Transarterial regional hypothermia provides robust neuroprotection in a rat model of permanent middle cerebral artery occlusion with transient collateral hypoperfusion

The robust neuroprotective effects of transarterial regional hypothermia have been demonstrated in the typical transient middle cerebral artery occlusion (tMCAO) model, but have not yet been tested in other ischemic stroke models, even though clinical ischemic conditions are diverse. In order to clarify these effects in a different ischemic stroke model, we employed a rat model of permanent MCAO (pMCAO) with transient collateral hypoperfusion (tCHP), which was achieved by direct MCA ligation through craniotomy and 1-h bilateral common carotid artery occlusion at the beginning of pMCAO. The infusion of 20 ml/kg of 4 degrees C cold saline (CS) or 37 degrees C warm saline (WS) into the ipsilateral internal carotid artery (ICA) was performed for 15 min in intra- or post-tCHP. Neurological scores, infarct/edema volumes, and neuronal apoptosis and reactive gliosis were compared between the CS and WS groups and a non-infusion control group after 48 h of reperfusion. Although brain temperatures were only reduced by 2-3 degrees C for 15 min, the CS group had significantly better neurological scores, smaller infarct/edema volumes, and less penumbral neuronal apoptosis and reactive gliosis than the control and WS groups. The post-tCHP CS group exhibited prominent neuroprotective effects, even though infarct volumes and neuronal apoptosis were reduced less than those in the intra-tCHP CS group. In conclusion, we demonstrated the neuroprotective effects of transarterial regional hypothermia in an ischemic model of pMCAO with tCHP. Even though MCAO is persistent, cold infusion via the ICA is neuroprotective for the penumbra, suggesting the wider therapeutic application of this therapy

Increased blood viscosity in ischemic stroke patients with small artery occlusion measured by an electromagnetic spinning sphere viscometer

Background and Purpose: High blood viscosity causes blood stagnation and subsequent pathological thrombotic events, resulting in the development of ischemic stroke. We hypothesize that the contribution of blood viscosity may differ among ischemic stroke subtypes based on specific pathological conditions. We tried to verify this hypothesis by measuring blood viscosity in acute ischemic stroke patients using a newly developed electromagnetic spinning sphere (EMS) viscometer. Methods: Measurements in acute ischemic stroke patients were performed 4 times during admission and data were compared with those obtained from 100 healthy outpatient volunteers. Results: We enrolled 92 patients (cardioembolism [CE]: 25, large-artery atherosclerosis [LAA]: 42, and small artery occlusion [SAO]: 25) in this study. Comparisons of blood viscosity between the ischemic stroke subgroups and control group revealed that blood viscosity at the date of admission was significantly higher in the SAO group (5.37±1.11 mPa・s) than in the control group (4.66±0.72 mPa・s) (p<0.01). Among all subtype groups showing a reduction in blood viscosity after 2 weeks, the SAO group showed the highest and most significant reduction, indicating that SAO patients had the most concentrated blood at the onset. Conclusions: Blood viscosity was significantly increased in the SAO group at the date of admission, which indicated the contribution of dehydration to the onset of ischemic stroke. The importance of dehydration needs to be emphasized more in the pathogenesis of SAO. The clinical application of the EMS viscometer is promising for understanding and differentiating the pathogenesis of ischemic stroke

Research on advanced intervention using novel bone marrOW stem cell (RAINBOW) : a study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke

Background: Stroke is a leading cause of death and disability, and despite intensive research, few treatment options exist. However, a recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for treating stroke have been reported, certain problems remain unsolved. Recent studies have demonstrated that bone marrow stromal cells (BMSCs) have therapeutic potential against stroke. We investigated the use of autologous BMSC transplantation as a next-generation cell therapy for treating stroke. In this article, we introduce the protocol of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW). Methods/design: RAINBOW is a phase 1, open-label, uncontrolled, dose-response study, with the primary aim to determine the safety of the autologous BMSC product HUNS001-01 when administered to patients with acute ischemic stroke. Estimated enrollment is 6-10 patients suffering from moderate to severe neurological deficits. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset. BMSCs are cultured with allogeneic human platelet lysate (PL) as a substitute for fetal calf serum and are labeled with superparamagnetic iron oxide for cell tracking using magnetic resonance imaging (MRI). HUNS00101 is stereotactically administered around the area of infarction in the subacute phase. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking, 18F-fuorodeoxyglucose positron emission tomography, and 123I-Iomazenil singlephoton emission computed tomography will be performed for 1 year after the administration. Discussion: This is a first-in-human trial for HUNS001-01 to the patients with acute ischemic stroke. We expect that intraparenchymal injection can be a more favorable method for cell delivery to the lesion and improvement of the motor function than intravenous infusion. Moreover, it is expected that the bio-imaging techniques can clarify the therapeutic mechanisms. Trial registration: The trial was registered at The University Hospital Medical Information Network on February 22, 2017 (UNIN ID: UMIN000026130). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations