology Res & Perspec

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SMTP‐7 (Stachybotrys microspora triprenyl phenol‐7) is a small molecule that promotes thrombolysis and suppresses inflammation possibly through plasminogen modulation and soluble epoxide hydrolase (sEH) inhibition, respectively. Here, we demonstrate an efficacy of SMTP‐7 in a severe embolic stroke model in monkeys. The middle cerebral artery was embolized by an autologous blood clot. Saline, SMTP‐7, or tissue‐type plasminogen activator (t‐PA) (n = 5 in each group) was given after 3 hours, and neurologic deficit scoring and infarct characterization were performed after 24 hours. Hemorrhagic infarct‐accompanied premature death was observed for two animals in t‐PA group. SMTP‐7 treatment significantly reduced the sizes of infarct by 65%, edema by 37%, and clot by 55% compared to saline treatment. Plasma levels of the products of plasminogen activation (plasmin‐α2‐antiplasmin complex) and sEH reaction (dihydroxyeicosatrienoic acid) in SMTP‐7 group were 794% (P < 0.05) and 60% (P = 0.085) compared to saline group, respectively. No significant changes in the plasma levels of MMP‐9, CRP, MCP‐1, and S100B were found. There was an inverse correlation between plasmin‐α2‐antiplasmin complex level and infarct volume (r = 0.93, P < 0.05), suggesting a role of thrombolysis in the SMTP‐7 action to limit infarct development. In conclusion, SMTP‐7 is effective in treating severe embolic stroke in monkeys under conditions where t‐PA treatment tends to cause hemorrhagic infarct‐associated premature death.

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Thrombolytic therapies for ischemic stroke: Triumphs and future challenges

Cited by 68 publications

References 55 publications

Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke

Neuroprotective effects of ammonium tetrathiomolybdate, a slow-release sulfide donor, in a rodent model of regional stroke

Combined Use of Emodin and Ginsenoside Rb1 Exerts Synergistic Neuroprotection in Cerebral Ischemia/Reperfusion Rats

Efficacy of SMTP‐7, a small‐molecule anti‐inflammatory thrombolytic, in embolic stroke in monkeys

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