Induced pluripotent stem cells can improve thrombolytic effect of low-dose rt-PA after acute carotid thrombosis in rat (original) (raw)

Experimental modeling of recombinant tissue plasminogen activator effects after ischemic stroke

Experimental Neurology, 2012

Recombinant tissue plasminogen activator (rt-PA) is currently the only approved drug for ischemic stroke treatment, with a dose of 0.9 mg/kg. Since the fibrinolytic activity of rt-PA has been reported in vitro to be 10-fold less potent in rodent than in human, in most in vivo experimental models of cerebral ischemia rt-PA is used at 10 mg/kg. The purpose of this study was to compare the effects of the "human" (0.9 mg/kg) and "rodent" (10 mg/kg) doses of rt-PA given at an early or a delayed time point in a mouse model of cerebral ischemia. Cerebral ischemia was induced by thrombin injection into the left middle cerebral artery of mice. Rt-PA (0.9 or 10 mg/kg) was intravenously administered 30 min or 4 h after the onset of ischemia. The degree of reperfusion after rt-PA was followed for 90 min after its injection. The neurological deficit, infarct volumes, edema and hemorrhagic transformations (HT) were assessed at 24 h. Reperfusion was complete after early administration of rt-PA at 10 mg/kg but partial with rt-PA at 0.9 mg/kg. Both doses given at 4 h induced partial reperfusion. Early administration of both doses of rt-PA reduced the neurological deficit, lesion volume and brain edema, without modifying post-ischemic HT. Injected at 4 h, rt-PA at 0.9 and 10 mg/kg lost its beneficial effects and worsened HT. In conclusion, in the mouse thrombin stroke model, the "human" dose of rt-PA exhibits effects close to those observed in clinic.

Potential of Stem Cell-Based Therapy for Ischemic Stroke

Frontiers in Neurology, 2018

Ischemic stroke is one of the major health problems worldwide. The only FDA approved anti-thrombotic drug for acute ischemic stroke is the tissue plasminogen activator. Several studies have been devoted to assessing the therapeutic potential of different types of stem cells such as neural stem cells (NSCs), mesenchymal stem cells, embryonic stem cells, and human induced pluripotent stem cell-derived NSCs as treatments for ischemic stroke. The results of these studies are intriguing but many of them have presented conflicting results. Additionally, the mechanism(s) by which engrafted stem/progenitor cells exert their actions are to a large extent unknown. In this review, we will provide a synopsis of different preclinical and clinical studies related to the use of stem cell-based stroke therapy, and explore possible beneficial/detrimental outcomes associated with the use of different types of stem cells. Due to limited/short time window implemented in most of the recorded clinical trials about the use of stem cells as potential therapeutic intervention for stroke, further clinical trials evaluating the efficacy of the intervention in a longer time window after cellular engraftments are still needed.

Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke

Vascular Health and Risk Management, 2014

In 1995, the NINDS (National Institute of Neurological Disorders and Stroke) tPA (tissue plasminogen activator) Stroke Study Group published the results of a large multicenter clinical trial demonstrating efficacy of intravenous tPA by revealing a 30% relative risk reduction (absolute risk reduction 11%-15%) compared with placebo at 90 days in the likelihood of having minimal or no disability. Since approval in 1996, tPA remains the only drug treatment for acute ischemic stroke approved by the US Food and Drug Administration. Over the years, an abundance of research and clinical data has supported the safe and efficacious use of intravenous tPA in all eligible patients. Despite such supporting data, it remains substantially underutilized. Challenges to the utilization of tPA include narrow eligibility and treatment windows, risk of symptomatic intracerebral hemorrhage, perceived lack of efficacy in certain high-risk subgroups, and a limited pool of neurological and stroke expertise in the community. With recent US census data suggesting annual stroke incidence will more than double by 2050, better education and consensus among both the medical and lay public are necessary to optimize the use of tPA for all eligible stroke patients. Ongoing and future research should continue to improve upon the efficacy of tPA through more rapid stroke diagnosis and treatment, refinement of advanced neuroimaging and stroke biomarkers, and successful demonstration of alternative means of reperfusion.

Tissue Plasminogen Activator for preclinical stroke research: Neither "rat" nor "human" dose mimics clinical recanalization in a carotid occlusion model

Scientific reports, 2015

Tissue plasminogen activator (tPA) is the only approved thrombolytic therapy for acute ischemic stroke, yet many patients do not recanalize. Enhancing thrombolytic efficacy of tPA is a major focus of stroke research. Traditionally, a "rat dose" of 10 mg/kg has been used in rodent models. Recent studies suggested that the clinical "human" dose (0.9 mg/kg) may better mimic clinical recanalization. These studies only compared the rat and clinical doses, and so we aimed to test recanalization efficacy of multiple tPA doses ranging from 0.9 to 10 mg/kg in a model of endothelial injury and vessel stenosis. The common carotid artery of rats was crushed and stenosed to allow in-situ occlusive thrombus formation (Folt's model of 'physiological' thrombus). Intravenous tPA was administered 60 minutes post-occlusion (n = 6-7/group). Sustained recanalization rates were 0%, 17%, 67% and 71%, for 0.9, 1.8, 4.5, and 10 mg/kg, respectively. Median time to sustained re...

The Outcome of Treatment With Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke

Background: Thrombolytic therapy is the recommended treatment of acute ischemic stroke. It is crucial to evaluate the treatment results with recombinant Tissue Plasminogen Activator (r-TPA) in patients with acute stroke. Objectives: This study aimed to evaluate treatment outcomes with r-TPA in patients with acute stroke in a referral stroke center in Iran. Materials & Methods: In this retrospective study, 87 patients with symptoms of acute stroke were examined. They were referred to a stroke center in Gilan Province, Iran, from June 2016 to April 2020 and received r-TPA (0.9 mg/kg). Demographic information, the time interval between the onset of symptoms and r-TPA administration, complications, and National Institutes of Health Stroke Scale (NIHSS) upon arrival and discharge and death of patients were extracted from their hospital files. The paired t-test, independent t-test, and Pearson correlation test were used to compare variables using IBM SPSS for Windows version 20.0 (IBM Corp., Armonk, NY, USA). Results: The Mean±SD of NIHSS reduced from 14.7±6.4 to 8.9±7.6 (P<0.001). The most common complication was Intracerebral Hemorrhage (ICH) (12.6%). The hospital mortality rate was 23%. ICH occurred among 40% (n=8) of those who expired, and 4.47% (n=3) of them survived, and this difference was significant (P<0.001). Conclusion: The recovery with r-TPA administration in the stroke center was acceptable. Mortality and ICH occurrence rates were higher than other non-Iranian studies. It seems that we should change the case selection criteria and prescription dose to achieve better results of treatment with TPA.

Combined Intravenous and Intra-Arterial Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke

Stroke, 2000

Background and Purpose-A retrospective analysis was performed on 20 consecutive patients who presented with severe acute ischemic stroke and were evaluated for a combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (rtPA) thrombolytic approach within 3 hours of onset. Methods-Twenty consecutive patients with carotid artery distribution strokes were evaluated and treated using a combined IV and IA rtPA approach over a 14-month period (September 1998 to October 1999. rtPA (0.6 mg/kg) was given intravenously (maximum dose 60 mg); 15% of the IV dose was given as bolus, followed by a continuous infusion over 30 minutes. A maximal IA dose, up to 0.3 mg/kg or 24 mg, whichever was less, was given over a maximum of 2 hours. IV treatment was initiated within 3 hours in 19 of 20 patients. All 20 patients underwent angiography, and 16 of 20 patients received local IA rtPA. Results-The median baseline National Institutes of Health Stroke Scale (NIHSS) score for the 20 patients was 21 (range 11 to 31). The median time from stroke onset to IV treatment was 2 hours and 2 minutes, and median time to initiation of IA treatment was 3 hours and 30 minutes. Ten patients (50%) recovered to a modified Rankin Scale (mRS) of 0 or 1; 3 patients (15%), to an mRS of 2; and 5 patients (25%), to an mRS of 4 or 5. One patient (5%) developed a symptomatic intracerebral hemorrhage and eventually died. One other patient (5%) expired because of complications from the stroke. Conclusions-We believe that the greater-than-expected proportion of favorable outcomes in these patients with severe ischemic stroke reflects the short time to initiation of both IV and IA thrombolysis. (Stroke. 2000;31:2552-2557.)

Investigating the Effect and Immunity of Tissue Plasminogen Activator in the Treatment of Acute Ischemic Stroke

Journal of Intellectual Disability - Diagnosis and Treatment, 2020

Background and Objective: Although current evidence has demonstrated the efficacy and immunity of Alteplase, further studies are needed to evaluate its functioning in the therapeutic system. This study aims to assess the effect and immunity of tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke (AIS). Methods: This study was conducted as a retrospective observational study on patients with AIS referred to Ahvaz Golestan Hospital in 2017-2018. By using the hospital database, demographic information, the cause of lack of thrombolytic therapy, the onset of symptoms and admission were extracted. The National Institutes of Health Stroke Scale (NIHSS) at the time of referral, 24 hours after treatment, and at the time of discharge, the modified Rankin Scale (mRS) scores at discharge time and 3 months after discharge, complications and mortality at the time of admission and 3 months after discharge were recorded. Results: The mean of the event to needle (hrs) was significantly lower in the tPA group (P <0.0001), and delay in visiting time and loss of golden time were of the main reasons for not receiving tPA in the control group. The mean difference and the decrease in NIHSS score 24 hours after admission and discharge in the tPA group was significantly higher (P <0.0001). At the time of discharge, the mean score of mRS in the two groups was not significantly different. Three months after treatment, the mean score of mRS in the tPA group was significantly lower than that in the control group (P <0.05). The percentage of patients with bleeding complications was higher in the tPA group (7.27%) than that in the control group (4.89%). The percentage of deaths during the hospital stay in the tPA group (3.64%) was higher than that in the control group (1.63%). Conclusion: Patients with AIS under intravenous thrombolytic therapy with tPA showed improvement in functional measurements and neurological outcomes compared with the control group. Lack of significant difference in the rate of complications and mortality between the two groups indicated the safety and high efficacy of thrombolytic therapy in patients with AIS.

Recombinant human tissue-type plasminogen activator therapy in acute thromboembolic stroke

Journal of Neurosurgery, 1987

✓ Systemic fibrinolytic therapy for acute stroke is no longer recommended because of resulting systemic fibrinolysis and the risk of intracerebral hemorrhage. Human tissue-type plasminogen activator (TPA) is a native enzyme that converts plasminogen to plasmin with subsequent clot lysis. The affinity for plasminogen is increased several-fold when the substrate is bound to fibrin. At appropriate dosage, “clot-specific” throm-bolysis may be achieved at the surface of the thrombus without creating systemic fibrinolysis. The authors designed a study to evaluate the effect of intravenous TPA administered 2 hours after acute thromboembolic stroke in rats. This time course was chosen to simulate an analogous clinical situation. Middle cerebral artery embolic stroke was caused by intracarotid injection of 0.025 cc of human blood clot in 16 rats. Regional cerebral blood flow, measured by the hydfogen clearance technique, and electroencephalographic (EEG) recordings were obtained every 30 min...

Therapeutic Potential of Human Induced Pluripotent Stem Cells in Experimental Stroke

Cell Transplantation, 2013

Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) is a major type of stroke, but there are currently very limited therapeutic options for its cure. Neural stem cells (NSCs) or neural precursor cells (NPCs) derived from various sources are known to survive and improve neurological functions when they are engrafted in animal models of stroke. Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients are novel cells that promise the autologous cell therapy for stroke. In this study, we successfully differentiated iPSCs derived from human fibroblasts into NPCs and found their robust therapeutic potential in a rodent MCAo stroke model. We observed the significant graft-induced behavioral recovery, as well as extensive neural tissue formation. Animal MRI results indicated that the majority of contralaterally transplanted iPSC-derived NPCs migrated to the peri-infarct area, showing a pathotropism critical for tissue recovery. The transplanted an...