Immunotherapy blocking the tissue plasminogen activator-dependent activation of N-methyl-d-aspartate glutamate receptors improves hemorrhagic stroke outcome (original) (raw)
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Circulation, 2003
Background-Platelet aggregation and fibrin deposition are key events leading to microvascular thrombosis and progressive impairment of downstream microvascular perfusion after stroke. We tested the hypothesis that inhibition of platelet function with a GP IIb/IIIa receptor antagonist would increase the efficacy and safety and increase the time window for thrombolytic therapy for stroke with full-and half-dose tissue plasminogen activator (tPA). Methods and Results-Rats were subjected to embolic middle cerebral artery occlusion. Four hours after ischemia, rats were treated with 7E3 F(abЈ) 2 (6 mg/kg) in combination with tPA at doses of 10 and 5 mg/kg, tPA alone at a dose of 10 or 5 mg/kg, 7E3 F(abЈ) 2 (6 mg/kg) alone, or saline. Combination treatment with 7E3 F(abЈ) 2 and tPA (full-or half-dose) significantly (PϽ0.05) reduced infarct volume and neurological deficits compared with saline-treated rats. However, treatment with 7E3 F(abЈ) 2 or tPA (full-or half-dose) alone did not reduce infarct volume. Quantitative measurements of cerebral microvessels perfused by FITC-dextran revealed that combination treatment with 7E3 F(abЈ) 2 and full-dose tPA significantly (PϽ0.05) increased the percentage of FITC-dextran-perfused vessels compared with saline and full-dose tPA-treated rats. In addition, treatment with 7E3 F(abЈ) 2 in combination with full-dose tPA significantly (PϽ0.05) decreased microvascular platelet accumulation and matrix metalloproteinase 9 immunoreactivity and protected against loss of collagen IV immunoreactivity. Conclusions-Combination treatment with 7E3 F(abЈ) 2 with full-and half-dose tPA at 4 hours after ischemia significantly reduces infarct volume and improves neurological outcome. Enhancement of patency and integrity of cerebral microvessels most likely contributes to the benefits observed with this combination therapy.
Journal of the Neurological Sciences, 2011
Introduction-Niaspan, an extended-release formulation of Niacin (vitamin B3), has been widely used to increase high density lipoprotein (HDL) cholesterol and to prevent cardiovascular diseases and stroke. We have previously demonstrated that Niaspan (40mg/kg) administered at 2 hours after stroke induces neuroprotection, while low dose Niaspan (20mg/kg) does not reduce infarct volume. Tissue plasminogen activator (tPA) is an effective therapy for acute stroke, but its use remains limited by narrow therapeutic window. We have previously demonstrated that intravenous administration of tPA 4 hours after stroke in rats does not reduce infarct volume. In this study, we tested whether combination treatment with low-dose Niaspan (20mg/kg) and tPA administered 4 hours after embolic stroke in a rat model reduces infarct volume and provides neuroprotection.
Translational stroke research, 2014
RTL1000 is a partial human MHC molecule coupled to a human myelin peptide. We previously demonstrated that RTL1000 was protective against experimental ischemic stroke in HLA-DR2 transgenic (DR2-Tg) mice. Since thrombolysis with recombinant tissue plasminogen activator (t-PA) is a standard therapy for stroke, we determined if RTL1000 efficacy is altered when combined with t-PA in experimental stroke. Male DR2-Tg mice underwent 60 min of intraluminal middle cerebral artery occlusion (MCAO). t-PA or vehicle was infused intravenously followed by either a single or four daily subcutaneous injections of RTL1000 or vehicle. Infarct size was measured by 2, 3, 5-triphenyltetrazolium chloride staining at 24 or 96 h of reperfusion. Our data showed that t-PA alone reduced infarct size when measured at 24 h but not at 96 h after MCAO. RTL1000 alone reduced infarct size both at 24 and 96 h after MCAO. Combining RTL1000 with t-PA did not alter its ability to reduce infarct size at either 24 or 96 ...
2020
Background and aim: Recombinant tissue plasminogen activator (r-TPA) is approved for treatment of acute ischemic stroke (AIS). Neuron-specific enolase (NSE) is a marker of brain damage in patients with traumatic brain injury, stroke and hypoxic encephalopathy. The present study assessed the effect of r-TPA treatment on serum NSE levels in patients with AIS.Patients and methods: The study included 53 patients with AIS. They comprised 25 patients who didn’t receive r-TPA and 28 patients who received r-TPA. Clinical severity of the stroke was assessed using National Institute of Health Stroke Scale (NIHSS). Modified Rankin score was used to evaluate the degree of disability in the affected patients. NSE was assessed at 24 h after r-TPA infusion using commercially available quantitative enzyme-linked immunosorbent assay kits. Radiological imaging included echocardiography, brain computed tomography, and carotid and vertebrobasilar duplex. Results: Patients subjected to r-TPA treatment h...
Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic
Trends in neurosciences, 2009
Thrombolysis with tissue-type plasminogen activator (tPA) is used for the treatment of patients with acute ischemic stroke. However, a growing body of evidence indicates that, besides the unquestionable benefit from its thrombolytic activity, tPA also has a deleterious effect on the ischemic brain including cytotoxicity and increased permeability of the neurovascular unit with the development of cerebral edema. Because an increasing number of acute stroke patients are treated with tPA, it is important to know the mechanisms of harmful effects of tPA on the ischemic brain. Here, the best studied pathways of tPA neurotoxicity are discussed along with future directions for a safer use of tPA as a thrombolytic agent in the setting of acute ischemic stroke.
Plasminogen Activators Potentiate Thrombin-Induced Brain Injury
2000
Background and Purpose-Evidence suggests that cerebral edema following intracerebral hemorrhage (ICH) results from a mass effect in combination with neurotoxic injury from clot-derived substrates such as thrombin. Thrombolytics can compete for thrombin inhibitors endogenous to the brain. This study examines the effect of intracerebral infusion of thrombolytics, tissue plasminogen activator (tPA), and urokinase (uPA), individually and in combination with thrombin. Methods-Various 100 L solutions were stereotactically infused into the right basal ganglia of adult male rats. Animals were euthanized 24 hours later, and brain sections were taken for measurement of water, sodium, and potassium content. Results-Regardless of dose, when infused independently tPA (2 g) and uPA (2000 and 5000 Plough units) failed to produce any significant tissue edema compared with vehicle control tissues. However, when either thrombolytic was infused concomitantly with thrombin (1 or 5 U), brain water, sodium, and potassium content all demonstrated a potentiation of thrombin-induced brain injury (PϽ0.05). In addition, animal deaths were significantly greater than expected in animals receiving a combination of tPA (2 g) and thrombin (5 U) compared with either drug alone (PϽ0.001). Conclusions-This study indicates that brain edema caused by thrombin can be greatly amplified by the presence of plasminogen activators, perhaps because the latter compete for naturally occurring thrombin inhibitors. In the context of ICH, our results suggest that the use of tPA or uPA to lyse clotted blood in brain parenchyma may promote edema formation in surrounding tissue. (Stroke. 1998;29:1202-1208.)