Poly (ADP-ribose) polymerase: An Overview of Mechanistic Approaches and Therapeutic Opportunities in the Management of Stroke

Neurochemical Research - Stroke is one of the leading causes of morbidity and mortality accompanied by blood supply loss to a particular brain area. Several mechanistic approaches such as...     

The role of exosomes in stroke

Molecular Biology Reports - Stroke is induced by a partial disruption of cerebral blood flow to the brain and is related to high morbidity and mortality. In the central nervous system, exosomes...     

What have genetically engineered mice taught us about ischemic injury?

Stroke, is the third leading cause of death and disability in the Western world. Stroke refers to set of ischemic conditions resulting from the occlusion or hemorrhage of blood vessels supplying the brain. Loss of blood flow to the brain results in neuronal injury due to both oxygen and nutrient deprivation and the activation of injurious signal cascades. Ultimately cerebral ischemia results in death and dysfunction of brain cells, and neurological deficits that reflect the location and size of the compromised brain area. Injury due to ischemic stroke occurs by a highly choreographed series of complex spatial and temporal events that evolve over hours to days. These events involve complex interactions between fundamental cell injury mechanisms including excitotoxicity and ionic imbalance, oxidative and nitrosative stress, apoptotic-like cell death and inflammatory responses. Genetically engineered mice have been valuable tools to probe putative mechanisms of neuronal death and uncover potential strategies that might render neurons resistant to ischemic injury. Findings from experimental stroke studies in genetically engineered animals are discussed.     

Embryonic stroke volume and cardiac output in the chick

Cine recordings of the hearts of chick embryos of 3 days and 2 hr to 4 days and 21 hr incubation were projected and measured. The measurements were converted to volumes. Stroke volume was determined from the difference in end diastolic and end systolic volume and multiplied by heart rate to yield cardiac output. Mean stroke volume was 0.0058 (±0.00036 SEM) mm³ per mg body wt; mean cardiac output was 0.956 (± 0.061 SEM) mm³/min per mg body wt. Stroke volume and cardiac output rose above their control values after intravascular injection of Ringer's solution, and even more so after the injection of dextran solution. The increases in stroke volume were due to increases in end diastolic volume, in the case of dextran injected embryos they occurred in spite of a simultaneous increase in end systolic volume. It is concluded that the rise in cardiac output with growth of the embryo is in large part due to an increase in stroke volume, and that the increase in stroke volume depends in part on the known increase in embryonic blood volume. The experiments further suggest that a rapid hydrostatic and osmotic equilibrium exists between embryonic blood plasma and an extra vascular compartment.     

microRNAs in stroke pathogenesis

Stroke is one of the leading causes of death and disability worldwide. There are two major types of stroke: cerebral ischemia caused by obstruction of blood vessels in the brain and haemorrhagic stroke that is triggered by the disruption of blood vessels. Thrombolytic therapy involving recombinant tissue plasminogen activator (rtPA) has been shown to be beneficial only when used within 4.5 hours of onset of acute ischemic stroke. rtPA treatment beyond this time window has been found to be unsuitable and usually resulting in haemorrhagic transformation. Stroke is a multifactorial disease that forms a possible end state for majority of patients suffering from diabetes, atherosclerosis and hypertension which are known risk factors. Although the biochemistry of stroke and related diseases is quite well understood, the knowledge on the molecular mechanisms underlying these diseases is still at its infancy. microRNAs that form a unique class of endogenous riboregulators of gene function, offer tremendous potential in unraveling the mechanisms underlying stroke pathogenesis. microRNA expression also reflects the response of individuals to drugs and therapy. Several microRNAs and their target genes, known to be involved in endothelial dysfunction, dysregulation of neurovascular integrity, edema formation, pro-apoptosis, inflammation and extra-cellular matrix remodeling contribute to the critical processes in the pathogenesis of stroke. In this review, we will also be discussing the role of microRNAs as possible diagnostic and prognostic biomarkers as well as potential therapeutic targets in stroke pathogenesis.     

Circulating damage marker profiles support a neuroprotective effect of erythropoietin in ischemic stroke patients

The German Multicenter EPO Stroke Trial, which investigated safety and efficacy of erythropoietin (EPO) treatment in ischemic stroke, was formally declared a negative study. Exploratory subgroup analysis, however, revealed that patients not receiving thrombolysis most likely benefited from EPO during clinical recovery, a result demonstrated in the findings of the G?ttingen EPO Stroke Study. The present work investigated whether the positive signal on clinical outcome in this patient subgroup was mirrored by respective poststroke biomarker profiles. All patients of the German Multicenter EPO Stroke Trial nonqualifying for thrombolysis were included if they (a) were treated per protocol and (b) had at least two of the five follow-up blood samples for circulating damage markers drawn (n = 163). The glial markers S100B and glial fibrillary acid protein (GFAP) and the neuronal marker ubiquitin C-terminal hydrolase (UCH-L1) were measured by enzyme-linked immunosorbent assay in serum on d 1, 2, 3, 4 and 7 poststroke. All biomarkers increased poststroke. Overall, EPO-treated patients had significantly lower concentrations (area under the curve) over 7 d of observation, as reflected by the composite score of all three markers (Cronbach α = 0.811) and by UCH-L1. S100B and GFAP showed a similar tendency. To conclude, serum biomarker profiles, as an outcome measure of brain damage, corroborate an advantageous effect of EPO in ischemic stroke. In particular, reduction in the neuronal damage marker UCH-L1 may reflect neuroprotection by EPO.     

Age-related changes in brain support cells: Implications for stroke severity

Stroke is one of the leading causes of adult disability and the fourth leading cause of mortality in the US. Stroke disproportionately occurs among the elderly, where the disease is more likely to be fatal or lead to long-term supportive care. Animal models, where the ischemic insult can be controlled more precisely, also confirm that aged animals sustain more severe strokes as compared to young animals. Furthermore, the neuroprotection usually seen in younger females when compared to young males is not observed in older females. The preclinical literature thus provides a valuable resource for understanding why the aging brain is more susceptible to severe infarction. In this review, we discuss the hypothesis that stroke severity in the aging brain may be associated with reduced functional capacity of critical support cells. Specifically, we focus on astrocytes, that are critical for detoxification of the brain microenvironment and endothelial cells, which play a crucial role in maintaining the blood brain barrier. In view of the sex difference in stroke severity, this review also discusses studies of middle-aged acyclic females as well as the effects of the estrogen on astrocytes and endothelial cells.     

Cerebroprotective effects of angiotensin II (AT 1) receptor antagonists?

The results of the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study show that treatment with an angiotensin receptor blocker (ARB) in the acute phase of a stroke improves mortality and cardiovascular morbidity. In addition, direct comparative antihypertensive trials have demonstrated beneficial effects of ARBs in preventing stroke. These possible cerebro-protective effects of ARBs are supported by animal studies, demonstrating that stimulation of the AT2 receptor was related to a reduction in both cerebral infarct size and mortality. In the present report, we review both pathophysiological and clinical evidence for possible cerebroprotective effects of ARBs, independent of their effect on blood pressure.     

醒脑开窍配合化痰祛瘀通络针刺法治疗风痰瘀阻证中风病恢复期66 例

目的:观察醒脑开窍合化痰祛瘀通络法治疗中风病恢复期的临床疗效。方法:根据《中药新药临床研究指导原则(试行)》中医证候诊断标准,结合中风诊断要点及辨证取穴,采用醒脑开窍针法配合化痰祛瘀通络针刺法治疗风痰瘀阻证中风病恢复期条件的中风病患者66例,每周治疗2次,3个月为1疗程。结果:(1)患者性别与发病年龄、病情轻重程度分布未呈现明显相关,未见显著性差异(P>0.05);年龄与病情轻重分布未见明显相关,未见显著性差异(P>0.05)。(2)两个疗程的临床症状治愈率明显高于一个疗程的,有显著性差异(P<0.01),患者性别与疗效相关性不显著,治疗后患者的生活能力较治疗前明显改善,有显著性差异(P<0.01);经3个月治疗的中风患者,临床症状基本治愈率达75.8%,经6个月治疗的患者,临床症状基本治愈率达98.5%。结论:醒脑开窍配合化痰祛瘀通络针刺法治疗中风风痰瘀阻证有确切疗效,且疗程越长,疗效越佳,为临床治疗风痰瘀阻证中风病恢复期辨证、取穴提供了依据。     

血尿酸水平与缺血性卒中相关分析

目的:研究血尿酸水平与缺血性卒中的相关性。方法:选择缺血性卒中患者(病例组)100例和健康体检者(对照组)100例,分别测定空腹血尿酸(UA)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C),并对病例组进行颈部动脉超声检查、NIHSS评分、BI指数计算。比较两组尿酸水平及病例组不同血尿酸水平下UA、TC、TG、LDL-C、HDL-C的指标变化及NIHSS评分、BI指数、颈部血管斑块形成率的差别。结果:病例组和对照组空腹血尿酸升高的例数,分别为46例和17例,分别占46%和17%;血尿酸平均浓度分别为485.96±76.03(μmoL/L)和343.12±61.46(μmoL/L),差异有统计学意义。病例组尿酸结果明显高于对照组,两组比较有显著性差异(P<0.01);病例组UA、TC、TG、LDL-C、HDL-C水平较正常对照组差异有显著意义(P<0.05)。对病例组血尿酸水平,颈部血管超声结果、NIHSS评分、BI指数进行分析。病例组患者血尿酸水平与病情及预后有平行关系,即血尿酸水平高,颈部血管斑块形成率高,病情重,预后差。结论:高尿酸血症(HUA)是缺血性卒中重要的危险因素,是防治缺血性卒中的综合因素之一。     

Pulsatile extracorporeal circulation during on-pump cardiac surgery enhances aortic wall shear stress

Controversy on superiority of pulsatile versus non-pulsatile extracorporeal circulation in cardiac surgery still continues. Stroke as one of the major adverse events during cardiopulmonary bypass is, in the majority of cases, caused by mobilization of aortic arteriosclerotic plaques that is inducible by pathologically elevated wall shear stress values. The present study employs computational fluid dynamics to evaluate the aortic blood flow and wall shear stress profiles under the influence of antegrade or retrograde perfusion with pulsatile versus non-pulsatile extracorporeal circulation. While, compared to physiological flow, a non-pulsatile perfusion resulted in generally decreased blood velocities and only moderately increased shear forces (48 Pa versus 20 Pa antegradely and 127 Pa versus 30 Pa retrogradely), a pulsatile perfusion extensively enhanced the occurrence of turbulences, maximum blood flow speed and maximum wall shear stress (1020 Pa versus 20 Pa antegradely and 1178 Pa versus 30 Pa retrogradely). Under these circumstances arteriosclerotic embolism has to be considered. Further simulations and experimental work are necessary to elucidate the impact of our findings on the scientific discourse of pulsatile versus non-pulsatile extracorporeal circulation.     

Implementation of intrinsic lumped parameter modeling into computational fluid dynamics studies of cardiopulmonary bypass

Stroke and cerebral hypoxia are among the main complications during cardiopulmonary bypass (CPB). The two main reasons for these complications are the cannula jet, due to altered flow conditions and the sandblast effect, and impaired cerebral autoregulation which often occurs in the elderly. The effect of autoregulation has so far mainly been modeled using lumped parameter modeling, while Computational Fluid Dynamics (CFD) has been applied to analyze flow conditions during CPB. In this study, we combine both modeling techniques to analyze the effect of lumped parameter modeling on blood flow during CPB. Additionally, cerebral autoregulation is implemented using the Baroreflex, which adapts the cerebrovascular resistance and compliance based on the cerebral perfusion pressure.     

High concentrations of visfatin in the peripheral blood of patients with acute basal ganglia hemorrhage are associated with poor outcome

Higher plasma visfatin concentration has been associated with clinical outcomes of traumatic brain injury. No published information exists to date about change in plasma visfatin after intracerebral hemorrhage. This study included one hundred and twenty-eight healthy controls and 128 patients with intracerebral hemorrhage. The unfavorable outcome was defined as modified Rankin Scale score >2 at 6 months. The patients had higher plasma visfatin measurements than control subjects. Plasma visfatin levels were highly correlated with National Institutes of Health Stroke Scale score and plasma C-reactive protein levels in the patients. A multivariate analysis identified plasma visfatin level as an independent predictor for 6-month mortality and unfavorable outcome. According to receiver operating characteristic curve analysis, the predictive value of the plasma visfatin concentration was similar to National Institutes of Health Stroke Scale score. In a combined logistic-regression model, visfatin improved the predictive value of National Institutes of Health Stroke Scale score for 6-month unfavorable outcome. Thus, increased plasma visfatin level is associated with 6-month clinical outcomes after intracerebral hemorrhage.     

通督调神针法联合穴位贴敷对老年气虚血瘀证缺血性脑卒中恢复期患者脑血流、血液流变学和血清NGF、BDNF的影响

摘要 目的：探讨通督调神针法联合穴位贴敷对老年气虚血瘀证缺血性脑卒中恢复期患者脑血流、血液流变学和血清神经生长因子（NGF）、脑源性神经营养因子（BDNF）的影响。方法：本次研究纳入我院于2021年3月~2022年5月期间收治的70例老年气虚血瘀证缺血性脑卒中恢复期患者。采用信封抽签法分为对照组（n=35）和观察组（n=35）。对照组接受常规治疗,观察组在对照组的基础上接受通督调神针法联合穴位贴敷治疗。对比两组疗效、美国国立卫生研究院卒中量表（NIHSS）评分、中医证候积分、脑卒中专用生活质量量表（SS-QOL）评分、Fugl-Meyer运动功能量表（FMA）评分、脑血流指标、血液流变学指标和NGF、BDNF水平。结果：观察组的临床总有效率为94.29%（33/35）,高于对照组的71.43%（25/35）（P<0.05）。观察组治疗4周后SS-QOL评分、FMA评分高于对照组同期,中医证候总积分、NIHSS评分低于对照组同期（P<0.05）。观察组治疗4周后血流阻力指数（RI）、搏动指数（PI）低于对照组同期,平均血流速度（Vm）高于对照组同期（P<0.05）。观察组治疗4周后全血低切黏度、血浆比黏度、全血高切黏度、纤维蛋白原均低于对照组同期（P<0.05）。观察组治疗4周后血清NGF、BDNF水平均高于对照组同期（P<0.05）。结论：通督调神针法联合穴位贴敷可有效改善老年气虚血瘀证缺血性脑卒中恢复期患者的脑血流、血液流变学,调节血清NGF、BDNF水平。     

The Margination of Particles in Areas of Constricted Blood Flow

Stroke is a leading cause of death globally and is caused by stenoses, abnormal narrowings of blood vessels. Recently, there has been an increased interest in shear-activated particle clusters for the treatment of stenosis, but there is a lack of literature investigating the impact of different stenosis geometries on particle margination. Margination refers to the movement of particles toward the blood vessel wall and is desirable for drug delivery. The current study investigated ten different geometries and their effects on margination. Microfluidic devices with a constricted area were fabricated to mimic a stenosed blood vessel with different extent of occlusion, constricted length, and eccentricity (gradualness of the constriction and expansion). Spherical fluorescent particles with a diameter of 2.11 μm were suspended in blood and tracked as they moved into, through, and out of the constricted area. A margination parameter, M, was used to quantify margination based on the particle distribution after velocity normalization. Experimental results suggested that a constriction leads to an enhanced margination, whereas an expansion is responsible for a decrease in margination. Further, margination was found to increase with increasing percent occlusion and constriction length, likely a result of higher shear rate and longer residence time, respectively. Margination decreases as the stenosis geometry becomes more gradual (eccentricity increases) with the exception of a sudden constriction/expansion geometry. The findings demonstrate the importance of geometric effects on margination and call for detailed numerical modeling and geometric characterization of the stenosed areas to fully understand the underlying physics.     

Cardiovascular effects of centrally administered endothelin-1 and its relationship to changes in cerebral blood flow

Intracerebroventricular (i.c.v.) injection of endothelin-1 (ET-1; 100 ng, i.c.v.) produced an initial pressor (24%) (peak at 3 min following ET-1 administration) and a delayed depressor (−40%) (30 and 60 min following ET-1 administration) effects in urethane anesthetized rats. The pressor effect of ET-1 was due to an increase (21%) in cardiac output, while the depressor effect of ET-1 was associated with a marked decrease (−46%) in cardiac output. Stroke volume significantly decreased at 30 and 60 min after the administration of ET-1. No change in total peripheral vascular resistance and heart rate was observed following central administration of ET-1. The effects of ET-1 on blood pressure, cardiac output and stroke volume were not observed in BQ123 (10 μg, i.c.v.) treated rats. Blood flow to the cerebral hemispheres, cerebellum, midbrain and brain stem was not affected at 3 min, but a significant decrease in blood flow to all the regions of the brain was observed at 30 and 60 min following central administration of ET-1. BQ123 pretreatment completely blocked the central ET-1 induced decrease in blood flow to the brain regions. It is concluded that the pressor effect of centrally administered ET-1 is not accompanied by a severe decrease in brain blood flow, however, a subsequent decrease in blood pressure is associated with a decrease in blood flow to the brain. The cardiovascular effects of ET-1 including decrease in brain blood flow are mediated through central ET_A receptors.     

Evaluation of the relationship among gene expressions and enzyme activities with antioxidant role and presenilin 1 expression in Alzheimer's disease

It is known that oxidative stress originating from reactive oxygen species plays a role in the pathogenesis of Alzheimer's disease. In this study, the role of antioxidant status associated with oxidative stress in Alzheimer's disease was investigated. Peripheral blood samples were obtained from 28 healthy individuals (as control) and 28 Alzheimer's patients who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria. Catalase, glutathione S-transferase and paraoxonase 1 enzyme activities in blood plasma and glutathione S-transferase enzyme activities in erythrocytes were determined by spectrophotometer. Catalase, glutathione S-transferase and presenilin 1 gene expressions in leukocytes were determined using qRT-PCR. Data were analysed with SPSS one-way anova , a LSD post hoc test at p < 0.05. The activity of each enzyme was significantly reduced in Alzheimer's patients compared to control. The catalase gene expression level did not change compared to the control. Glutathione S-transferase and presenilin 1 gene expression levels were increased compared to the control.     

Epigenetic variations in early cardiovascular performance and hematopoiesis can be explained by maternal and clutch effects in developing zebrafish (Danio rerio)

This is the first study to show maternal and clutch effects on early developmental parameters like blood cell concentration and cardiac performance (heart rate, stroke volume and cardiac output) in developing zebrafish larvae (2-8 days post fertilization, dpf). Ten individuals per parental pair and developmental stage were analyzed. A pronounced interclutch variation of heart rate has been found in younger stages (2-4 dpf), while interclutch variation of heart rate was small in later stages (8 dpf). This effect was more pronounced in offspring from parental fish nourished with living food. The opposite effect was observed in interclutch variation of blood cell concentration. Here only older stages showed significant interclutch variations. Stroke volume and cardiac output had very small interclutch variations throughout all stages. Heart rate was strongly dependent with developmental stage in all groups. Nutritional maternal effects on heart performance and also in blood cell concentration could be detected in the offspring of parent animals either fed with flake food or with living food. Red blood cell count, calculated as a product from red blood cell concentration, was not significantly different in both feeding groups. The number of spawned eggs was not different. In summary, these data indicate that "clutch effects" caused by maternal and/or genetic influences can affect the developmental pattern of cardiac performance and blood cell concentration.     

Microgravity and the lung.

Although environmental physiologists are readily able to alter many aspects of the environment, it is not possible to remove the effects of gravity on Earth. During the past decade, a series of space flights were conducted in which comprehensive studies of the lung in microgravity (weightlessness) were performed. Stroke volume increases on initial exposure to microgravity and then decreases as circulating blood volume is reduced. Diffusing capacity increases markedly, due to increases in both pulmonary capillary blood volume and membrane diffusing capacity, likely due to more uniform pulmonary perfusion. Both ventilation and perfusion become more uniform throughout the lung, although much residual inhomogeneity remains. Despite the improvement in the distribution of both ventilation and perfusion, the range of the ventilation-to-perfusion ratio seen during a normal breath remains unaltered, possibly because of a spatial mismatch between ventilation and perfusion on a small scale. There are unexpected changes in the mixing of gas in the periphery of the lung, and evidence suggests that the intrinsic inhomogeneity of the lung exists at a scale of an acinus or a few acini. In addition, aerosol deposition in the alveolar region is unexpectedly high compared with existing models.     

Electroacupuncture increased cerebral blood flow and reduced ischemic brain injury: dependence on stimulation intensity and frequency

Stroke causes ischemic brain injury and is a leading cause of neurological disability and death. There is, however, no promising therapy to protect the brain from ischemic stress to date. Here we show an exciting finding that optimal electroacupuncture (EA) effectively protects the brain from ischemic injury. The experiments were performed on rats subjected to middle cerebral artery occlusion (MCAO) with continuous monitoring of cerebral blood flow. EA was delivered to acupoints of "Shuigou" (Du 26) and "Baihui" (Du 20) with different intensities and frequencies to optimize the stimulation parameters. The results showed that 1) EA at 1.0-1.2 mA and 5-20 Hz remarkably reduced ischemic infarction, neurological deficit, and death rate; 2) the EA treatment increased the blood flow by >100%, which appeared immediately after the initiation of EA and disappeared after the cessation of EA; 3) the EA treatment promoted the recovery of the blood flow after MCAO; 4) "nonoptimal" parameters of EA (e.g., <0.6 mA or >40 Hz) could not improve the blood flow or reduce ischemic injury; and 5) the same EA treatment with optimal parameters could not increase the blood flow in naive brains. These novel observations suggest that appropriate EA treatment protects the brain from cerebral ischemia by increasing blood flow to the ischemic brain region via a rapid regulation. Our findings have far-reaching impacts on the prevention and treatment of ischemic encephalopathy, and the optimized EA parameters may potentially be a useful clue for the clinical application of EA.