Potential age-dependent effects of estrogen on neural injury

In 2000, approximately 10 million women were receiving hormone replacement therapy (HRT) for alleviation of menopausal symptoms. A number of prior animal studies suggested that HRT may be neuroprotective and cardioprotective. Then, in 2003, reports from the Women's Health Initiative (WHI) indicated that long-term estrogen/progestin supplementation led to increased incidence of stroke. A second branch of the WHI in women with prior hysterectomy found an even stronger correlation between estrogen supplementation alone and stroke incidence. Follow-up analyses of the data, as well as data from other smaller clinical trials, have also demonstrated increased stroke severity in women receiving HRT or estrogen alone. This review examines the studies indicating that estrogen is neuroprotectant in animal models and explores potential reasons why this may not be true in postmenopausal women. Specifically, age-related differences in estrogen receptors and estrogenic actions in the brain are discussed, with the conclusion that animal models of disease must closely mimic human disease to produce clinically relevant results.     

Dehydroascorbic acid for the treatment of acute ischemic stroke

In animal models of acute ischemic stroke, intravenous dehydroascorbic acid (DHAA), unlike ascorbic acid (AA), readily enters brain and is converted in both normal and ischemic brain into protective ascorbic acid. When given parenterally DHAA minimizes infarct volume and facilitates functional recovery. I hypothesize the same effect will occur in humans with acute ischemic stroke. Efficacy in reducing infarct volume is demonstrable in mice and rats even when DHAA is infused three hours after the experimental infarct. Moreover, there is fivefold mechanistic rational for DHA beside excellent pharmacokinetics and rapid penetration of brain and conversion to protective AA: (1) in ischemic brain, there is a precipitous decline in AA which can be reversed by intravenous DHAA; (2) after reduction of DHAA to AA in both normal and ischemic brain, AA can reduce oxidized vitamin E and glutathione, other protectors of brain against damaging reactive oxygen species which build up in ischemic brain; (3) AA itself can protect brain against damaging reactive oxygen species; (4) AA is an essential cofactor for several enzymes in brain including ten-eleven translocase-2 which upregulates production of protective molecules like brain-derived neurotrophic factor; and (5) DHAA after conversion to AA prevents both lipid oxidation and presumably oxidation of other labile substances (e.g., dopamine) in ischemic brain. In terms of safety, based on all available animal information, DHAA is safe in the proposed dosing regimen. For human clinical trials, the methodology for conducting the proposed animal safety, clinical pharmacology and phase II efficacy studies is straightforward. Finally, if DHAA preserved brain substance and function in humans, it could be employed in pre-hospital stroke patients.     

干细胞治疗缺血性脑卒中的研究进展

背景：干细胞是一类种类多样,具有自我复制更新能力、多向分化潜能和高度增殖潜能的细胞,其治疗缺血性脑损伤将具有良好的前景。干细胞疗法为缺血性脑卒中的治疗提供了一种新的途径,但其机制尚不能完全明确。 目的：综述干细胞的类型及其治疗缺血性脑卒中机制的研究进展。 方法：第一作者应用计算机检索1992年1月至2012年9月PubMed数据库、中国期刊全文数据库有关干细胞分类及其移植治疗缺血性脑卒中疗效、安全性、机制方面的文章,英文检索词“stem cells,brain ischemic stroke,transplantation,treatment”;中文检索词“干细胞,缺血性脑卒中,移植,治疗”。共检索到168篇相关文献,61篇文献符合纳入标准。 结果与结论：虽然干细胞移植治疗脑卒中尚处于动物模型研究阶段,但已初步显示出其广阔的发展前景。多项干细胞移植治疗脑卒中促进功能恢复的临床Ⅰ期或Ⅱ期试验已经完成。干细胞移植治疗缺血性脑卒中的实验病例没有出现不良反应并显示出功能促进效果。干细胞移植治疗缺血性脑卒中存在的主要问题包括干细胞的来源、移植途径、干细胞在宿主体内存活及与宿主脑的整合问题、治疗的有效性以及安全性等。面对已经取得的一些机制研究和临床试验结果,如何安全而迅速地将治疗缺血性脑卒中的干细胞疗法从实验推向临床,仍然是需要努力的方向。     

Is magnesium neuroprotective following global and focal cerebral ischaemia? A review of published studies.

Neuroprotective activity with magnesium associated with animal models of cerebral ischaemia, seizure, perinatal hypoxia/ischaemia, subarachnoid haemorrhage and traumatic brain injury has provided the justification for clinical stroke trials. However, the recent IMAGES stroke clinical trial found magnesium to be largely ineffective. Hence, due to the negative stroke trial outcome, current FAST-MAG trial and our own experience with magnesium in cerebral ischaemia animal models, we thought it prudent to review these preclinical and clinical studies. We reviewed nine studies describing the use of magnesium following global cerebral ischaemia and fourteen following focal cerebral ischaemia. Four global ischaemia and six focal ischaemia studies did not show a significant neuroprotective effect with magnesium. In the majority of positive magnesium studies animal body temperature was not monitored post-ischaemia. Thus the effects of post-ischaemic hypothermia cannot be ruled out as a confounding factor in positive magnesium cerebral ischaemia studies. Moreover, data from our own laboratory indicates that magnesium is only neuroprotective when combined with post-ischaemic hypothermia. These data provide a possible explanation of why the IMAGES trial was largely unsuccessful, as current stroke patient management does not involve hypothermia induction. Future preclinical and clinical cerebral ischaemia trials with magnesium should consider combining treatment with mild hypothermia.     

Systemically administered human bone marrow-derived mesenchymal stem home into peripheral organs but do not induce neuroprotective effects in the MCAo-mouse model for cerebral ischemia

Mesenchymal stem cells (MSC) from bone marrow induce neuroprotective effects and improve clinical symptoms in animal models for acute cerebral ischemia. So far only few data are available from the murine system. Moreover, no data exist regarding neuroprotective effects depending on the application route. Because most preclinical trials regarding restorative therapy in stroke are performed in mice, we aimed to investigate the neuroprotective capacities of human MSC (hMSC) in the middle cerebral artery occlusion (MCAo)-mouse model of cerebral ischemia. As systemic transplantation of MSC could provide a gentle therapeutic procedure for the (mostly elderly) stroke patients, we analyzed effects of this application at a clinically relevant time point. Bone marrow-derived hMSCs were administered intravenously 24 h after MCAo. Mortality and clinical outcome of the transplanted mice did not differ from PBS-treated controls. After 3 and 7 days hMSC were robustly detected in lung, spleen, kidney and intestine, but not in the brain. MRI measurements revealed no differences in infarct size in hMSC injected animals compared to controls. In the neurogenic subventricular zone and the dentate gyrus no significant increase of endogenous cell proliferation was detected following systemic hMSC transplantation. This data further prove the week neurogenic and neuroprotective effect and the limitations of systemically administered hMSCs in cerebral ischemia.     

Protecting the brain: the search for a clinically effective neuroprotective drug for stroke

The idea that it should be possible to develop a neuroprotective drug that protects the brain from some of the consequences of an acute ischaemic stroke has been in existence for some time and has developed from our increasing knowledge of the biochemical consequences of an acute ischaemic episode. A variety of drugs have been developed to interfere with these biochemical changes. However, while many of these compounds have been shown to be efficacious in animal models of stroke, none has succeeded in clinical trials and reached the market in the Western world. Partly as a result of these failures, guidelines have been published and further extended that detail criteria that should be met before a novel compound is progressed to clinical investigation. These guidelines are reviewed herein, and the author suggests the probability that none of the compounds that have previously failed clinically would have fulfilled the current selection criteria for advancement to clinical trial. It is proposed that NXY-059 (Cerovive) is the first neuroprotective agent to reach the clinical trial phase that meets all the suggested guidelines for neuroprotective drug development, and the preclinical profile of this compound is reviewed.     

Pathways to ischemic neuronal cell death: are sex differences relevant?

We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. Now, a new concept is emerging: the mechanisms and outcome of cerebral ischemic injury are influenced strongly by biological sex as well as the availability of sex steroids to the brain. The principal mammalian estrogen (17 β estradiol or E2) is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However, it is becoming increasingly clear that although hormones are a major contributor to sex-specific outcomes, they do not fully account for sex-specific responses to cerebral ischemia. The purpose of this review is to highlight recent studies in cell culture and animal models that suggest that genetic sex determines experimental stroke outcome and that divergent cell death pathways are activated after an ischemic insult. These sex differences need to be identified if we are to develop efficacious neuroprotective agents for use in stroke patients.     

Neuroprotection in stroke by complement inhibition and immunoglobulin therapy

Activation of the complement system occurs in a variety of neuroinflammatory diseases and neurodegenerative processes of the CNS. Studies in the last decade have demonstrated that essentially all of the activation components and receptors of the complement system are produced by astrocytes, microglia, and neurons. There is also rapidly growing evidence to indicate an active role of the complement system in cerebral ischemic injury. In addition to direct cell damage, regional cerebral ischemia and reperfusion (I/R) induces an inflammatory response involving complement activation and generation of active fragments, such as C3a and C5a anaphylatoxins, C3b, C4b, and iC3b. The use of specific inhibitors to block complement activation or their mediators such as C5a, can reduce local tissue injury after I/R. Consistent with therapeutic approaches that have been successful in models of autoimmune disorders, many of the same complement inhibition strategies are proving effective in animal models of cerebral I/R injury. One new form of therapy, which is less specific in its targeting of complement than monodrug administration, is the use of immunoglobulins. Intravenous immunoglobulin (IVIG) has the potential to inhibit multiple components of inflammation, including complement fragments, pro-inflammatory cytokine production and leukocyte cell adhesion. Thus, IVIG may directly protect neurons, reduce activation of intrinsic inflammatory cells (microglia) and inhibit transendothelial infiltration of leukocytes into the brain parenchyma following an ischemic stroke. The striking neuroprotective actions of IVIG in animal models of ischemic stroke suggest a potential therapeutic potential that merits consideration for clinical trials in stroke patients.     

Neuroprotective potential of Piroxicam in cerebral ischemia: An in silico evaluation of the hypothesis to explore its therapeutic efficacy by inhibition of aquaporin-4 and acid sensing ion channel1a

Cerebral stroke is caused by acute interruption of the brain arterial blood supply and is one of the major health problems with no effective treatments so far apart from the thrombolytic recombinant tissue plasminogen activator (rt-PA), which must be administered within 3h of stroke onset. This emerges it as the third leading cause of mortality worldwide. Acidosis and brain edema are the prominent metabolic features of ischemic brain. The combined inhibition of aquaporin-4 (AQP4) and ASIC1a channels may offers a new neuroprotective approach in cerebral stroke management. Moreover, the combined inhibition of AQP4 and ASIC1a with NSAID remains unknown against neuroprotection in animal models of cerebral ischemia. NSAIDs are believed to act as a pharmacological molecule that reported to have an antioxidant and anti-inflammatory properties. Therefore, the target of the present in silico study was to determine the neuroprotective efficacy of Piroxicam, a NSAID in animal model of cerebral ischemia/reperfusion (I/R) injury and efforts were made to analyze its inhibitory effects on aquaporin-4 activation and ASIC1a channels mediated downstream survival/damage mechanisms. Thus we hypothesized that Piroxicam, a NSAID can act as a neuroprotective agent in animal model of cerebral ischemia/reperfusion (I/R) injury due to its inhibitory effects on aquaporin-4 channel and ASIC1a channels. It is indeed vital that we do not give up the fight to develop compounds to treat stroke despite the many years of setbacks. One of the mottos of our proposed hypothesis is to find out a successful modality of effective substantial treatment of brain stroke with other anti stroke therapeutics available till date.     

亚甲蓝治疗缺血性脑卒中的研究进展

脑卒中作为全球高致死、高致残的疾病，一直被广泛研究。亚甲蓝作为一种被美国食品药品管理局（FDA）批准用于治疗高铁血红蛋白血症和氰化物中毒的药物已有一百二十余年，而在近期研究中发现其具有神经保护作用，并在缺血性脑卒中的动物模型中展现出良好的保护作用。我们就近年来亚甲蓝治疗缺血性脑卒中的研究进行简要综述。     

For ischemic brain damage, is preclinical evidence of neuroprotection by presynaptic blockade of glutamate release enough?

Some drugs blocking glutamate release produce reduced brain injury in some animal models of cerebral ischemia whereas others lack a clear effect. Meta-analysis is a widely used technique in clinical and epidemiological studies. However, it has never been used in the analysis of preclinical studies. In order to estimate quantitatively the current state of the knowledge concerning the neuroprotective effect of drugs inhibiting glutamate release and to attempt to resolve the apparent controversy in relation to the neuroprotective properties of these drugs, a meta-analysis was performed. It identified a significant difference between drugs blocking glutamate release and controls. Therefore, we hypothesize that inhibition of presynaptic glutamate release could be a major goal in neuroprotection when ischemic brain damage is present and that meta-analysia could be a useful tool for preclinical studies,     

外泌体在缺血性脑卒中的研究进展

正1外泌体概述外泌体是直径在30~100 nm的胞外囊泡,通过细胞被释放到细胞外液中~([1])。它们存在于生物体液中,诸如血液和脑脊液。外泌体携带有DNA、RNA、蛋白质和脂质等。由于外泌体的微泡结构为其内在的小分子提供了一个安全稳定的环境,同时这些信号小分子利用循环系统在胞间信号交换发挥重要作用,这让外泌体表现出一个成熟、稳定的信号传输系统~([2])。研究发现,外泌体中的m RNA和micro RNA     

Statins: Mechanisms of neuroprotection

Clinical trials report that the class of drugs known as statins may be neuroprotective in Alzheimer's and Parkinson's disease, and further trials are currently underway to test whether these drugs are also beneficial in multiple sclerosis and acute stroke treatment. Since statins are well tolerated and have relatively few side effects, they may be considered as viable drugs to ameliorate neurodegenerative diseases. However, the mechanism of their neuroprotective effects is only partly understood. In this article, we review the current data on the neuroprotective effects of statins and their underlying mechanisms.     

Use of antiretroviral drugs to prevent HIV-1 transmission through breast-feeding: from animal studies to randomized clinical trials

The major remaining challenge in the prevention of mother-to-child transmission is the reduction of the risk in settings where breast-feeding is common. This review gives an update on ongoing or planned antiretroviral intervention studies in resource-limited settings that are aimed at reducing the risk of mother-to-infant HIV transmission during lactation. These strategies include antiretroviral therapy given to the mother to reduce viral load in plasma and breast milk as well as antiretroviral regimens providing prophylaxis to uninfected infants during the period of breast-feeding. The rationale for the interventions based on animal models and human studies is described as well as the study designs of clinical trials. Potential risks and benefits of these interventions to mothers and infants are also highlighted. Laboratory studies nested within several of these trials will provide a better understanding of the pathogenesis of postnatal HIV transmission and its potential prevention using antiretroviral drugs.     

Assessment of brain tissue viability in acute ischemic stroke by BOLD MRI.

The introduction of new neuroprotective treatment strategies for acute stroke patients has provided a requirement for neuroimaging methods capable of identifying salvageable tissue in acute stroke patients. Substantial positron emission tomography evidence points to the fact that a peri-infarct zone with blood flow of 20-45% of normal, metabolic rate of oxygen of >35% of normal and oxygen extraction ratio (OER) of >0.7 are indices of tissue at risk of infarction, yet with potential for recovery. The sensitivity of T(2) to blood oxygen level dependent (BOLD) effects allows the mismatch between oxygen delivery and consumption in the brain to be imaged. Previous evidence from animal models of cerebral hypoperfusion and ischemic stroke strongly suggest that T(2) BOLD MRI highlights viable and salvageable brain regions. The Hahn-echo T(2) and diffusion show distinct flow thresholds in the rat brain so that the former parameter probes areas with high OER and the latter genuine ischemia. In the flow-compromised tissue showing negative T(2) BOLD, substantial residual perfusion is evident as revealed by bolus-tracking perfusion MRI, in agreement with the idea that tissue metabolic viability must be preserved for expression of BOLD. It is concluded that BOLD MRI may have potential for the assessment of tissue viability in acute ischemic stroke.     

Distribution of the hematopoietic growth factor G‐CSF and its receptor in the adult human brain with specific reference to Alzheimer's disease

The granulocyte colony‐stimulating factor (G‐CSF), being a member of the hematopoietic growth factor family, is also critically involved in controlling proliferation and differentiation of neural stem cells. Treatment with G‐CSF has been shown to result in substantial neuroprotective and neuroregenerative effects in various experimental models of acute and chronic diseases of the central nervous system. Although G‐CSF has been tested in a clinical study for treatment of acute ischemic stroke, there is only fragmentary data on the distribution of this cytokine and its receptor in the human brain. Therefore, the present study was focused on the immunohistochemical analysis of the protein expression of G‐CSF and its receptor (G‐CSF R) in the adult human brain. Since G‐CSF has been shown not only to exert neuroprotective effects in animal models of Alzheimer's disease (AD) but also to be a candidate for clinical treatment, we have also placed an emphasis on the regulation of these molecules in this neurodegenerative disease. One major finding is that both G‐CSF and G‐CSF R were ubiquitously but not uniformly expressed in neurons throughout the CNS. Protein expression of G‐CSF and G‐CSF R was not restricted to neurons but was also detectable in astrocytes, ependymal cells, and choroid plexus cells. However, the distribution of G‐CSF and G‐CSF R did not substantially differ between AD brains and control, even in the hippocampus, where early neurodegenerative changes typically occur.     

The future of asthma therapy

Asthma is one of the most common, and now most heavily investigated, of modern diseases. Research along two fronts, involving experimental models of asthma and human clinical trials, proceeds in parallel, often with investigators unaware of their counterpart's findings. Here, we review the unique immunological insights into asthma pathogenesis and therapy that may be gained from comparison of human clinical trial results and analogous experimental studies. The pitfalls and benefits of animal models of asthma are discussed, and we briefly review ongoing asthma clinical studies that are based on immunological principals. Finally, we use new insights from human and animal studies to construct a refined immunopathologic disease model that may be of use in designing future experimental and therapeutic studies.     

Lauroylethanolamide and linoleoylethanolamide improve functional outcome in a rodent model for stroke

Ischemic stroke is a significant health problem affecting over 6 million people in the United States alone. In addition to surgical and thrombolytic therapeutic strategies for stroke, neuroprotective therapies may offer additional benefit. N-acylethanolamines (NAEs) are signaling lipids whose synthesis is upregulated in response to ischemia, suggesting that they may be neuroprotective. To date only three NAEs, arachidonylethanolamide (NAE 20:4), palmitoylethanolamide (NAE 16:0) and oleoylethanolamide (NAE 18:1) have shown to exert neuroprotective effect in animal models for stroke. Here, we describe neuroprotective effects of the hitherto uncharacterized NAEs, lauroylethanolamide (NAE 12:0) and linoleoylethanolamide (NAE 18:2) in a middle cerebral artery occlusion model of stroke. Pretreatment with NAE 18:2 prior to ischemia/reperfusion (I/R) injury resulted in both significantly reduced cortical infarct volume and improved functional outcome as determined using the neurological deficit score. NAE 12:0 improved neurological deficits without a significant reduction lesion size. Our results suggest that NAEs, as a whole, provide neuroprotection during I/R injury and may have therapeutic benefit when used as complementary treatment with other therapies to improve stroke outcome.     

The future of asthma therapy: integrating clinical and experimental studies

Asthma is one of the most common, and now most heavily investigated, of modern diseases. Research along two fronts, involving experimental models of asthma and human clinical trials, proceeds in parallel, often with investigators unaware of their counterpart's findings. Here, we review the unique immunological insights into asthma pathogenesis and therapy that may be gained from comparison of human clinical trial results and analogous experimental studies. The pitfalls and benefits of animal models of asthma are discussed, and we briefly review ongoing asthma clinical studies that are based on immunological principals. Finally, we use new insights from human and animal studies to construct a refined immunopathologic disease model that may be of use in designing future experimental and therapeutic studies.     

Functional Recovery after Brain Infarction: Plasticity and Neural Transplantation

In the past, little attention has been given to the role of brain plasticity for the long term functional outcome in experimental stroke although there is substantial evidence for plasticity in other experimental models of neurological disorders. Under clinical conditions, functional improvement occurs in most stroke survivors during the initial months after the ischemic incidence. Recent PET studies in stroke patients, investigated two months or later after stroke, indicate a considerable potential for functional plasticity in the adult human cerebral cortex. Research aimed at the identification of the mechanisms underlying functional recovery should be given high priority, particularly with regard to environmental factors and pharmacological interventions.
Pilot experiments of environmental enrichment significantly improved the functional outcome of laboratory animals after brain infarction. Fetal neocortical tissue grafted into the infarcted area in adult rats received afferent fibres from the intact brain and responded to contralateral sensory stimulation with increased metabolic activity, indicating functional integration between neocortical grafts and host afferent systems. However, reciprocal connections from the graft to the host tissue were rare, and it remains to be shown whether grafting will be able to restore the complex cortical organization of the infarcted tissue.