Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival

Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to the single chain form (sc-tPA), the two-chains form of tPA (tc-tPA) activates the MET receptor, leading to the recruitment of N-Methyl-D-Aspartate receptors (NMDARs) and to the endocytosis and proteasome-dependent degradation of NMDARs containing the GluN2B subunit. Accordingly, tc-tPA down-regulated GluN2B-NMDAR-driven signalling, a process prevented by blockers of HGFR/MET and mimicked by its agonists, leading to a modulation of neuronal death. Thus, our present study unmasks a new mechanism of action of tPA, with its two-chains form mediating a crosstalk between MET and the GluN2B subunit of NMDARs to control neuronal survival.

Tissue-type plasminogen activator induces TNF-α-mediated preconditioning of the blood-brain barrier

Ischemic tolerance is a phenomenon whereby transient exposure to a non-injurious preconditioning stimulus triggers resistance to a subsequent lethal ischemic insult. Despite the fact that not only neurons but also astrocytes and endothelial cells have a unique response to preconditioning stimuli, current research has been focused mostly on the effect of preconditioning on neuronal death. Thus, it is unclear if the blood-brain barrier (BBB) can be preconditioned independently of an effect on neuronal survival. The release of tissue-type plasminogen activator (tPA) from perivascular astrocytes in response to an ischemic insult increases the permeability of the BBB. In line with these observations, treatment with recombinant tPA increases the permeability of the BBB and genetic deficiency of tPA attenuates the development of post-ischemic edema. Here we show that tPA induces ischemic tolerance in the BBB independently of an effect on neuronal survival. We found that tPA renders the BBB resistant to an ischemic injury by inducing TNF-α-mediated astrocytic activation and increasing the abundance of aquaporin-4-immunoreactive astrocytic end-feet processes in the neurovascular unit. This is a new role for tPA, that does not require plasmin generation, and with potential therapeutic implications for patients with cerebrovascular disease.

DWI Lesion Characteristics As A Predictor For Outcome In Acute Stroke Patients Treated By IV-tPA

Background Thrombolysis with tissue-type plasminogen activator (IV-tPA) is a well-proved, widely used treatment in acute ischemic stroke patients, many predictors of functional outcome have been proposed as Age, vascular risk factors, initial clinical evaluation on admission using National institute of health stroke scale(NIHSS), functional state of patient(b.L) baseline before stroke and 3 months (3m) after stroke using modified Rankin stroke scale (MRS)and the most controversial Diffusion weighted image characteristics (volume, heterogeneity) Objective To evaluate DWI MRI characteristics (volume, heterogeneity) as a predictor for outcome in Acute stroke patients treated by IV-tPA Patients and Methods This study will be done on a sample of 100 acute ischemic stroke Egyptian patients receiving intra-venous tissue -type plasminogen activator presenting to Ain-Shams university hospitals Results Highly statistically significant (p-value < 0.001) Positive correlation (r = 0.394) between volume (DWI) and MRS (3m) post discharge in studied patients, No statistically significant (pvalue > 0.05) relation between heterogeneity and other studied parameters (MRS, NIHSS D & ADC values) in studied patients Conclusion DWI infarct volume is a predictor for outcome in acute ischemic stroke patients treated by tPA

Influences of Intravenous Thrombolysis with Recombinant Tissue-type Plasminogen Activator on the Outcome of Atrial Fibrillation Patients with Acute Ischemic Stroke: A Case a Case-control Study of 227 Patients

Background: It is a debatable topic about the benefit of intravenous (IV) thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) for atrial fibrillation (AF) patients with acute ischemic stroke (AIS). This study aimed to identify whether IV rt-PA could improve the short-term outcome of patients with AF-AIS.Methods: Medical data of patients with AIS onset within 72hs admitted in the department of neurologic of our hospital between January 1st, 2015 and December 31, 2020 were extracted. The AF-AIS patients were selected and divided into IV rt-PA group (group A) and non-rt-PA group (group B). The baseline characteristics, imaging changes and modified Rankin Scale (mRS) score (≤ 2 as good prognosis, > 2 as poor, = 6 as death) at discharge were obtained to compare the differences between the two groups. Logistic regression was used to analyze the factors influencing on the outcome. Results: Among a total of 1663 AIS patients, there were 280 had AF, of them 227 AF-AIS cases were conformed to the inclusion criteria, including 45 in group A and 182 in group B. All of AF-AIS patients, 48.0% had larger size of infarction and 62.1% had National Institute of Health stroke scale (NIHSS)score more than 10, the differences in the size and NIHSS between the two groups were not significant. A total of 51 cases (22.5%) died during hospitalization, the difference between group A and group B was not obvious (20.0% vs. 23.1%, P=0.658). The cumulative poor outcome (including deaths) at discharge was 75.3%, the difference between the two groups was also not significant (77.8% vs. 74.7%, P=0.671). The incidence of hemorrhagic transformation (HT) in group A was higher than that of in group B (40.0% vs. 21.4, P=0.010), the same was true for parenchymal hematoma (PH) in group A than group B (22.2% vs. 5.5%, P = 0.001). On univariate analysis, poor outcome was significantly associated with infarct size, NIHSS and PH, but not thrombolysis. The proportion of PH in patients with poor outcome between the two groups was also not remarkable. On adjusted multiple logistic regression analysis, both baseline infarction size [(P=0.013, odds ratio (OR) =4.558, 95% 95% confidence interval (CI): 1.373- 15.133] and NIHSS (P<0.001, OR=1.348, 95% CI=1.219-1.491) but not thrombolysis or PH entered into the final model as significant independent risk factors of poor outcome. Conclusion: Patients with AF-AIS had larger infarction size, higher NIHSS score, higher rate of mortality and worse outcome, for them, the IV rt-PA increased the incidence of PH except significantly improved their short-term prognosis.