Neuroprotective actions of a histidine analogue in models of ischemic stroke

Histidine is a naturally occurring amino acid with antioxidant properties, which is present in low amounts in tissues throughout the body. We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4-hydroxynonenal (HNE). We now report that the histidine analogue histidyl hydrazide is effective in reducing brain damage and improving functional outcome in a mouse model of focal ischemic stroke when administered intravenously at a dose of 20 mg/kg, either 30 min before or 60 min and 3 h after the onset of middle cerebral artery occlusion. The histidine analogue also protected cultured rat primary neurons against death induced by HNE, chemical hypoxia, glucose deprivation, and combined oxygen and glucose deprivation. The histidine analogue prevented neuronal apoptosis as indicated by decreased production of cleaved caspase-3 protein. These findings suggest a therapeutic potential for HNE-scavenging histidine analogues in the treatment of stroke and related neurodegenerative conditions.     

The number and affinity of fibrinogen receptors in blood platelets of patients with ischemic stroke]

Parameters of fibrinogen binding with blood platelets (number of receptors and their affinity) have been studied in patients with ischemic stroke. Due to the increased platelet ability to aggregate in the ischemic diseases such studies seem helpful. The studies involved 13 patients with ischemic stroke. Blood platelets collected from younger patients (under 50 years) possessed significantly higher number of receptors binding fibrinogen than blood platelets of healthy individuals (p less than 0.02). These receptors significantly more strongly bound ligand than those in the control group (p less than 0.05), and in the group of older patients with stroke (less than 0.05). Fibrinogen binding to blood platelets in patients over 50 years of age did not differ significantly from that in the control group. These results may indicate, that the increased platelet aggregation might be a significant pathogenic factor of the stroke in younger patients.     

Neuroprotection in acute ischemic stroke – current status

With the growing understanding of the mechanism of cell death in ischemia, new approaches for treatment such as neuroprotection have emerged. The basic aim of this strategy is to interfere with the events of the ischemic cascade, blocking the pathological processes and preventing the death of nerve cells in the ischemic penumebra. This concept involves inhibition of the pathological molecular events which eventually leads to the influx of calcium, activation of free radicals and neuronal death. Despite encouraging data from experimental animal models, all clinical trials of neuroprotective therapies have to date been unsuccessful. This article reviews some of the reasons for the failure of neuroprotection in the clinical trials so far. Despite all the negative reports, we believe it would be wrong to give up at this point, since there is still reasonable hope of finding an effective neuroprotection for stroke.     

急性脑梗死血清肌钙蛋白-T升高的临床观察

目的:探讨急性脑梗死患者血清肌钙蛋白水平升高与梗死严重程度、梗死部位和预后的关系。方法:247例急性脑梗死患者,在住院的第一天内完成12导联心电图及血清肌钙蛋白-T(cTnT)水平的检查。以0.5ng/ml为界,将患者分为cTnT水平升高组和cTnT水平正常组。结果:26例(10.5%)血清cTnT水平升高。与cTnT水平正常组相比,cTnT水平升高组患者入院时NIHSS评分更严重,岛叶受累的发生率更高,预后较差,异常心电图发生率较高。结论:血清cTnT水平升高的急性脑梗死患者梗死更严重,预后较差,这些患者大多岛叶受累和ECG异常。     

Oxaloacetate: a novel neuroprotective for acute ischemic stroke

It is well established that glutamate acts as an important mediator of neuronal degeneration during cerebral ischemia. Different kind of glutamate antagonists have been used to reduce the deleterious effects of glutamate. However, their preclinical success failed to translate into practical treatments. Far from the classical use of glutamate antagonists employed so far, the systemic administration of oxaloacetate represents a novel neuroprotective strategy to minimize the deleterious effect of glutamate in the brain tissue after ischemic stroke. The neuroprotective effect of oxaloacetate is based on the capacity of this molecule to reduce the brain and blood glutamate levels as a result of the activation of the blood-resident enzyme glutamate-oxaloacetate transaminase. Here we review the recent experimental and clinical results where it is demonstrated the potential applicability of oxaloacetate as a novel and powerful neuroprotective treatment against ischemic stroke.     

Levels of acute phase proteins remain stable after ischemic stroke

Background  

Inflammation and inflammatory biomarkers play an important role in atherosclerosis and cardiovascular disease. Little information is available, however, on time course of serum markers of inflammation after stroke.     

Endogenous granulocyte colony-stimulating factor: a biomarker in acute ischemic stroke

Granulocyte colony-stimulating factor (G-CSF) may protect ischemic brain injury either in animal or human. No studies have reported that endogenous G-CSF (enG-CSF) level is related to the severity of ischemic stroke. This study was designed to assess the severity of ischemic patients correlated with the alteration of enG-CSF on the 1st day after an ischemic event. Patient's plasma enG-CSF and scoring of National Institute of Health Stroke Scale were measured on the 1st day after ischemic stroke. The acute ischemic stroke could significantly induce enG-GCF secretion as compared with healthy control group (16.77 vs. 22.86 μg/L, p = 0.001). Elevated enG-CSF concentration was positively correlated with the severity of stroke patients on day 1 after the event (p = 0.006; Spearman correlation coefficient = 0.268). The enG-CSF is a good biomarker for prediction of severity of acute ischemic stroke.     

Analysis of acute ischemic stroke DNA markers in Russian and Moldavian populations

Polymorphisms c.202G > A of prothrombin F2 gene, c.1691G > A of coagulation factor V F5 gene, c.675delinsG of plasminogen activator 1 gene, and (?5)T > C Kozak gene of thrombocytic receptor were studied in the Russian and Moldavian ethnic groups. We have found no association between these polymorphisms and the risk of ischemic stroke development in both ethnic groups. No association was revealed between the risk of stroke development and various combinations of the single nucleotide polymorphisms examined in the sample of ischemic stroke patients from Russia.     

The effect of moderate hypothermia in acute ischemic stroke on pericyte migration: an ultrastructural study

Pericytes are essential components of the blood–brain barrier together with endothelial cells and astrocytes. Any disturbance of brain perfusion may result in blood–brain barrier dysfunction due to pericyte migration from the microvascular wall. The neuroprotective influence of hypothermia on ischemic brain injury has been clearly shown in models of both global and focal ischemia. Leakage of plasma proteins contributes to the extension of neuronal injury and hypothermia has a neuroprotective influence during the ischemic insult. This line of thinking impelled us to investigate the possible role of the pericytes in the occurrence of hypothermic protection during cerebral ischemia.In this study, we examined at the ultrastructural level the effect of moderate hypothermia on microvascular pericyte responses using a rat model of permanent middle cerebral artery occlusion. Twenty rats were divided into four groups. Middle cerebral artery occlusion was performed in all rats except the control group (first group), which was used to determine the pericyte morphology under normal conditions. In the second group, pericyte response to irreversible ischemia under normothermic conditions was examined at the end of the first hour. In the third group, pericyte response to hypoxia was examined under normothermic conditions three hours after ischemia. In the fourth group, temporalis muscle temperature was maintained at 27–29 °C for 1 h after middle cerebral artery occlusion and pericyte response was then examined at the ultrastructural level. In ischemic normothermic conditions at the end of the first hour (Group 2), a separation was observed between pericytes and the basement membrane and this was interpreted as pericyte migration from the microvascular wall. In ischemic normothermic conditions at the end of the third hour (Group 3), basement membrane disorganization and increased space between the basement membranes were seen in addition to the differentiation of second group. In ischemic hypothermic conditions at the end of the first hour (Group 4), pericyte separation or migration from basement membrane were not seen and the blood–brain barrier remained firm. These findings were interpreted by the authors as a possible relationship between pericyte behavior and neural protection during hypothermia. We suggest that hypothermia may delay the pericyte response but not necessarily attenuate it, and should be associated with hypothermic protection.     

The effect of moderate hypothermia in acute ischemic stroke on pericyte migration: An ultrastructural study

Pericytes are essential components of the blood–brain barrier together with endothelial cells and astrocytes. Any disturbance of brain perfusion may result in blood–brain barrier dysfunction due to pericyte migration from the microvascular wall. The neuroprotective influence of hypothermia on ischemic brain injury has been clearly shown in models of both global and focal ischemia. Leakage of plasma proteins contributes to the extension of neuronal injury and hypothermia has a neuroprotective influence during the ischemic insult. This line of thinking impelled us to investigate the possible role of the pericytes in the occurrence of hypothermic protection during cerebral ischemia.In this study, we examined at the ultrastructural level the effect of moderate hypothermia on microvascular pericyte responses using a rat model of permanent middle cerebral artery occlusion. Twenty rats were divided into four groups. Middle cerebral artery occlusion was performed in all rats except the control group (first group), which was used to determine the pericyte morphology under normal conditions. In the second group, pericyte response to irreversible ischemia under normothermic conditions was examined at the end of the first hour. In the third group, pericyte response to hypoxia was examined under normothermic conditions three hours after ischemia. In the fourth group, temporalis muscle temperature was maintained at 27–29 °C for 1 h after middle cerebral artery occlusion and pericyte response was then examined at the ultrastructural level. In ischemic normothermic conditions at the end of the first hour (Group 2), a separation was observed between pericytes and the basement membrane and this was interpreted as pericyte migration from the microvascular wall. In ischemic normothermic conditions at the end of the third hour (Group 3), basement membrane disorganization and increased space between the basement membranes were seen in addition to the differentiation of second group. In ischemic hypothermic conditions at the end of the first hour (Group 4), pericyte separation or migration from basement membrane were not seen and the blood–brain barrier remained firm. These findings were interpreted by the authors as a possible relationship between pericyte behavior and neural protection during hypothermia. We suggest that hypothermia may delay the pericyte response but not necessarily attenuate it, and should be associated with hypothermic protection.     

Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke

Among 105 patients given recombinant tissue plasminogen activator (rt-PA, alteplase) intravenously for acute stroke, 2 (1.9%) had lingual angioedema, which progressed to a fatal anaphylactoid reaction in 1. The authors review the 2 cases and possible mechanisms responsible. They warn that patients who are taking an angiotensin-converting-enzyme inhibitor may be at increased risk for angioedema with concomitant alteplase therapy.     

Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial

Background

Pneumonia is a major risk factor of death after acute stroke. In a mouse model, preventive antibacterial therapy with moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly. In this study we investigate whether this approach is effective in stroke patients.

Methods

Preventive ANtibacterial THERapy in acute Ischemic Stroke (PANTHERIS) is a randomized, double-blind, placebo-controlled trial in 80 patients with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Patients received either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Primary endpoint was infection within 11 days. Secondary endpoints included neurological outcome, survival, development of stroke-induced immunodepression, and induction of bacterial resistance.

Findings

On intention-to treat analysis (79 patients), the infection rate at day 11 in the moxifloxacin treated group was 15.4% compared to 32.5% in the placebo treated group (p = 0.114). On per protocol analysis (n = 66), moxifloxacin significantly reduced infection rate from 41.9% to 17.1% (p = 0.032). Stroke associated infections were associated with a lower survival rate. In this study, neurological outcome and survival were not significantly influenced by treatment with moxifloxacin. Frequency of fluoroquinolone resistance in both treatment groups did not differ. On logistic regression analysis, treatment arm as well as the interaction between treatment arm and monocytic HLA-DR expression (a marker for immunodepression) at day 1 after stroke onset was independently and highly predictive for post-stroke infections.

Interpretation

PANTHERIS suggests that preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the pivotal role of immunodepression in developing post-stroke infections.

Trial Registration

Controlled-Trials.com ISRCTN74386719     

Serum levels of heat shock protein 27 in patients with acute ischemic stroke

Expression of intracellular heat shock protein 27 (Hsp27) rises in the brain of animal models of cerebral ischemia and stroke. Hsp27 is also released into the circulation and the aim of the present study was to investigated if serum Hsp27 (sHsp27) levels are altered in patients with acute ischemic stroke. sHsp27 was measured in 15 patients with acute ischemic stroke and in 14 control subjects comparable for age, sex, and cardiovascular risk factors. In patients, measurements were performed at admission and 1, 2, and 30 days thereafter. At admission, mean sHsp27 values were threefold higher in patients than in controls. In patients, sHsp27 values dropped after 24 h, rose again at 48 h, and markedly declined at 30 days, indicating the presence of a temporal trend of sHsp27 values following acute ischemic stroke.     

Deep transformation models for functional outcome prediction after acute ischemic stroke

In many medical applications, interpretable models with high prediction performance are sought. Often, those models are required to handle semistructured data like tabular and image data. We show how to apply deep transformation models (DTMs) for distributional regression that fulfill these requirements. DTMs allow the data analyst to specify (deep) neural networks for different input modalities making them applicable to various research questions. Like statistical models, DTMs can provide interpretable effect estimates while achieving the state-of-the-art prediction performance of deep neural networks. In addition, the construction of ensembles of DTMs that retain model structure and interpretability allows quantifying epistemic and aleatoric uncertainty. In this study, we compare several DTMs, including baseline-adjusted models, trained on a semistructured data set of 407 stroke patients with the aim to predict ordinal functional outcome three months after stroke. We follow statistical principles of model-building to achieve an adequate trade-off between interpretability and flexibility while assessing the relative importance of the involved data modalities. We evaluate the models for an ordinal and dichotomized version of the outcome as used in clinical practice. We show that both tabular clinical and brain imaging data are useful for functional outcome prediction, whereas models based on tabular data only outperform those based on imaging data only. There is no substantial evidence for improved prediction when combining both data modalities. Overall, we highlight that DTMs provide a powerful, interpretable approach to analyzing semistructured data and that they have the potential to support clinical decision-making.     

Neuroprotection by tempol in a model of iron-induced oxidative stress in acute ischemic stroke

Studies suggest iron exacerbates the damage caused by ischemic stroke. Our aim was to elucidate the effect of iron overload on infarct size after middle cerebral artery occlusion (MCAO) and to evaluate the efficacy of tempol, a superoxide dismutase mimetic, as a neuroprotective agent. Rats were administered iron +/- tempol before MCAO; control rats received saline. The middle cerebral artery was occluded for 24 h, and the size of the resultant infarct was assessed and expressed as the percentage of the hemisphere infracted (%HI). Iron treatment increased infarct size compared with control (51.83 +/- 3.55 vs. 27.56 +/- 3.28%HI iron treated vs. control, P = 0.01); pretreatment with tempol reversed this (51.83 +/- 3.55 vs. 26.09 +/- 9.57%HI iron treated vs. iron + tempol treated, P = 0.02). We hypothesized that reactive oxygen species (ROS) were responsible for the iron-induced damage. We measured ROS generated by exogenous iron in brain and peripheral vasculature from rats that had not undergone MCAO. There was no increase in ROS production in the brain of iron-treated rats or in brain slices incubated with iron citrate. However, ROS generation in carotid arteries incubated with iron citrate was significantly increased. ROS generation from the brain was assessed after MCAO by dihydroethidine staining; there was a dramatic increase in the ROS generation by the brain in the iron-treated rats compared with control 30 min after MCAO. We propose that iron-induced ROS generation in the cerebral vasculature adds to oxidative stress during an ischemic episode after the disruption of the blood-brain barrier.