Neuroprotection In Acute Stroke Research Articles

Secondary neurodegeneration of ipsilateral substantia nigra in acute ischemic stroke.

Secondary neurodegeneration after stroke is a complex phenomenon affecting remote and synaptically linked cerebral areas. The involvement of the substantia nigra in this process has been rarely described in infarcts involving the striatum. We are presenting a case of ischemic stroke involving the right striatum due to atrial fibrillation and associated in a few days with the neuroimaging finding of hyperintensity of the ipsilateral substantia nigra and striatonigral tract on T2-fluid attenuated inversion recovery and diffusion-weighted imaging sequences of brain magnetic resonance imaging. This finding was not related to clinical manifestations and substantially disappeared within 3 months from stroke onset. The pathophysiology of secondary degeneration of the substantia nigra is poorly understood and it relies on animal models and autoptic studies. The main putative mechanism is not ischemic but excitotoxic with a different role of the internal and external globus pallidus and a different effect on the pars compacta and pars reticularis of the substantia nigra. In animal models, inflammatory mechanisms seem play a role only in the late phase. The main studies on humans were presented in detail. A better understanding of the secondary degeneration of the substantia nigra has the potentiality to offer a chance for neuroprotection in acute stroke, but further studies are needed.

Mice and Rats Exhibit Striking Inter-species Differences in Gene Response to Acute Stroke.

Neuroprotection in acute stroke has not been successfully translated from animals to humans. Animal research on promising agents continues largely in rats and mice which are commonly available to researchers. However, controversies continue on the most suitable species to model the human situation. Generally, putative agents seem less effective in mice as compared with rats. We hypothesized that this may be due to inter-species differences in stroke response and that this might be manifest at a genetic level. Here we used whole-genome microarrays to examine the differential gene regulation in the ischemic penumbra of mice and rats at 2 and 6h after permanent middle cerebral artery occlusion (pMCAO; Raw microarray CEL data files are available in the GEO database with an accession number GSE163654). Differentially expressed genes (adj. p ≤ 0.05) were organized by hierarchical clustering, correlation plots, Venn diagrams and pathway analyses in each species and at each time-point. Emphasis was placed on genes already known to be associated with stroke, including validation by RT-PCR. Gene expression patterns in the ischemic penumbra differed strikingly between the species at both 2h and 6h. Nearly 90% of significantly regulated genes and most pathways modulated by ischemia differed between mice and rats. These differences were evident globally, among stroke-associated genes, immediate early genes, genes implicated in stress response, inflammation, neuroprotection, ion channels, and signal transduction. The findings of this study may have significant implications for the choice of species for screening putative stroke therapies.

Transcranial Direct Current Stimulation as a Neuroprotection in Acute Stroke Before and After Thrombectomy

Transcranial Direct Current Stimulation as a Neuroprotection in Acute Stroke Before and After Thrombectomy

Neuroprotection In Acute Stroke

Stroke is the leading cause of adult disability and remains the third most common cause of death in industrialized nations. The concept of neuroprotection mainly came from the studies of the pathology and pathophysiology of ischemic brain injury. Greater understanding of the pathophysiology of neuronal damage in ischemic stroke has generated interest in neuroprotection as a management strategy. Neuroprotective agents in stroke treatment, have generated long-term interest that have the potential to preserve brain tissue and improve overall outcome. One arm of neuroprotective agents limits acute injury to neurons in the ischemic penumbra. Many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury. Other neuroprotective agents prevent potentially detrimental events associated with return of blood flow. Returning blood contains leukocytes that may occlude small vessels and release toxic products. In fact they should act targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. The past few decades have produced a plethora of negative neuroprotective trial results. The questions of feasibility and practicability cannot be resolved simultaneously. In the future, optimal therapy may be achieved by combining neuroprotective agents with complementary mechanisms. Relevant areas of interest include the search for safe and effective treatment strategies that combine neuroprotection reperfusion, better use of advanced brain imaging for patient selection, and wider implementation of prehospital conducted clinical trials.

Major publications in the critical care pharmacotherapy literature in 2015.

Recently published practice guidelines and research reports on pharmacotherapy in critical care patient populations are summarized. The Critical Care Pharmacotherapy Literature Update (CCPLU) Group is composed of over 50 experienced critical care pharmacists who evaluate 31 peer-reviewed journals monthly to identify literature pertaining to pharmacotherapy in critical care populations. Articles are chosen for summarization in a monthly CCPLU Group publication on the basis of applicability and relevance to clinical practice and strength of study design. From January to December 2015, a total of 121 articles were summarized; of these, 3 articles presenting clinical practice guidelines and 12 articles presenting original research findings were objectively selected for inclusion in this review based on their potential to change or reinforce current evidence-based practice. The reviewed guidelines address the management of intracranial hemorrhage (ICH), adult advanced cardiac life support (ACLS) and post-cardiac arrest care, and the management of supraventricular tachycardia (SVT). The reviewed research reports address topics such as nutrition in critically ill adults, administration of β-lactams for severe sepsis, anticoagulant selection in the context of continuous renal replacement therapy, early goal-directed therapy in septic shock, magnesium use for neuroprotection in acute stroke, and progesterone use in patients with traumatic brain injury. Important recent additions to the critical care pharmacy literature include updated joint clinical practice guidelines on the management of spontaneous ICH, ACLS, and SVT.

Prehospital Use of Magnesium Sulfate as Neuroprotection in Acute Stroke

BackgroundMagnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of neuroprotective agents has hindered earlier phase 3 trials of neuroprotective agents.MethodsWe randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability).ResultsAmong the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (±SD) age was 69±13 years, 42.6% were women, and the mean pretreatment score on the Los Angeles Motor Scale of stroke severity (range, 0 to 10, with higher scores indicating greater motor deficits) was 3.7±1.3. The final diagnosis of the qualifying event was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. The median interval between the time the patient was last known to be free of stroke symptoms and the start of the study-drug infusion was 45 minutes (interquartile range, 35 to 62), and 74.3% of patients received the study-drug infusion within the first hour after symptom onset. There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group (P=0.28 by the Cochran–Mantel–Haenszel test); mean scores at 90 days did not differ between the magnesium group and the placebo group (2.7 in each group, P=1.00). No significant between-group differences were noted with respect to mortality (15.4% in the magnesium group and 15.5% in the placebo group, P=0.95) or all serious adverse events.ConclusionsPrehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days. (Funded by the National Institute of Neurological Disorders and Stroke; FAST-MAG ClinicalTrials.gov number, NCT00059332.)

Cell therapy for ischaemic stroke

While acute neuroprotection in acute stroke has proven difficult and ended in many failures, there is increasing interest in restorative therapies that target brain remodelling. Cell therapy (transplantation of cells) shows promise, with a growing body of pre-clinical evidence demonstrating improved functional outcomes in animal models; however, questions still remain concerning mechanisms of action. Clinical trials are already underway and will increase in the next few years; their appropriate design and execution along with continued pre-clinical work are necessary for the field to advance and satisfy a large unmet clinical need.

Translati onal challenges of neuroprotection strategy in ischemic stroke

AbstractNeuroprotection is a therapeutic strategy that attempts to save neurons from irreversible injury by modifying the effects of the ischemic cascade or facilitating reperfusion. Although numerous agents have shown neuroprotective effect in preclinical trials, their translation to clinical trials failed to show any meaningful effect. The Stroke Therapy Academic Industry Roundtable (STAIR) guidelines were made for performing research on neuroprotective agents in pre-clinical and clinical trials. Although the STAIR guidelines have been available for more than ten years, we still do not have any adequate neuroprotective agents. Reasons for unsuccessful translation from preclinical to clinical research can be considered along stages of drug development: 1) preclinical, 2) transitional and 3) clinical. By extending the therapeutic window for application of intravenous thrombolysis in acute stroke patients to 4.5 hours, as well as increasing the use intra-arterial thrombolysis and development of mechanical devices for thrombectomy in 6 hour period we may be able to achieve some degree of neuroprotection in acute stroke. Future therapy is likely to add to the current thrombolytic therapy with potential neuroprotective drugs or procedures.

Quantitative Temporal Profiles of Penumbra and Infarction During Permanent Middle Cerebral Artery Occlusion in Rats

The basic premise of neuroprotection in acute stroke is the presence of salvageable tissue, but the spatiotemporal volume profiles of the penumbra and infarction remain poorly defined in preclinical animal models of acute stroke used to evaluate therapies for clinical application. Our aim was to define these profiles using magnetic resonance imaging (MRI) quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) for dual-parameter voxel analysis in the rat suture permanent middle cerebral artery occlusion (pMCAO) model. Eleven male Sprague Dawley rats were subjected to pMCAO with MRI measurements of quantitative CBF and ADC at baseline, over the first 4 h (n=9) and at 7, 14, and 21 days (n=4). Voxel analysis of CBF and ADC was used to characterize brain tissue ischemic transitions. Penumbra, core, and hyperemic infarction volumes were significantly elevated (P<0.05) and unchanged over the first 4 h of pMCAO while the total lesion volume progressively rose. At 7, 14, and 21 days, tissue compartment transitions reflected infarction, tissue cavitation, and selective ischemic neuronal necrosis. Anatomical distribution of penumbra and core revealed marked heterogeneity with penumbra scattered within core and penumbra persisting even after 4 h of permanent MCAO.

Is It Time to Definitely Abandon Neuroprotection in Acute Ischemic Stroke?

See related article, pages 1751–1758. Since the ischemic penumbra was discovered and since a therapeutic window for acute ischemic stroke has been postulated, stroke experts are looking for safe and effective drugs to treat as many acute ischemic stroke patients as possible. Maturation of ischemic damage is a complex process, triggered by hypoperfusion at critical levels and spontaneously evolving toward cell death. It is a self-perpetuating process in which some critical steps (such as ion pumps failure and iNOS production) maintain and enhance the process.1 Reperfusion may reverse the ischemic cascade but, at the same time, induces a further damage. The risk/benefit ratio of reperfusion depends on the amount of penumbral salvageable tissue, that is “individual” and only partially predictable.2,3 Spontaneous reperfusion may occur, and symptoms may reverse, partially or totally, but the percentages of spontaneous reperfusion so far reported account for approximately the 24% of all stroke cases.4 A review of published articles about cerebral angiography in stroke reported that the percentage of spontaneous reperfusion …

Clinical pharmacological issues in the development of acute stroke therapies

The demonstration of the ischaemic penumbra in animal models and the effectiveness of reperfusion therapy in humans led to considerable optimism for neuroprotection in acute stroke. Initial experience with failure of phase II and III trials led to the STAIR recommendations for pre-clinical and clinical studies. Review of pre-clinical studies suggests that selection of agents for clinical development may not have been optimal. The neuroprotective agent NXY-059 fulfilled pre-clinical and many clinical STAIR criteria but a second large phase III study failed to demonstrate any benefit. Many of the STAIR criteria have not been fulfilled in the development of recent neuroprotective agents. Other issues not addressed include the use of animal models more reflective of older stroke patients with physiological derangement, demonstration of drug distribution to the proposed site of action in humans, selection of patients with salvageable tissue, achieving very early treatment, refinement of measurement of neurological impairment and disability, and physiological optimization in proof of concept human studies. Increasing the number and quality of clinical centres undertaking acute stroke research, use of surrogate imaging markers and adaptive dose designs in phase II trials could improve the likelihood of identifying an effective neuroprotective. Neuroprotection in acute stroke remains a significant challenge but has not been clearly shown to be ineffective. Given the profound burden of stroke and limited applicability of reperfusion to currently at best 10% patients, further proof of concept studies of neuroprotection remain indicated with careful review of pre-clinical data and more rigorous phase II trial design.

Novel Thyroxine Derivatives, Thyronamine and 3-iodothyronamine, Induce Transient Hypothermia and Marked Neuroprotection Against Stroke Injury

Mild hypothermia confers profound neuroprotection in ischemia. We recently discovered 2 natural derivatives of thyroxine, 3-iodothyronamine (T(1)AM) and thyronamine (T(0)AM), that when administered to rodents lower body temperature for several hours without induction of a compensatory homeostatic response. We tested whether T(1)AM- and T(0)AM-induced hypothermia protects against brain injury from experimental stroke. We tested T(1)AM and T(0)AM 1 hour after and 2 days before stroke in a mouse model of focal ischemia. To determine whether T(1)AM and T(0)AM require hypothermia to protect against stroke injury, the induction of hypothermia was prevented. T(1)AM and T(0)AM administration reduced body temperature from 37 degrees C to 31 degrees C. Mice given T(1)AM or T(0)AM after the ischemic period had significantly smaller infarcts compared with controls. Mice preconditioned with T(1)AM before ischemia displayed significantly smaller infarcts compared with controls. Pre- and postischemia treatments required the induction of hypothermia. T(1)AM and T(0)AM treatment in vitro failed to confer neuroprotection against ischemia. T(1)AM and T(0)AM, are potent neuroprotectants in acute stroke and T(1)AM can be used as antecedent treatment to induce neuroprotection against subsequent ischemia. Hypothermia induced by T(1)AM and T(0)AM may underlie neuroprotection. T(1)AM and T(0)AM offer promise as treatments for brain injury.

Blood pressure lowering in acute ischaemic stroke: an update on the role of angiotensin receptor blockers

Blood pressure lowering in acute ischaemic stroke: an update on the role of angiotensin receptor blockers

Intravenous Magnesium for Neuroprotection in Acute Stroke: Neuropharmacology Supports Clinical Hope. Response

Intravenous Magnesium for Neuroprotection in Acute Stroke: Neuropharmacology Supports Clinical Hope. Response

Effects of aging on hypothermic neuroprotection in acute stroke

Experimental studies in young animals repeatedly confirmed potent neuroprotective effects of hypothermia on cerebral ischemia. It is, however, unclear as to whether the similar protective effects can be obtained in aged animals or patients. Experimental studies of gerbil forebrain ischemia showed that the extent of hypothermic behavioral protection was less remarkable in aged animals than in young animals. In a randomized controlled trial of hypothermia for resuscitated patients with cardiac arrest, the possibility of good outcome was found to decrease with age. In a pilot study of hypothermia performed in young patients with large cerebral infarction (49±14 years), survivors were shown to have considerably good functional outcome in spite of late hypothermic induction at 17 h after stroke in average. In our study performed in stroke patients undergoing hypothermia within 6 h after stroke (60±10 years), 83% of young patients (60 years or less) had good functional outcome, while only 20% of aged patients (more than 60 years) had good outcome. Such an age-related difference was not observed in patients undergoing conventional therapy. The age appears to be an important influential factor for hypothermic neuroprotection in ischemic stroke. It is hypothecated that hypothermia may facilitate neuronal regeneration in young ischemic brain leading to better functional outcome.

Ability of NMDA and non-NMDA receptor antagonists to inhibit cerebral ischemic damage in aged rats

Although stroke is a major cause of death and disability in the elderly, the inhibitory effects of neuroprotectants in acute stroke have been investigated using experimental cerebral ischemic models of young animals. Recent clinical trials have found that few neuroprotectants are effective. These observations indicate that effects in the clinical setting do not always reflect data from young animals. Thus, we compared the effects of the NMDA receptor antagonist MK-801 and of the AMPA receptor antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo( F)quinixaline] on ischemic cerebral damage in the photothrombosis model of aged and young rats. MK-801 administered immediately after MCA occlusion significantly ( P<0.05) reduced the extent of cerebral damage in young, but not in aged, rats and the effects of NBQX were similar. In separate experiments, we evaluated brain damage after microinjecting NMDA or kainic acid into the cortex using a stereotaxic apparatus. We found no significant differences in focal cerebral damage caused by NMDA between young and aged rats. On the other hand, kainic acid caused all of the aged rats tested to die, but none of the young rats. Our observations indicate that NMDA and AMPA receptor antagonists are less effective in aged, than in young, rats and that cerebral damage by receptor agonists depends on the type of receptor, such as NMDA and AMPA.

Brain attack: a new approach to stroke

‘Brain attack’ is a new term to describe the acute presentation of stroke which emphasises the need for urgent action. The article describes the basis for this new approach to acute stroke treatment. Rational treatment requires individual causes of stroke to be identified early and treatment targeted at the mechanism. Acute stroke treatment aims to preserve the ischaemic penumbra, protect neurons against further ischaemia and enhance brain plasticity to maximise recovery. There is a strong evidence base supporting the routine use of aspirin, but not heparin, in acute ischaemic stroke. There is also convincing evidence supporting intravenous thrombolysis using recombinant tissue plasminogen activator in selected patients within 3 hours of stroke onset. Surprisingly, as many as 33% of suspected-stroke patients arrive in Accident & Emergency departments in the UK within 3 hours of onset. New techniques in MR imaging, particularly diffusion weighted imaging, are transforming the approach to diagnosis of acute stroke. Although neuroprotective drugs have proved disappointing, active neuroprotection in acute stroke should include control of blood pressure within certain limits, antipyretic therapy, maintenance of blood glucose, and early feeding and fluid replacement. Surgical hemicraniectomy should be considered in patients with malignant cerebral oedema. There is good evidence that the best way to enhance recovery from stroke is to admit the patient to a stroke unit. To enable patients to benefit from the early active approach outlined in the article, the following are needed: the development of acute stroke units; imaging protocols; and education of patients, general practitioners and the ambulance services. Stroke care has become a specialised field, requiring input from stroke physicians, as well as the multidisciplinary rehabilitation team. The British Association of Stroke Physicians (BASP) has therefore developed a curriculum which is designed to lead to the development of a new sub-specialty of stroke medicine.

WHY DO NEUROPROTECTIVE DRUGS WORK IN ANIMALS BUT NOT HUMANS?

Many neuroprotective agents that seemed promising in animal studies of ischemic brain injury prove to have no effect when tested in clinical trials, suggesting that fundamental elements of translational research require better definition. A number of modifications have led to improvements in preclinical and human studies since the earliest controlled trials failed to confirm hypotheses suggested by animal data. Continued re-evaluation and sharing of information derived from the laboratory bench or the patient's bedside should eventually lead to effective neuroprotection in acute stroke. Experimental data should be carefully studied to improve the quality of agents coming to clinical trials and to design trial phasing that effectively determines drug safety and efficacy. This article will examine preclinical modeling and its translation to prospective studies of acute stroke therapy and will focus on some potential solutions directed at clinical trial design.

Neuroprotection for acute stroke: making clinical trials work.

With the exception of the National Institutes of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator, clinical trials in stroke have failed to show improved outcome. If further negative results such as those of recent large neuroprotective trials are to be avoided, trial methodology must be reevaluated. Because there is little evidence from animal focal ischemia models for protection of white matter, glia, or subcortical neurons, the logical target population for initial clinical trials is patients with middle cerebral artery stroke involving cerebral cortex. Clinical differentiation of moderate to large middle cerebral stroke from lacunar stroke is possible with the Oxfordshire Community Stroke Project classification but less readily achieved by numerical stroke scales. Several imaging techniques can further distinguish middle cerebral stroke patients with a "penumbra" potentially amenable to intervention from those without a penumbra, in whom outcome appears already determined. The window for intervention may be better defined by imaging than by time alone. Shortened follow-up periods may reduce variation in outcome attributable to differences in provision of rehabilitation or secondary preventative treatments among centers, and imaging may provide useful surrogate end points. Clinical trials restricted to patients with large middle cerebral stroke accompanied by radiological evidence of a penumbra should be an essential component of drug development. Slower recruitment may be offset by extended time windows and requirements for fewer patients. Imaging may define surrogate evidence of biological effect prior to embarking on a phase 3 program.

Rough road to development for neuroprotectants in acute stroke

Although the results of recent studies of neuroprotective agents in acute stroke have been disappointing, researchers appear to be undeterred and further trials are underway. The lack of efficacy seen with agents such as tirilazad and lubeluzole may be dose related. The new studies have taken the recent findings into consideration and researchers are hoping that significant effects will be seen in subsequent trials. At the American Heart Association’s 21st International Joint Conference on Stroke and Cerebral Circulation [ San Antonio, Texas, US; January 1996 ], results from the latest investigations into a variety of neuroprotective agents were presented.