Current treatments and development of modern therapies for stroke
Stroke is the third most common cause of death and disability.Currently, there is an unmet need for better drug treatments for thiscomplex disease. In this article, Felicity N. E. Gavins discussescurrent treatments and the potential for new drugs for stroke
Stroke is the third most common cause of death and disability. Currently, there is an unmet need for better drug treatments for this complex disease. In this article, Felicity N. E. Gavins discusses current treatments and the potential for new drugs for stroke
Stroke is the third most common cause of death and long-term disability worldwide, with approximately 4 million new cases occurring each year. Approximately, 75–85 per cent of all strokes are ischaemic in origin and 15–20 per cent are haemorrhagic.1
Currently, there is relatively little investment in developing drugs for stroke and, accordingly, a lack of clinical candidates.
In 1999, the Stroke Therapy Academic Roundtable (STAIR) was formed, paving the way for discussion of old and new preclinical trials. The STAIR VI (2008) met recently at an expert consensus conference and have put together recommendations (to be published shortly), which it is hoped will result in better translation of results from bench to bedside.1
Revascularising the ischaemic brain and arousing sleeping neurons (by restoring oxygen and glucose), will improve the outcome in patients with acute stroke.2
Therapeutic approaches are mainly aimed at acute ischaemic stroke. The two major drug classes (thrombolytic and antiplatelet agents, which also are used to treat myocardial infarction) are less effective and sometimes detrimental in ischaemic stroke relative to myocardial infarction.
Current drug treatments are problematic because of their small therapeutic window and the risk of haemorrhage, as well as the difficulty in ensuring correct diagnosis, selecting the most suitable patients and making use of the small time window available for treatment.3
Currently, the only approved drug for ischaemic stroke treatment is the tissue plasminogen activator (t-PA) alteplase (Actilyse), which produces reperfusion by dissolving or breaking the thrombus. The effectiveness of thrombolytic drugs depends on the effectiveness of their delivery to the damaged vessel.
Various major, randomised-controlled trials (NINDS, ATLANTIS, ECASS-1 and ECASS-II) all demonstrate that, if tPA is administered within three hours of the onset of stroke, then an increase in functional outcome is observed.
Recently, according to a recommendation from the European Stoke Organisation (based on findings from a randomised trial, ECASS 3), Alteplase can be given up to four and a half hours after onset of ischaemic stroke rather than three hours (PJ, 7 February 2009, p126).
In addition, this time window could be extended up to six hours, although evidence for this is being collected (eg, IST-3 trial). Extension of this window and provision of a higher local drug concentration could be achieved by intra-arterial administration of the thrombolytic agent proximal to the offending thrombus.
Initial results from trials using intra-arterial prouroukinase showed significant improvements compared with tPA alone.3
Secondary treatment of stroke patients often involves anticoagulants. Traditionally, both heparin and warfarin are used, but low molecular weight heparins (bemiparin, dalteparin, enoxaparin and tinzaparin) are increasingly employed due to their longer action and lower risk of inducing thrombocytopenia or osteoporosis compared with unfractionated heparin.
Stroke can cause infarction of brain tissue with resultant irreversible neurological damage associated with reductions in neuronal adenosine triphosphate and cell death. This area of infarction is termed the core region.
The surrounding area, or penumbra, contains a collateral circulation that continues to perfuse the brain, although the supply of oxygen will be decreased, and evidence shows the presence of inflammatory cascades and cell death in this area.
Much work has focused on the cellular and biochemical pathways of stroke, revealing profiles of gene activation. Indeed, targeting the molecular and cellular penumbra may reveal drug targets for stroke intervention.
Role of excitotoxicity
Excitotoxicity (a process that damages and kills nerve cells) occurs when the neurotransmitter glutamate, released in response to ischaemia, overactivates its receptors (eg, N-methyl-D-aspartic acid [NMDA] receptor and a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate [AMPA] receptor). This allows an influx of calcium ions, which, in turn, activates enzymes, such as endonucleases, proteases and phospholipases, causing damage.
Most neuroprotectant therapies, such as NMDA antagonists, appear to have been unsuccessful (and, in some cases, have worsened the outcome) in ischaemic stroke but, when co-administered with a thrombolytic agent, appear to have shown a positive effect in transient ischaemia.
Complexin genes (complexin I and II differentially expressed in human brain) are regulators of neurotransmitter release and may provide the reason underlying the excessive sustained release of glutamate after acute stroke.
Role of inflammation
It is well accepted that an inflammatory response is triggered after an ischaemic stroke. Inflammation during ischaemic stroke may occur due to thrombus of large (eg, carotid, middle cerebral and basilar) arteries or small (eg, lenticulostriate, basilar penetrating and medullary) arteries or due to an embolus.
Many studies have shown the presence and active state of leukocytes (neutrophils and monocytes, which can be recruited as early as 30 minutes after ischaemia and reperfusion) and resident cells (eg, microglia, astrocytes and endothelial cells) following stroke.
The involvement of resident brain cells versus blood-borne cells remains unknown. Upregulation of cytokines and adhesion molecules occurs and this can induce damage to the blood-brain barrier and extracellular matrix, leading to oedema (a major clinical complication in stroke) and the further recruitment of leukocytes and platelets.
Endothelial cells are important in the pathophysiology of stroke. During the hypoxic stage of the stroke, endothelial cells swell and form microvilli. This reduces the vessel size and increases the plugging by erythrocytes, leukocytes and platelets.
Endothelial cells are also involved in vascular tone of a vessel, which becomes disrupted. Activation of the endothelial cells upregulates a variety of adhesion molecules that recruit platelets and leukocytes, increasing the inflammatory response.
Many drug candidates have been considered for targeting a specific aspect of the inflammatory cascade, such as adhesion molecules. These have led to failed clinical trials (eg, enlimomab and Leukarrest).
An interleukin-1 antagonist (IL-1RA) has been administered to patients within six hours of stroke, although the clinical benefits remain unknown. However, no major side effects were observed and inflammatory cells were reduced. The area of inflammation is an active one in terms of potential targets for stroke patients, although results to date have been highly disappointing.
Sadly, most drugs showing beneficial effects in animal stroke models go on to fail in clinical trials. For example, exogenous administration of growth factors (eg, brain-derived neuro-trophic factor) has promoted recovery from stroke in rodents but, in humans, the trial was stopped.
This questions the usefulness of animal models in understanding the pathophysiology of stroke and the potential development of therapeutic agents for stroke.
However, these studies have often been conducted in healthy, young animals. Moreover, these models have focused on single targets in the hope that this provides the key to stroke treatment.
Clearly, this is not the answer to a dynamic pathology and we should be revisiting failed drug targets along with new targets for potential combination therapies for this complex disease.
Despite the failure of many animal models to predict success in the clinic, they provide further evidence for the biology of stroke and the response to these therapies, enabling us to learn more about this disease. The use of animals for obtaining targets of stroke (particularly when stroke itself is a multifactorial disease) is a constant debate.
Animal models have included transient global brain ischaemia in gerbils, rats and mice. These correlated reasonably well with clinical findings and all show selective and delayed neuron death in the hippocampus, which matches that seen in the human. However, careful interpretation will always be needed.
Many animal models focus on the occlusion of the middle cerebral artery (MCA). Focal ischaemic models are generated using a filament that is guided up the cerebral artery until it occludes the MCA.4–6 This is routinely performed in rodents, taking advantage of genetically modified animals to investigate the molecular and cellular pathophysiology of stroke.
Other stroke models include the placement of homologous blood clots in the MCA, which may prove more relevant clinically.
Experimental studies and novel therapies
Advances in neuroimaging, such as positron emission tomography and magnetic resonance imaging (MRI; perfusion weighted and diffusion weighted), have aided the assessment of patients. Many groups are now looking into refining these techniques, including ways to calculate MRI “signatures”, so this area is promising.
Neuroimaging in animals is now being recognised as an important step in helping to understand the pathophysiology of stroke and develop potential therapeutic drugs.
In the late 1980s and ’90s, much focus was on targeting glutamate receptors. Of particular significance were the NMDA receptor antagonists MK-801, CGS-19755 and gavestinel, but these failed phase III clinical trials due to side effects.
Despite further potential glutamate receptor drug targets being produced (NPS-1506 and Traxoprodil), none has proved successful, possibly due to the hyperacute release of glutamate.
Recently, however, a new non-competitive NMDA receptor antagonist, Neu2000, has been tested in phase I trials.
Compounds that target the excitotoxicity associated with stroke, in particular the enhancement of glutamate transport function, may be valuable. Recently, ceftriaxone pretreated animals were shown to induce ischaemic tolerance in focal ischamia mediated by the astrocytic glutamate transporter protein, GLT-1(EAAT2).
The application of ex vivo gene therapy is also being investigated with potentially fewer side effects. Combination therapy of caspase inhibitors with MK801 has been used in rodent models of stroke to block NMDA receptors or fibroblast growth factor, both of which have shown neuroprotection.
AMPA receptor antagonists have also been tried in humans but, to date, none has been successful, again, due to their side effects (eg, kidney toxicity). Recent improvement of a non-competitive AMPA receptor antagonist (2,3-benzodiazepine) appears to have few side effects, although it is in its early stages.
Recent in vivo studies have indicated that acid sensing ion channel blockers might provide neuroprotection, as seen in rodent models of cerebral ischaemia. This requires further investigation.
Hypothermia has also been suggested as a possible treatment in transient ischaemia, although there is debate on whether the activity of tPA may be reduced on cooling, as observed in vitro.
Hypothermia may also be beneficial in reducing the activities of matrix metalloproteinases, which play a role in blood-brain barrier function and possible angiogenesis and remodelling after stroke, but evidence is still being collected.
Stem cell therapy
Many advances have been made in stem cell research. Cell therapies for the treatment of myocardial infarction and stroke are being tested in early clinical trials.
Small trials have already been performed using haematopoeitic stem and progenitor stem cells, although outcomes have been mixed. For example, Layton Bioscience have developed LBS-Neurons (NT2/D1 tetatoma cell line that can differentiate into neurons on retinoic acid addition), which have been used in phase I and phase II studies.
These studies showed several significant findings as assessed by the European stroke scale, indicating the safety and feasibility of neuron transplantation for patients with motor stroke.
Another group, the ReNeurob Group, has developed a fetal neural stem cell line (CTX0E03) that can differentiate into mature cells with the characteristics of the cells from which they were derived. These cells have already been tested in rodent models and a non-human primate model, and a proposal is with the US Food and Drug Administration for a potential phase I trial.
Clearly, this is an exciting time in stem cell research and although further studies are clearly needed, it may provide potential treatments and therapies for stroke.
This article focuses on several areas, although this is by no means an exhaustive list. From a preclinical point of view, a better understanding and interpretation of results from in vivo animal studies is required.
Also, development of other animal models, which may better replicate what happens in the human, is needed.
However, advancement in this field can only be achieved if we can fully understand and characterise stroke, thus enabling possible new therapeutic targets to be identified and failed targets to be revisited with a new insight.
It is clear that there remains an unmet need for drug treatment for stroke patients. The financial costs of trying to find and develop new drug targets are becoming increasingly higher.
Future research directions may focus on prospective combination therapies, which may prove to be the way forward in stroke treatment. This can only be possible with careful interpretation and use of in vivo experiments in animals and in vitro studies.
Particular emphasis must be on providing drugs that support the rescue of the penumbra but have an extended efficacy, thus increasing the current three-hour therapeutic window.
Felicity N. E. Gavins is a research lecturer at the Centre of Integrative Mammalian Physiology and Pharmacology and the department of neuroscience and mental health at Imperial College, London.
1. Zaleska MM, Mercado ML, Chavez J, Feuerstein GZ, Pangalos MN, Wood A. The development of stroke therapeutics: promising mechanisms and translational challenges. Neuropharmacology 2009;56:329–41.
2. Venables G. Translating research into practice: lessons from trials of thrombolysis in acute stroke. Annals of Indian Academy of Neurology 2008;11:203–6.
3. Bentley P, Sharma P. Pharmacological treatment of ischemic stroke. Pharmacology and Therapeutics 2005;108:334–52.
4. Liang D, Dawson TM, Dawson VL. What have genetically engineered mice taught us about ischemic injury? Current Molecular Medicine 2004;4:207–25.
5. Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989;20:84–91.
6. Gavins FN, Dalli J, Flower RJ, Granger DN, Perretti M. Activation of the annexin 1 counter-regulatory circuit affords protection in the mouse brain microcirculation. The FASEB Journal 2007;21:1751–8.
Citation: The Pharmaceutical Journal URI: 10882365
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