Journal: Translational stroke research
Over 700 drugs have failed in stroke clinical trials, an unprecedented rate thought to be attributed in part to limited and isolated testing often solely in “young” rodent models and focusing on a single secondary injury mechanism. Here, extracellular vesicles (EVs), nanometer-sized cell signaling particles, were tested in a mouse thromboembolic (TE) stroke model. Neural stem cell (NSC) and mesenchymal stem cell (MSC) EVs derived from the same pluripotent stem cell (PSC) line were evaluated for changes in infarct volume as well as sensorimotor function. NSC EVs improved cellular, tissue, and functional outcomes in middle-aged rodents, whereas MSC EVs were less effective. Acute differences in lesion volume following NSC EV treatment were corroborated by MRI in 18-month-old aged rodents. NSC EV treatment has a positive effect on motor function in the aged rodent as indicated by beam walk, instances of foot faults, and strength evaluated by hanging wire test. Increased time with a novel object also indicated that NSC EVs improved episodic memory formation in the rodent. The therapeutic effect of NSC EVs appears to be mediated by altering the systemic immune response. These data strongly support further preclinical development of a NSC EV-based stroke therapy and warrant their testing in combination with FDA-approved stroke therapies.
This study aimed to review available published reports concerning sudden unexpected postnatal collapse (SUPC) of apparently healthy infants within the first days of postnatal life, establish a structured presentation and delineate recommendations for preventive measures. All published reports of SUPC cases were retrospectively analyzed, and three not previously published SUPC cases at Karolinska University Hospital were detailed to exemplify the varying presentations and outcomes of SUPC. We found 398 published cases of SUPC occurring during first postnatal week. Estimated incidence of the SUPC of a presumably healthy infant after birth differs widely, ranging from 2.6 cases to 133 cases/100,000. However, definition, inclusion, and exclusion criteria vary substantially between reports. Our summary indicates that reported SUPC occurs more frequently than expected from recent surveys. About half of the infants die, and of the remaining survivors, half have neurological sequela. Of the 233 cases of sudden unexpected death described, no etiology was found in 153 cases. When a defined time for the SUPC event is described, approximately one third of reported events occur during the first 2 h, between 2 and 24 h and between 1 and 7 days after birth, respectively. Adequate education of caregivers and appropriate surveillance during the first days of newborns should enable us to save hundreds of lives.
Active transport of microRNAs (miRNA) in extracellular vesicles (EV) occurs in disease. Circulating EV-packaged miRNAs in the serum of stroke patients were compared to stroke mimics with matched cardio- and cerebrovascular risk factors, with corroboration of results in a pre-clinical model. An unbiased miRNA microarray was performed in stroke vs. stroke mimic patients (n = 39). Results were validated (n = 173 patients) by real-time quantitative polymerase chain reaction. miRNA expression was quantified in total serum/EV (n = 5-7) of naïve adult spontaneously hypertensive stroke-prone rats (SHRSP), their normotensive reference strain (Wistar Kyoto, WKY) and in circulating EV (n = 3), peri-infarct brain (n = 6), or EV derived from this region (n = 3) in SHRSP following transient middle cerebral artery occlusion (tMCAO). Circulating EV concentration did not differ between stroke and stroke mimic patients. The microarray identified many altered EV-packaged miRNAs: levels of miRNA-17-5p, -20b-5p and -93-5p (miRNA-17 family members) and miRNA-27b-3p were significantly (p ≤ 0.05) increased in stroke vs. stroke mimic patients. Patients with small vessel disease (SVD) consistently had the highest miRNA levels. Circulating EV concentration was unaltered between naïve SHRSP and WKY but levels of miRNA-17-5p and -93-5p were significantly increased in SHRSP. tMCAO in SHRSP did not further alter circulating EV miRNA-17 family member expression and nor did it change total miRNA-17 family levels in peri-infarct brain tissue or in EV isolated from this region at 24 h post-tMCAO. Changes in EV packaged miRNA expression was validated in patients with stroke, particularly those with SVD and corroborated pre-clinically. Together, altered circulating EV levels of miRNA-17 family members may reflect the chronic sequelae underlying cerebrovascular SVD rather than the acute ischemic stroke itself.
Interleukin-1 receptor antagonist (IL-1 RA) is an anti-inflammatory protein used clinically to treat rheumatoid arthritis and is considered a promising candidate therapy for stroke. Here, we sought to update the existing systematic review and meta-analysis of IL-1 RA in models of ischaemic stroke, published in 2009, to assess efficacy, the range of circumstances in which efficacy has been tested and whether the data appear to be confounded due to reported study quality and publication bias. We included 25 sources of data, 11 of which were additional to the original review. Overall, IL-1 RA reduced infarct volume by 36.2 % (95 % confidence interval 31.6-40.7, n = 76 comparisons from 1283 animals). Assessments for publication bias suggest 30 theoretically missing studies which reduce efficacy to 21.9 % (17.3-26.4). Efficacy was higher where IL-1 RA was administered directly into the ventricles rather than peripherally, and studies not reporting allocation concealment during the induction of ischaemia reported larger treatment effects. The preclinical data supporting IL-1 RA as a candidate therapy for ischaemic stroke have improved. The reporting of measures to reduce the risk of bias has improved substantially in this update, and studies now include the use of animals with relevant co-morbidities.
In acute stroke patients, penumbral tissue is non-functioning but potentially salvageable within a time window of variable duration and represents target tissue for rescue. Reperfusion by thrombolysis and/or thrombectomy can rescue penumbra and improve stroke outcomes, but these treatments are currently available to a minority of patients. In addition to the utility of Glasgow Oxygen Level Dependent (GOLD) as an MRI contrast capable of detecting penumbra, its constituent perfluorocarbon (PFC) oxygen carrier, combined with normobaric hyperoxia, also represents a potential acute stroke treatment through improved oxygen delivery to penumbra. Preclinical studies were designed to test the efficacy of an intravenous oxygen carrier, the perfluorocarbon emulsion Oxycyte® (O-PFC), combined with normobaric hyperoxia (50% O2) in both in vitro (neuronal cell culture) and in vivo rat models of ischaemic stroke. Outcome was assessed through the quantification of lipid peroxidation and oxidative stress levels, mortality, infarct volume, neurological scoring and sensorimotor tests of functional outcome in two in vivo models of stroke. Additionally, we investigated evidence for any positive or negative interactions with the thrombolytic recombinant tissue plasminogen activator (rt-PA) following embolus-induced stroke in rats. Treatment with intravenous O-PFC + normobaric hyperoxia (50% O2) provided evidence of reduced infarct size and improved functional recovery. It did not exacerbate oxidative stress and showed no adverse interactions with rt-PA. The positive results and lack of adverse effects support human trials of O-PFC + 50% O2 normobaric hyperoxia as a potential therapeutic approach. Combined with the diagnostic data presented in the preceding paper, O-PFC and normobaric hyperoxia is a potential theranostic for acute ischaemic stroke.
Clinical evidence suggests that patients with subcortical ischemic vascular dementia (SIVD) perform better at cognitive tests after exercise. However, the underlying mechanism for this effect is largely unknown. Here, we examined how treadmill exercise changes the cognitive function and white matter cellular pathology in a mouse model of SIVD. Prolonged cerebral hypoperfusion was induced in 2-month-old male C57BL/6J mice by bilateral common carotid artery stenosis. A week later, the mice were randomly divided into a group that received 6-week treadmill exercise and a sedentary group for observation. In multiple behavioral tests (Y-maze, novel object recognition, and Morris water maze tests), the treadmill exercise training was shown to ameliorate cognitive decline in the hypoperfused SIVD mice. In addition, immunohistological analyses confirmed that there was a larger population of oligodendrocyte precursor cells in the subventricular zone of exercised versus sedentary mice. Although further investigations are needed to confirm a causal link between these findings, our study establishes a model and cellular foundation for investigating the mechanisms through which exercise preserves cognitive function in SIVD.
Intracerebral hemorrhage in combination with intraventricular hemorrhage (IVH) is a severe type of stroke frequently leading to prolonged clinical care, continuous disability, shunt dependency, and high mortality. The molecular mechanisms induced by IVH are complex and not fully understood. Moreover, the treatment options for IVH are limited. Intraventricular recombinant tissue plasminogen activator (rt-PA) dissolves the blood clot in the ventricular system; however, whether the clinical outcome is thereby positively affected is still being debated. The mechanistic cascade induced by intraventricular rt-PA therapy may cure and harm in parallel. Despite the fact that intraventricular blood clots are thereby dissolved, blood derivatives enter the parenchyma and may still adversely affect functional structures of the brain: Smaller blood clots may obstruct the perivascular (Virchow-Robin) space and thereby the glymphatic system with detrimental consequences for cerebrospinal fluid (CSF)/interstitial fluid (ISF) flow. These clots, blood cells but also blood derivatives in the perivascular space, destabilize the blood-brain barrier from the brain parenchyma side, thereby also functionally weakening the neurovascular unit. This may lead to further accommodation of serum proteins in the ISF and particularly in the perivascular space further contributing to the adverse effects on the neuronal microenvironment. Finally, the arterial (Pacchionian) granulations have to cope with ISF containing this “blood, cell, and protein cocktail,” resulting in obstruction and insufficient function of the arterial granulations, followed by a malresorptive hydrocephalus. Particularly in light of currently improved knowledge on the physiologic and pathophysiologic clearance of cerebrospinal fluid and interstitial fluid, a critical discussion and reevaluation of our current therapeutic strategies to treat intraventricular hemorrhages are needed to successfully treat patients suffering from this severe type of stroke. In this review, we therefore summarize and discuss recent clinical trials and future directions for the field of IVH with respect to the currently increased understanding of the glymphatic system and the neurovascular unit pathophysiology.
The poor clinical relevance of experimental models of stroke contributes to the translational failure between preclinical and clinical studies testing anti-inflammatory molecules for ischemic stroke. Here, we (i) describe the time course of inflammatory responses triggered by a thromboembolic model of ischemic stroke and (ii) we examine the efficacy of two clinically tested anti-inflammatory drugs: Minocycline or anti-CD49d antibodies (tested in stroke patients as Natalizumab) administered early (1 h) or late (48 h) after stroke onset. Radiological (lesion volume) and neurological (grip test) outcomes were evaluated at 24 h and 5 days after stroke. Immune cell responses peaked 48 h after stroke onset. Myeloid cells (microglia/macrophages, dendritic cells, and neutrophils) were already increased 24 h after stroke onset, peaked at 48 h, and remained increased-although to a lesser extent-5 days after stroke onset. CD8+ and CD4+ T-lymphocytes infiltrated the ipsilateral hemisphere later on (only from 48 h). These responses occurred together with a progressive blood-brain barrier leakage at the lesion site, starting 24 h after stroke onset. Lesion volume was maximal 24-48 h after stroke onset. Minocycline reduced both lesion volume and neurological deficit only when administered early after stroke onset. The blockade of leukocyte infiltration by anti-CD49d had no impact on lesion volume or long-term neurological deficit, independently of the timing of treatment. Our data are in accordance with the results of previous clinical reports on the use of Minocycline and Natalizumab on ischemic stroke. We thus propose the use of this clinically relevant model of thromboembolic stroke with recanalization for future testing of anti-inflammatory strategies for stroke.
Recent work suggests that repetitive transcranial magnetic stimulation (rTMS) may beneficially alter the pathological status of several neurological disorders, although the mechanism remains unclear. The current study was designed to investigate the effects of rTMS on behavioral deficits and potential underlying mechanisms in a rat photothrombotic (PT) stroke model. From day 0 (3 h) to day 5 after the establishment of PT stroke, 5-min daily continuous theta-burst rTMS (3 pulses of 50 Hz repeated every 200 ms, intensity at 200 G) was applied on the infarct hemisphere. We report that rTMS significantly attenuated behavioral deficits and infarct volume after PT stroke. Further investigation demonstrated that rTMS remarkably reduced synaptic loss and neuronal degeneration in the peri-infarct cortical region. Mechanistic studies displayed that beneficial effects of rTMS were associated with robust suppression of reactive micro/astrogliosis and the overproduction of pro-inflammatory cytokines, as well as oxidative stress and oxidative neuronal damage especially at the late stage following PT stroke. Intriguingly, rTMS could effectively induce a shift in microglial M1/M2 phenotype activation and an A1 to A2 switch in astrocytic phenotypes. In addition, the release of anti-inflammatory cytokines and mitochondrial MnSOD in peri-infarct regions were elevated following rTMS treatment. Finally, rTMS treatment efficaciously preserved mitochondrial membrane integrity and suppressed the intrinsic mitochondrial caspase-9/3 apoptotic pathway within the peri-infarct cortex. Our novel findings indicate that rTMS treatment exerted robust neuroprotection when applied at least 3 h after ischemic stroke. The underlying mechanisms are partially associated with improvement of the local neuronal microenvironment by altering inflammatory and oxidative status and preserving mitochondrial integrity in the peri-infarct zone. These findings provide strong support for the promising therapeutic effect of rTMS against ischemic neuronal injury and functional deficits following stroke.
The aim of this study was to assess the association between admission to stroke centers for acute ischemic stroke and complications and mortality during hospitalization in a Chinese population by means of an observational study using data from the China Stroke Center Data-Sharing Platform. We compared in-hospital complications and mortality for patients admitted with acute ischemic stroke (N = 13,236) between November 1, 2018 and December 31, 2018 at stroke center (SH) and non-stroke center (CH) hospitals using distance to hospitals as an instrumental variable to adjust for potential prehospital selection bias. The results showed that complication rates during hospitalization among ischemic stroke patients who received thrombolytic therapy (n = 11,203) were lower in the SH group than in the CH group: 11.1% vs 15.7% (absolute difference, - 5.11% [95% CI, - 6.05 to - 3.99%], odds ratio [OR] 0.85 [95% CI, 0.74 to 0.92]). The incidence of intracranial hemorrhage was reduced from 4.2 to 3.2%: SH group vs CH group, 3.2% vs 4.2% (absolute difference, - 1.24% [95% CI, - 1.65 to - 0.82%], OR 0.83 [95% CI, 0.69 to 0.0.98]). Furthermore, the total mortality rate in the SH group was also lower than in the CH group: SH group vs CH group, 2.2% vs 3.0% (absolute difference, - 0.92% [95% CI, - 1.48 to - 0.53%], OR 0.85 [95% CI, 0.73 to 0.96]). The data showed that admission to SH hospitals was associated with a lower risk of treatment complications and death for patients with an acute ischemic stroke receiving thrombolytic therapy.