CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 12, Issue 2, 2013

Despite advances in the diagnosis and treatment of acute ischaemic stroke in the past two decades, stroke has remained the third cause of mortality and the single leading cause of disability worldwide. The immediate goal of acute ischaemic stroke therapy is to salvage the ischaemic penumbra through recanalisation of the occluded cerebral blood vessel. This is currently achieved through thrombolytics, which are pharmacological agents that can break up a clot blocking the flow of blood. To date, the only approved thrombolytic for treatment of acute ischaemic stroke is recombinant tissue plasminogen activator (alteplase, rt-PA), however, alteplase is substantially underused because of concerns regarding adverse bleeding risk. This limitation has fuelled the search for other thrombolytic agents, which display greater fibrin dependence and selectivity, but lack detrimental effects within the central nervous system. Development of alternative fibrinolytic agents that might be easier and safer to administer could lead to wider acceptance and use of thrombolytic therapy for stroke. Although other thrombolytic agents (e.g. streptokinase) have failed to show benefit over alteplase, there is still on-going research in search of alternative agents with higher target specificity and better safety profile. The potential thrombolytic agents with trials in progress include desmoteplase, tenecteplase, reteplase, plasmin and microplasmin. This review summarises current therapies with thrombolytics (e.g. alteplase and urokinase), their limitations and side effects, and also discusses ongoing clinical studies with the various potential emerging thrombolytic agents.

Intravenous recombinant human tissue plasminogen activator (rtPA, formulated as alteplase) is the primary therapy for acute ischaemic stroke by breaking down a clot of an occluded vessel. There are several randomised controlled trials and observational studies that support the use of rtPA to improve functional outcome following acute ischaemic stroke. However, thrombolytic therapy with rtPA can be associated with a number of complications. Many of the rtPArelated complications result from its thrombolytic action including bleeding (intracerebral and systemic haemorrhage), reperfusion injury with oedema, and angioedema. Other rtPA complications such as reocclusion and secondary embolisation are related to ineffective thrombolysis or redistribution of the lysed clot. In addition to its thrombolytic properties, rtPA can act upon the brain parenchyma leading to seizures and neurotoxicity. Many of these complications have been reported in both pre-clinical experiments and in clinical trials. In animal studies, these complications of rtPA can confound the experimental results achieved, and have to be taken into account in future experiments. In the clinical setting, these complications are not always life-threatening, but can be serious and often lead to prolonged stays in intensive care units, increase the need for medical treatment, lengthen hospital stays, delay rehabilitation and increase morbidity and mortality. Some of these complications could be prevented through adherence to treatment guidelines or at least minimised through early detection and proper management. It is imperative that physicians caring for stroke patients have knowledge of these complications associated with rtPA treatment, and their management.

The only effective treatment licensed for acute ischaemic stroke is intravenous thrombolysis within 4.5 hours from stroke onset. An alternative method of restoring blood flow is mechanical thrombectomy (MT). Although this is highly effective at recanalization, it remains unclear whether it is more effective than thrombolysis in improving clinical outcomes. This review examines key clinical outcomes from published studies and reviews ongoing studies to identify devices, patient population, and stated outcomes of MT. We discuss the issues when comparing clinical outcomes from different trials and suggest measures to help standardize reporting. We used routine review methodology to search relevant databases for stroke and MT published between 1999 - 2012 and active trials between August 2011 - May 2012. The studies in this review had an overall patient population of 8354. The most widely used primary outcome (94% of studies) was successful recanalization. The mean mortality across the studies was 17% (range 7 - 44), 64% of studies reported neurological improvement and 97% reported functional outcome with 42% (range 15 - 54)] achieving independence in activities of daily living. Mean symptomatic intracerebral haemorrhage was 11% (range 0 – 45%). There were significant differences in outcome reporting between studies. Evidence from published studies shows a strong relationship between recanalization and good outcomes although nonstandardization makes comparisons difficult. There is a trend towards higher recanalization, lower mortality, and better functional outcome in more recent studies. To examine effectiveness of MT vs thrombolysis, randomized controlled trials are needed. Several are currently in progress but it remains to be seen if procedures and outcomes are reported in a standardized manner.

Neuroprotection as approach to stroke therapy has recently seen a revival of sorts, fueled in part by the continuing necessity to improve acute stroke care, and in part by the identification of novel drug targets. 12/15- Lipoxygenase (12/15-LOX), one of the key enzymes of the arachidonic acid cascade, contributes to both neuronal cell death and vascular injury. Inhibition of 12/15-LOX may thus provide multifactorial protection against ischemic injury. Targeting 12/15-LOX and related eicosanoid pathways is the subject of this brief review.

Neurorestorative therapies for stroke aim to reverse disability by reparative mechanisms (rather than to thrombolyse or to neuroprotect). A substantial and persuasive body of pre-clinical evidence has come from the evaluation of antibodies against Nogo-A (a myelin-associated inhibitor of plasticity) in rat models of stroke. Particularly impressive is the benefit of this therapy in models of permanent middle cerebral artery occlusion (MCAO) when given to elderly animals after a one week delay, in adult rats with co-morbidities, and in adult rats when treatment is delayed by up to 9 weeks after stroke (although antibodies against Nogo-A did not reverse disability in mice after proximal MCAO with reperfusion). We predict that antibodies against Nogo-A will improve outcome further when combined with suitable additional rehabilitation, and also that antibodies against Nogo-A will improve outcome in animal models of haemmorhagic stroke that affect the same brain regions as ischemic stroke caused by MCAO. Antibodies against Nogo-A have been shown to be safe in Phase I clinical trials for acute spinal cord injury, and this may eventually facilitate a trial in stroke.

No pharmacological intervention has been shown convincingly to improve neurological outcome in stroke patients after the brain tissue is infarcted. While conventional therapeutic strategies focus on preventing brain damage, stem cell treatment has the potential to repair the injured brain tissue. Stem cells not only produce a source of trophic molecules to minimize brain damage caused by ischaemia/reperfusion and promote recovery, but also potentially turn to new cells to replace those lost in ischaemic core. Although preclinical studies have shown promise, stem cell therapy for stroke treatment in human is still at an early stage and it is difficult to draw conclusions from current clinical trials about the efficacy of the different treatments used in humans. This article reviews the potential of various types of stem cells, from embryonic to adult to induced pluripotent stem cells, in stroke therapy, highlights new evidence from the ongoing clinical trials and discusses some of the problems associated with translating stem cell technology to a clinical therapy for stroke.

The objective of this study was to characterize the effect of albumin therapy on the expression of Toll-like receptor 4 (TLR 4), anti-inflammation cytokines and CD4+CD25+forkhead box P3 (Foxp3)+ regulatory T lymphocytes (Treg cells) in the ischemic brain and peripheral immune system after Middle Cerebral Artery Occlusion (MCAO). Adult male Kunming mice were subjected to MCAO, the suture was withdrawn 2 h later followed by an intravenous administration of 25% albumin (1.25 g/kg) or saline (5 ml/kg) through caudal vein. We demonstrated that albumin administration elevated the serum albumin level supranormally at 6 h and 24 h after MCAO in mice. In addition, we showed that both in the ischemic brain and in the spleen, albumin administration significantly depressed the increase of TLR 4 mRNA expression by quantitative real-time polymerase chain reaction (QRT-PCR), and significantly increase the anti-inflammatory related interleukin-10 (IL-10) and transforming growth factor beta1 (TGF-β1) mRNA expression by transcription-polymerase chain reaction (RT-PCR) after MCAO. In the spleen, compared to sham group, strong TLR 4 immunoreactivity was noted in the saline group; while compared to saline group, albumin administration markedly reduced the immunoreactivity of TLR 4 after MCAO by immunohistochemistry. Moreover, albumin administration significantly increased the percentage of Treg in spleen CD4+ cells by flow cytometry. In conclusion, the decrease of TLR 4 expression and the increase of Treg cell, IL-10, and TGF-β1 expression may partly contribute to the neuroprotective effect of albumin therapy on MCAO induced immune inflammatory responses.

Background: Most studies evaluating long-term efficacy after coil embolisation of intracranial aneurysms have not differentiated between ruptured and unruptured aneurysms. Objectives: The aim of this study was to analyse factors that influence recanalisation in ruptured and unruptured aneurysms. Methods: We performed a retrospective analysis of 182 (98 ruptured, 84 unruptured) aneurysms, treated with coil embolisation alone that received follow-up with digital substraction angiography (DSA). Results: At 6 months 26%of the aneurysms showed recanalisation. Multivariate variance analysis revealed that different factors influenced recanalisation in ruptured and unruptured aneurysms. In ruptured aneurysms patient age was a determinant, with younger patients recanalising more frequently than older ones (p = 0.016). Also, low initial packing density led to higher recanalisation rates (p = 0.015) than higher packing. In the unruptured aneurysm group these factors were not significant. Here, only a larger aneurysm volume led to higher recanalisation rates (p = 0.027). Conclusions: Our data suggest that in ruptured aneurysms, high packing density is a key factor to prevent recanalisation, while in unruptured aneurysms, aneurysm volume is the main predictor for recanalisation.

Cerebral vasospasm is a common and serious complication of aneurysmal subarachnoid haemorrhage. Despite the improvements in treatment of aneurysmal subarachnoid haemorrhage (aSAH), cerebral vasospasm complicating aSAH has remained the main cause of morbidity and mortality. Subarachnoid haemorrhage (SAH)-induced vasospasm is a complex entity caused by vasculopathy, impaired autoregulation, and hypovolaemia, causing a regional reduction of cerebral brain perfusion which can then induce ischaemia. Cerebral vasospasm can present either asymptomatically detected only radiologically or symptomatically (delayed ischaemic neurologic deficit). The various diagnostic approaches include the use of transcranial doppler, digital subtraction angiography and multimodal computed tomography (CT) and magnetic resonance (MR) techniques. Although digital subtraction angiography is usually the gold standard for the diagnosis of cerebral vasospam, transcranial doppler is commonly the first-screening method for the detection of cerebral vasospam. The treatment of subarachnoid haemorrhage -induced vasospasm include the use of both medical and endovascular therapy. The aim of this review is to discuss the various current therapeutic options and future perspective measures for reducing cerebral vasospasm induced stroke after SAH.

Atrial fibrillation is a major risk factor for first and recurrent ischaemic stroke, and anticoagulation, mainly by use of coumarin medications, is an effective strategy for reducing ischaemic stroke occurrence in these patients. However, the coumarin medications have disadvantages. Over the past decade, important strides have been made towards developing improved anticoagulant medications. This review discusses these new developments and what they mean for the future of primary and secondary ischaemic stroke prevention in patients with atrial fibrillation. Relevant papers were identified with electronic searches of the Medline and EMBASE databases. Ongoing trials were checked using the Trials Results Centre website. The direct thrombin inhibitors, and the factor Xa inhibitors are the two major new anticoagulant drug classes under development at present. In phase III trials, dabigatran and rivaroxaban demonstrated at least as good performance as warfarin at reducing the rate of ischaemic stroke, systemic embolus, and haemorrhagic ischaemic stroke, whilst maintaining a comparable or lower rate of major bleeding events. Drug level monitoring was not required due to stable pharmacodynamics. AZD0837, apixaban, YM-150, edoxaban and betrixaban all showed promising results in phase II trials, as did S35972 in animal, in vitro and ex vivo models. The future of these new anticoagulants looks encouraging, although there are still some significant challenges to overcome. We need to consider the accumulation of long-term safety and efficacy data, and the development of effective means of reversal of anticoagulation for the direct thrombin inhibitors and factor Xa inhibitors.

Oxytocin is a nonapeptide mammalian hormone, best known for its role in childbirth, parturition and lactation. It has been implicated in the control of social behaviors and relationships, such as monogamy or promiscuous behaviors. The putative involvement of oxytocin in schizophrenia was first postulated following several pioneer reports of oxytocin use in schizophrenia and observations of increased oxytocin levels in the cerebrospinal fluid of schizophrenic patients, although this latter finding has subsequently been challenged. More recently, oxytocin plasma levels have been found to be decreased in schizophrenic individuals, particularly in those exhibiting hyponatremic polydipsia and emotional dysregulation. Some authors report that intranasal oxytocin administration to schizophrenic patients may reduce symptomatology. The aim of the present paper was to review studies investigating symptomatology, social cognition and emotion recognition changes in DSM-IV-TR schizophrenic patients, after administration of intranasal oxytocin at different doses. Literature search was conducted in March, 2012. PubMed and Scopus databases were used to find studies for inclusion in the systematic review. Oxytocin may represent an important novel adjunctive treatment for patients with schizophrenia. However, some limitations of current studies cannot be overlooked and further investigations are certainly needed.

Parkinson's disease (PD) is a neurodegenerative disease of the central nervous system. Although PD is commonly characterized by well-known clinical manifestations, it also involves imbalances in the cortico-subcortical excitation and inhibition processes. Functional electrical stimulation can improve the motor condition of PD patients as a supplement to levodopa therapy. In this study, clinical (using specific tests) and paraclinical (using single-pulse transcranial magnetic stimulation) examinations revealed an improvement in the motor symptoms and the bilateral activation of the primary motor areas of the upper limbs after unilateral functional electrical stimulation in PD patients.

More than 30 different Transient Receptor Potential channels (TRP) have been identified in mammals and are grouped in 6 families. Members of these subunit families, specifically of the vanilloid TRP (TRPV), melastatin TRP (TRPM), ankyrin TRP (TRPA), polycystin TRP (TRPP) and canonical or classical TRP (TRPC) family, are considered relevant in central nervous system neurodegenerative diseases. In fact, TRP channels have received increased attention in recent years, since they are involved in a broad array of pathways and respond to different environmental stimuli. Preclinical research has identified TRPs involved in hereditary neuropathies as well as in a heterogeneous group of neuronal disorders. Moreover, changes in TRP channel expression and functionality have been associated to diabetic thermal hyperalgesia, painful neuropathies and headache. At the molecular level, TRPs are involved in a wide range of mechanisms regulating osmosis, thermal, stretch, chemical and sensory signaling, highlighting TRPs as potential targets for pharmacological intervention. The area of small molecule TRP agonists-antagonists drug development is moving rapidly. This review will evaluate current evidence that supports particular TRP channels as targets for novel drugs, summarizing the current perspectives for the therapeutic potential of TRP agonists and antagonists in the treatment of a wide range of neuropathies, along with potential adverse effects that may limit drug development.