Influence of temperature on ischemic brain: basic and clinical principles

In the last decades, the interest in the association between body temperature and stroke outcome has reemerged, and the use of animal models has made it possible to know the underlying pathogenic mechanisms involved, most of them with pending confirmation in human clinics. In this work, we will review the effects of hyperthermia and hypothermia and its pathogenesis on ischemic stroke, and the evidence of the efficacy and safety of anti-hyperthermic and hypothermic treatments. We will describe how treatment of hyperthermia on ischemic stroke patients, improves patient comfort and outcome, both in the short and the long term, but new clinical studies are needed in this field. Despite the theoretical and experimental bases in favor of hypothermia for the treatment of brain ischemia, there is no definitive clinical evidence that has proved its benefits, so far. With current knowledge, an objective of a body temperature between 35.5 and 36.5 °C seems an optimal therapeutic target for both hyperthermic and normothermic patients.     

Glutamate neurotransmission and calcium metabolism in cerebral ischaemia and under normal conditions

This article is dedicated to the mechanisms of ischaemic brain damage. The processes of glutamate-calcium cascade connected with formation of focal brain necrosis within the period of therapeutic window (the first 3-6 h after the induction of cerebral ischaemia) are discussed. The basis mechanisms of energy-dependent ionic pumps failure, development of glutamate excitotoxicity, disorders of calcium metabolism are analyzed. The results of own investigations are presented. The significant increases in the concentrations of excitatory aminoacidergic neurotransmitters (glutamate and aspartate) in the cerebrospinal fluid were demonstrated in patients with acute ischaemic strokes from the first hours of illness with no dependency on vascular origin of strokes. The extent and duration of these increases were of prognostic value for determining the severity and outcome of the stroke. It was showed that along with "excitotoxicity", the pathogenesis of ischaemic stroke also involves a deficiency of protective inhibitory GABAergic mechanisms and developing imbalance between the excitatory and inhibitory neurotransmitters systems. The significant increase of the level of the specific autoantibodies to phencyclidine-binding protein of glutamate NMDA-receptors was found out in blood serum of patients beginning from the first 3 h after stroke onset and it directly correlated with the severity of ischaemic stroke. The great attention is paid to the role of astroglia in energy metabolism and glutamate neurotransmission, to the mechanisms of regulation of concentrations of neurotransmitter amino acids in the synaptic cleft, as well as to the mechanisms of spreading depression waves and zinc neurotoxicity.     

Type I cannabinoid receptor trafficking: all roads lead to lysosome

The majority of G-protein-coupled receptors (GPCRs) function at the cell surface, where they are activated by their ligands present in the extracellular milieu. Interestingly, type I cannabinoid receptor (CB(1) R), one of the most abundant GPCRs in the central nervous system, is predominantly intracellular. The important physiological roles of CB(1) R have sparked interest in the elucidation of the molecular mechanisms underlying the trafficking of this receptor and the role of intracellular CB(1) Rs. Thus far, results from different groups have been, at least in part, contradictory and the basis of CB(1) R intracellular localization remains controversial. In this commentary, by comparing the studies examining CB(1) R trafficking and localization, we identify technical or experimental ground responsible for the conflicting results. Finally, we propose a possible mechanism of CB(1) R trafficking that may reconcile the different models.     

Early Depression Screening Is Feasible in Hospitalized Stroke Patients

Background and Purpose

Post-stroke depression (PSD) is common but is not routinely assessed for in hospitalized patients. As a Comprehensive Stroke Center, we screen all stroke inpatients for depression, though the feasibility of early screening has not been established. We assessed the hypothesis that early depression screening in stroke patients is feasible. We also explored patient level factors associated with being screened for PSD and the presence of early PSD.

Methods

The medical records of all patients admitted with ischemic stroke (IS) or intracerebral hemorrhage (ICH) between 01/02/13 and 15/04/13 were reviewed. A depression screen, modified from the Patient Health Questionnaire-9, was administered (maximum score 27, higher scores indicating worse depression). Patients were eligible if they did not have a medical condition precluding screening. Feasibility was defined as screening 75% of all eligible patients.

Results

Of 303 IS and ICH inpatients, 70% (211) were eligible for screening, and 75% (158) of all eligible patients were screened. More than one-third of all patients screened positive for depression (score > 4). Women (OR 2.06, 95% CI 1.06–4.01) and younger patients (OR 0.97, 95% CI 0.96–0.99) were more likely to screen positive. Screening positive was not associated with poor discharge/day 7 outcome (mRS > 3; OR 1.45, 95% CI 0.74–2.83).

Conclusions

Screening stroke inpatients for depression is feasible and early depression after stroke is common. Women and younger patients are more likely to experience early PSD. Our results provide preliminary evidence supporting continued screening for depression in hospitalized stroke patients.     

卒中后抑郁与血清炎性细胞因子水平及神经功能损害的相关性分析

目的：探讨急性脑梗死患者不同时间卒中后抑郁（PSD）发病与血清炎性细胞因子水平、神经功能缺损、日常生活能力的相关性。方法：用Hamilton抑郁量表（HDRS）筛查280例符合条件的急性脑梗死患者急性期与恢复期PSD的发病情况,并同时测定血清炎性细胞因子hs-CRP、TNF-α、IL-6的水平,NIHSS评分进行神经功能缺损评估,Barthel指数进行日常生活能力的评估,分析PSD的发生与各因素之间的相关性,采用多因素logistic回归分析进行危险因素分析。结果：脑梗死恢复期PSD的发病率高于急性期,但无明显差异。急性期PSD组血清炎性细胞因子水平高于非PSD组,有显著性差异,而急性期、恢复期神经功能缺损和日常生活能力与非PSD组比较均有显著性差异;急性期血清TNF-α、IL-6和Barthel指数,恢复期NIHSS评分、Barthel指数与PSD发生的OR值分别1.765、1.646、1.817、1.188、2.015。结论：PSD的发病机制在病程的不同时间可能存在着差异,急性期血清升高的炎性细胞因子水平和降低的日常生活能力,恢复期神经功能缺损的程度和降低的日常生活能力是不同时间PSD发病的危险因素。     

A Prospective Study of the Incidence and Correlated Factors of Post-Stroke Depression in China

Background

Post-stroke depression (PSD) is commonly observed among stroke survivors. However, statistical analysis of such data is scarce in developing countries. The purpose of this study is to examine the incidence of PSD and its relationship with stroke characteristics in China.

Methods

This was a prospective hospital-based study. Stroke patients were assessed within two weeks after acute ischemic stroke onset and then reevaluated at three months. Hamilton Depression Scale (HAMD) was used for screening depression (PSD). Subjects with HAMD score of ≥7 were further assessed with the World Health Organization Composite International Diagnostic Interview. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS). Stroke outcome was measured by the modified Rankin Scale (mRS).

Results

One hundred and two stroke patients were recruited, only ninety-one patients completed del period (men = 53, 63.74%), with mean age 60.0±10.4 years (range, 34–82 years). The incidence of PSD was 27.47% two weeks after stroke. The occurrence of PSD was unrelated with age, stroke type, stroke lesion and the history of disease. In univariate analysis gender, PSD was correlated with female gender. In multivariate logistic regression analysis, poor stroke outcome (mRS≥3) (OR 12.113, CI 1.169 to 125.59, P<0.05) was the important predictors of PSD.

Conclusions

The study indicated that gender, functional dependence and stroke outcome are determinants of PSD occurrence during the first 2 weeks after stroke in China.     

The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential

Stroke is the 2nd leading cause of death worldwide and the leading cause of physical disability and cognitive issues. Although we have made progress in certain aspects of stroke treatment, the consequences remain substantial and new treatments are needed. Hypertension has long been recognised as a major risk factor for stroke, both haemorrhagic and ischaemic. The renin angiotensin system (RAS) plays a key role in blood pressure regulation and this, plus local expression and signalling of RAS in the brain, both support the potential for targeting this axis therapeutically in the setting of stroke. While historically, focus has been on suppressing classical RAS signalling through the angiotensin type 1 receptor (AT₁R), the identification of a counter-regulatory axis of the RAS signalling via the angiotensin type 2 receptor (AT₂R) and Mas receptor has renewed interest in targeting the RAS. This review describes RAS signalling in the brain and the potential of targeting the Mas receptor and AT₂R in preclinical models of ischaemic stroke. The animal and experimental models, and the route and timing of intervention, are considered from a translational perspective.     

Trophic factors and cell therapy to stimulate brain repair after ischaemic stroke

Brain repair involves a compendium of natural mechanisms that are activated following stroke. From a therapeutic viewpoint, reparative therapies that encourage cerebral plasticity are needed. In the last years, it has been demonstrated that modulatory treatments for brain repair such as trophic factor- and stem cell-based therapies can promote neurogenesis, gliogenesis, oligodendrogenesis, synaptogenesis and angiogenesis, all of which having a beneficial impact on infarct volume, cell death and, finally, and most importantly, on the functional recovery. However, even when promising results have been obtained in a wide range of experimental animal models and conditions these preliminary results have not yet demonstrated their clinical efficacy. Here, we focus on brain repair modulatory treatments for ischaemic stroke, that use trophic factors, drugs with trophic effects and stem cell therapy. Important and still unanswered questions for translational research ranging from experimental animal models to recent and ongoing clinical trials are reviewed here.     

Rat models of upper extremity impairment in stroke

Stroke remains the leading cause of adult disability, with upper extremity motor impairments being the most prominent functional deficit in surviving stroke victims. The development of animal models of upper extremity dysfunction after stroke has enabled investigators to examine the neural mechanisms underlying rehabilitation-dependent motor recovery as well as the efficacy of various adjuvant therapies for enhancing recovery. Much of this research has focused on rat models of forelimb motor function after experimentally induced ischemic or hemorrhagic stroke. This article provides a review of several different methods for inducing stroke, including devascularization, photothrombosis, chemical vasoconstriction, and hemorrhagia. We also describe a battery of sensorimotor tasks for assessing forelimb motor function after stroke. The tasks range from measures of gross motor performance to fine object manipulation and kinematic movement analysis, and we offer a comparison of the sensitivity for revealing motor deficits and the amount of time required to administer each motor test. In addition, we discuss several important methodological issues, including the importance of testing on multiple tasks to characterize the nature of the impairments, establishing stable baseline prestroke motor performance measures, dissociating the effects of acute versus chronic testing, and verifying lesion location and size. Finally, we outline general considerations for conducting research using rat models of stroke and the role that these models should play in guiding clinical trials.     

重复经颅磁刺激对卒中后抑郁的治疗效果及机制

卒中后抑郁（post-stroke depression,PSD）是并发于脑血管病的一种情感障碍疾病，发病率高，预后差。重复经颅磁刺激（repetitive transcranial magnetic stimulation,r TMS）是通过磁场变化在大脑中产生感应电流来刺激皮层的非创伤性脑刺激技术，是临床上治疗PSD的一种重要非药物治疗方法，可以显著改善PSD患者的抑郁症状。但目前rTMS的作用机制不明确。本文总结了PSD治疗中有效的rTMS刺激方案，并结合PSD的单胺类神经递质相关致病假说及PSD的临床治疗手段，探索了rTMS通过对单胺类神经递质的调控参与PSD治疗的可能机制。rTMS刺激诱导的皮层单胺类递质释放增加、葡萄糖代谢上升、皮层兴奋性增加，提高了单胺类神经递质和脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）水平，进而引发前额叶抑制功能上升、与下游脑区连接改变、脑网络功能的调整，可能是rTMS治疗PSD的重要机制之一。     

Compensatory Limb Use and Behavioral Assessment of Motor Skill Learning Following Sensorimotor Cortex Injury in a Mouse Model of Ischemic Stroke

Mouse models have become increasingly popular in the field of behavioral neuroscience, and specifically in studies of experimental stroke. As models advance, it is important to develop sensitive behavioral measures specific to the mouse. The present protocol describes a skilled motor task for use in mouse models of stroke. The Pasta Matrix Reaching Task functions as a versatile and sensitive behavioral assay that permits experimenters to collect accurate outcome data and manipulate limb use to mimic human clinical phenomena including compensatory strategies (i.e., learned non-use) and focused rehabilitative training. When combined with neuroanatomical tools, this task also permits researchers to explore the mechanisms that support behavioral recovery of function (or lack thereof) following stroke. The task is both simple and affordable to set up and conduct, offering a variety of training and testing options for numerous research questions concerning functional outcome following injury. Though the task has been applied to mouse models of stroke, it may also be beneficial in studies of functional outcome in other upper extremity injury models.     

Nox2 Knockout Delays Infarct Progression and Increases Vascular Recovery through Angiogenesis in Mice following Ischaemic Stroke with Reperfusion

Evidence suggests the NADPH oxidases contribute to ischaemic stroke injury and Nox2 is the most widely studied subtype in the context of stroke. There is still conjecture however regarding the benefits of inhibiting Nox2 to improve stroke outcome. The current study aimed to examine the temporal effects of genetic Nox2 deletion on neuronal loss after ischaemic stroke using knockout (KO) mice with 6, 24 and 72 hour recovery. Transient cerebral ischaemia was induced via intraluminal filament occlusion and resulted in reduced infarct volumes in Nox2 KO mice at 24 h post-stroke compared to wild-type controls. No protection was evident at either 6 h or 72 h post-stroke, with both genotypes exhibiting similar volumes of damage. Reactive oxygen species were detected using dihydroethidium and were co-localised with neurons and microglia in both genotypes using immunofluorescent double-labelling. The effect of Nox2 deletion on vascular damage and recovery was also examined 24 h and 72 h post-stroke using an antibody against laminin. Blood vessel density was decreased in the ischaemic core of both genotypes 24 h post-stroke and returned to pre-stroke levels only in Nox2 KO mice by 72 h. Overall, these results are the first to show that genetic Nox2 deletion merely delays the progression of neuronal loss after stroke but does not prevent it. Additionally, we show for the first time that Nox2 deletion increases re-vascularisation of the damaged brain by 72 h, which may be important in promoting endogenous brain repair mechanisms that rely on re-vascularisation.     

Mesenchymal stem cells: therapeutic outlook for stroke

Adult bone marrow-derived mesenchymal stem cells (MSCs) display a spectrum of functional properties. Transplantation of these cells improves clinical outcome in models of cerebral ischemia and spinal cord injury via mechanisms that may include replacement of damaged cells, neuroprotective effects, induction of axonal sprouting, and neovascularization. Therapeutic effects have been reported in animal models of stroke after intravenous delivery of MSCs, including those derived from adult human bone marrow. Initial clinical studies on intravenously delivered MSCs have now been completed in human subjects with stroke. Here, we review the reparative and protective properties of transplanted MSCs in stroke models, describe initial human studies on intravenous MSC delivery in stroke, and provide a perspective on prospects for future progress with MSCs.     

The Relationship between Frontal Lobe Lesions,Course of Post-Stroke Depression,and 1-year Prognosis in Patients with First-Ever Ischemic Stroke

Background and Purpose

Most studies on post-stroke depression (PSD) have focused on a certain time point after stroke instead of the time course of PSD. The aim of this study was to determine the relationship between frontal lobe lesions, course of PSD over a year following the stroke onset, and the 1-year prognosis in patients with first-ever ischemic stroke.

Methods

A total of 1067 patients from the prospective cohort study on the incidence and outcome of patients with post stroke depression in China who were diagnosed with first-ever ischemic stroke and attended 4 follow-up visits at 14±2 days, 3 months, 6 months, and 1 year after stroke onset, were enrolled in the study. PSD was diagnosed according to DSM-IV. The course of PSD was divided into the following two categories: persistent/recurrent depression and no/transient depression. Patients with any ischemic lesion responsible for the indexed stroke event located in the frontal lobe were defined as patients with frontal lobe lesions. Modified Rankin Scale (mRS) ≥2 at 1-year was considered to be poor prognosis.

Results

There were 109 patients with and 958 patients without frontal lobe lesions that formed the frontal lobe (FL) and no-frontal lobe (NFL) groups, respectively. After adjusting for confounding variables, frontal lobe lesion was significantly associated with persistent/recurrent PSD (OR 2.025, 95%CI 1.039–3.949). Overall, 32.7% of patients in the FL group had poor prognosis at 1- year compared with 22.7% in the NFL group (P = 0.021). Compared with no/transient depression, persistent/recurrent depression was found to be an independent predictor of poor prognosis at 1-year both in FL and NFL groups.

Conclusions

Long-term and periodical screening, evaluation and treatment are needed for PSD after the onset of ischemic stroke, particularly for patients with frontal lobe infarction.     

Decline in the Recovery from Synaptic Depression in Heavier Aplysia Results from Decreased Serotonin-Induced Novel PKC Activation

The defensive withdrawal reflexes of Aplysia are important behaviors for protecting the animal from predation. Habituation and dishabituation allow for experience-dependent tuning of these reflexes and the mechanisms underlying these forms of behavioral plasticity involve changes in transmitter release from the sensory to motor neuron synapses through homosynaptic depression and the serotonin-mediated recovery from depression, respectively. Interestingly, dishabituation is reduced in older animals with no corresponding change in habituation. Here we show that the cultured sensory neurons of heavier animals (greater than 120g) that form synaptic connections with motor neurons have both reduced recovery from depression and reduced novel PKC Apl II activation with 5HT. The decrease in the recovery from depression correlated better with the size of the animal than the age of the animal. Much of this change in PKC activation and synaptic facilitation following depression can be rescued by direct activation of PKC Apl II with phorbol dibutyrate, suggesting a change in the signal transduction pathway upstream of PKC Apl II activation in the sensory neurons of larger animals.     

Publication Bias in Reports of Animal Stroke Studies Leads to Major Overstatement of Efficacy

The consolidation of scientific knowledge proceeds through the interpretation and then distillation of data presented in research reports, first in review articles and then in textbooks and undergraduate courses, until truths become accepted as such both amongst “experts” and in the public understanding. Where data are collected but remain unpublished, they cannot contribute to this distillation of knowledge. If these unpublished data differ substantially from published work, conclusions may not reflect adequately the underlying biological effects being described. The existence and any impact of such “publication bias” in the laboratory sciences have not been described. Using the CAMARADES (Collaborative Approach to Meta-analysis and Review of Animal Data in Experimental Studies) database we identified 16 systematic reviews of interventions tested in animal studies of acute ischaemic stroke involving 525 unique publications. Only ten publications (2%) reported no significant effects on infarct volume and only six (1.2%) did not report at least one significant finding. Egger regression and trim-and-fill analysis suggested that publication bias was highly prevalent (present in the literature for 16 and ten interventions, respectively) in animal studies modelling stroke. Trim-and-fill analysis suggested that publication bias might account for around one-third of the efficacy reported in systematic reviews, with reported efficacy falling from 31.3% to 23.8% after adjustment for publication bias. We estimate that a further 214 experiments (in addition to the 1,359 identified through rigorous systematic review; non publication rate 14%) have been conducted but not reported. It is probable that publication bias has an important impact in other animal disease models, and more broadly in the life sciences.     

Association of Serum 25-Hydroxyvitamin D with Symptoms of Depression After 6 Months in Stroke Patients

Our aim was to determine whether there was a relationship between 25-hydroxyvitamin D (25[OH] D) and post-stroke depression (PSD). Two hundred and forty-four ischemic stroke patients admitted to the hospital within the first 24 h after stroke onset were consecutively recruited and followed up for 6 months. Clinical information was collected. Serum 25[OH] D levels were measured at baseline. Based on the symptoms, diagnoses of depression were made in accordance with DSM-IV criteria for depression at 6-month after stroke. At 6-month, 91 patients (37.3 %) showed depression and in 60 patients (24.6 %) this depression was classified as major. There was a significant difference in median serum 25[OH] D levels between PSD patients and no depression cases [8.3 (IQR, 6.8–9.5) vs. 15.6 (IQR, 13.2–20.3) ng/ml, respectively; P < 0.001]. Serum 25[OH] D levels ≤11.2 ng/ml were independently associated with PSD [odds ratio 10.32, 95 % confidence interval 4.97–28.63; P < 0.001], after adjusting for possible confounders. Serum 25[OH] D levels reduced at admission was found to be associated with PSD. Additional research is needed on vitamin D supplementation to improve the outcome of patients with PSD.