局部动脉注射阿替普酶溶栓治疗急性缺血性脑卒中的临床效果

目的分析局部动脉注射阿替普酶溶栓治疗急性缺血性脑卒中的临床效果。方法本溪市中心医院从2011年1月至2013年10月期间共收治90例急性缺血性脑卒中患者,患者在入院的6 h内接受了阿替普酶溶栓的局部动脉注射治疗,观察总结患者接受治疗24 h和3个月内的疗效,并依据临床观察和NHISS评分结果来评价患者的神经功能恢复情况。结果 90例患者当中有58例前循环缺血患者和32例后循环缺血患者,在接受溶栓治疗的24 h内有64例患者神经功能得到良好恢复,占总数的71.11%,还有26例患者神经功能不良,占总数的28.89%;3个月后通过随访了解到有82例患者神经功能良好,占总数的91.11%,8例患者功能仍然处于不良状态,占总数的8.89%,治疗前后患者的神经功能恢复比较差异具有统计学意义（P〈0.05%）。结论局部动脉注射阿替普酶溶栓治疗急性缺血性脑卒中,患者能够得到有效恢复,疗效显著,值得在临床上推广使用。     

Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke

Ischemic stroke results from brain blood vessel blockage by thrombus, and produces neuronal cell damage and death. While thrombolytic therapy with tPA has achieved some success in clinic, the strategy of using neuroprotective agents to treat ischemic stroke has been disappointing thus far. In the present work, we synthesized TBN, a derivative of the clinically useful stroke drug TMP armed with a powerful free radical-scavenging nitrone moiety. TBN retains the thrombolytic activity of the parent TMP and possesses strong antioxidative properties. TBN demonstrates significant activity in the rat MCAo stroke model. The results suggest that design of molecules possessing both thrombolytic and neuroprotective properties may be a novel strategy for effective stroke therapeutics.     

缺血性脑卒中溶栓药物研究进展

缺血性脑卒中是一种高发病率、高死亡率的重大健康危机。溶栓药物能快速溶解血栓、减少出血副作用、实现血管再通,对缺血性脑卒中治疗起到关键性的作用。重组组织纤溶酶原激活剂(rtPA)是FDA批准的唯一缺血性脑卒中药物,但在临床使用中有诸多限制。近年来,基于tPA的溶栓药物及治疗策略发展迅速,文中结合笔者课题组及目前国内外的相关研究成果,回顾了该领域的最新进展,为新型溶栓药物发展提供科学依据和思路。     

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     

Mesenchymal stem cell therapy of brain ischemic stroke in rats

Mesenchymal stem cell (MSCs)-based therapy is a promising attempt to improve the recovery after stroke. Our experiments were carried out on inbred Wistar-Kyoto rats. MSCs were isolated, expanded in culture, and labeled with vital fluorescent dye PKH-26. Animals were subjected to middle cerebral artery occlusion (MCAO). After three days, MCAO 5 × 10⁶ isolated MSCs were injected into the tail vein of the experimental rats. The control animal group received PBS injections (negative control). Therapy results were evaluated by the following parameters: behavioral and neurological testing, the inured brain areas, damaged brain structures, neuron state, and vessel quantity in the region close to with necrosis zone. It was shown that control animals (PBS injection) did not return to their initial behavioral and neurological state within 6 weeks, while the experimental animals (MSCs injection), within 2–3 weeks after MCAO, had parameters like intact rats. The size of the damaged region in the control group was larger than in the experimental group by a factor of approximately 1.3. The damage in MSC-treated rats was limited to the neocortex; caudate nucleus, capsula externa and piriform cortex remained uninjured. The small vessel quantity in the “border” regions was twice as high as compared to the control group and approximately equal to the number of vessels in an intact brain. For the first time, we demonstrated that the vessel quantity in the neocortex and caudate nucleus of the contralateral hemisphere after MSC transplantation was twice as high as in control rats. It is concluded that the MSC transplantation exerts a beneficial influence upon the brain tissue reparation after stroke.     

Mesenchymal stem cells-based therapy of brain ischemic stroke in rat

Mesenchymal stem cells (MSCs)-based therapy is a promising modern attempt to improve the recovery after stroke. Experiments were carried out on inbred Wistar-Kyoto rats. MSCs were isolated, expanded in cultute and labeled with vital fluorescent dye PKH-26. Animals were subjected to middle cerebral artery occlusion (MCAO), followed by injection of 5 x 10(6) rat MSCs into the tail vein 3 days after MCAO. Control group animals received PBS injection (negative control). Therapy results were estimated by the following parameters: behavioral and neurological testing, the brain injure area, the state of damaged region "border" zone and the vessels quantity in the "borden" area. It was shown that control group animals (PBS injection) did not restore their initial behavioral and neurological state, while the experimental group animals (MSCs injection) showed the same parameters as intact rats at 2-3 weeks after MCAO. The size of the damaged region in the control group was approximately 1.5 as large as in the experimental group. The damage in the experimental group was limited to neocortex; caudate nucleus, capsula externa and piriform cortex remained uninjured. Small vessels quantity in the "border" regions was twine higher compared to control group and was approximately equal to an intact brain vessel number. Moreover, it was shown for the first time that after MSCs transplantation the vessels quantity in the neocortex and caudate putamen of contralateral hemisphere was twice as much as in control. We demonstrated that the MSCs transplantation definitely exerted a positive influence upon the brain tissue reparation after stroke.     

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.     

Neural stem cell transplantation therapy for brain ischemic stroke: Review and perspectives

Brain ischemic stroke is one of the most common causes of death and disability, currently has no efficient therapeutic strategy in clinic. Due to irreversible functional neurons loss and neural tissue injury, stem cell transplantation may be the most promising treatment approach. Neural stem cells (NSCs) as the special type of stem cells only exist in the nervous system, can differentiate into neurons, astrocytes, and oligodendrocytes, and have the abilities to compensate insufficient endogenous nerve cells and improve the inflammatory microenvironment of cell survival. In this review, we focused on the important role of NSCs therapy for brain ischemic stroke, mainly introduced the methods of optimizing the therapeutic efficacy of NSC transplantation, such as transfection and overexpression of specific genes, pretreatment of NSCs with inflammatory factors, and co-transplantation with cytokines. Next, we discussed the potential problems of NSC transplantation which seriously limited their rapid clinical transformation and application. Finally, we expected a new research topic in the field of stem cell research. Based on the bystander effect, exosomes derived from NSCs can overcome many of the risks and difficulties associated with cell therapy. Thus, as natural seed resource of nervous system, NSCs-based cell-free treatment is a newly therapy strategy, will play more important role in treating ischemic stroke in the future.     

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.     

Identifying the brain regions associated with acute spasticity in patients diagnosed with an ischemic stroke

Spasticity is a common impairment found in patients that have been diagnosed with a stroke. Little is known about the pathophysiology of spasticity at the level of the brain. This retrospective study was performed to identify an association between the area of the brain affected by an ischemic stroke and the presence of acute spasticity. Physical and occupational therapy assessments from all patients (n?=?441) that had suffered a stroke and were admitted into a local hospital over a 4-year period were screened for inclusion in this study. Subjects that fit the inclusion criteria were grouped according to the presence (n?=?42) or absence (n?=?129) of acute spasticity by the Modified Ashworth Scale score given during the hospital admission assessment. Magnetic resonance images from 20 subjects in the spasticity group and 52 from the control group were then compared using lesion density plots and voxel-based lesion–symptom mapping. An association of acute spasticity with the gray matter regions of the insula, basal ganglia, and thalamus was found in this study. White matter tracts including the pontine crossing tract, corticospinal tract, internal capsule, corona radiata, external capsule, and the superior fronto-occipital fasciculus were also found to be significantly associated with acute spasticity. This is the first study to describe an association between a region of the brain affected by an infarct and the presence of acute spasticity. Understanding the regions associated with acute spasticity will aid in understanding the pathophysiology of this musculoskeletal impairment at the level of the brain.     

Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke

Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.     

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.