- Blood/Brain Biomarkers of Inflammation After Stroke and Their Association With Outcome: From C-Reactive Protein to Damage-Associated Molecular Patterns. [REVIEW, JOURNAL ARTICLE]
- Neurotherapeutics 2016 Aug 18.
Stroke represents one of the most important causes of disability and death in developed countries. However, there is a lack of prognostic tools in clinical practice to monitor the neurological condition and predict the final outcome. Blood biomarkers have been proposed and studied in this indication; however, no biomarker is currently used in clinical practice. The stroke-related neuroinflammatory processes have been associated with a poor outcome in stroke, as well as with poststroke complications. In this review, we focus on the most studied blood biomarkers of this inflammatory processes, cytokines, and C-reactive protein, evaluating its association with outcome and complications in stroke through the literature, and performing a systematic review on the association of C-reactive protein and functional outcome after stroke. Globally, we identified uncertainty with regard to the association of the evaluated biomarkers with stroke outcome, with little added value on top of clinical predictors such as age or stroke severity, which makes its implementation unlikely in clinical practice for global outcome prediction. Regarding poststroke complications, despite being more practical scenarios in which to make medical decisions following a biomarker prediction, not many studies have been performed, although there are now some candidates for prediction of poststroke infections. Finally, as potential new candidates, we reviewed the pathophysiological actions of damage-associated molecular patterns as triggers of the neuroinflammatory cascade of stroke, and their possible use as biomarkers.
- Interleukin-6 Blockade as Rescue Therapy in Autoimmune Encephalitis. [EDITORIAL]
- Neurotherapeutics 2016 Aug 16.
- Neuroimmune Response in Ischemic Preconditioning. [REVIEW, JOURNAL ARTICLE]
- Neurotherapeutics 2016 Aug 15.
Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of pro- and anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammtory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke.
- Antigen Presentation After Stroke. [REVIEW, JOURNAL ARTICLE]
- Neurotherapeutics 2016 Aug 11.
Stroke induces a local inflammatory reaction and a plethora of innate immune responses in the brain where antigen-presenting cells become prominent. However, to date, it is still unclear whether antigen presentation is relevant to the neuropathological and functional outcome of stroke. Stroke does not trigger overt autoimmune reactions, but neural antigens have been found in lymphoid tissues of patient with stroke and it is unknown whether they promote tolerance or immune reactions that under certain conditions might contribute to the functional worsening observed in some patients. Autoantibodies to neural molecules have also been reported in patients with stroke, but the subclass of antibodies is important for their function, and the contribution of such findings to stroke outcome is not yet clear. Notably, stroke induces immunodepression highlighted by a transient lymphopenia, lymphoid organ atrophy, and monocyte deactivation. While these effects might reduce the chances of autoreactivity, they increase the risk of infection in patients with stroke and most frequently in those with severe stroke. Therefore any potential brain protective effect of stroke-induced immunodepression by attenuating or preventing lymphocyte-mediated brain damage is confounded by stroke severity and an increased incidence of infections. Systemic inflammation due to a number of comorbidities that are frequent in patients with stroke is also associated to a poor outcome. Herein, we review some relevant findings regarding the identification of neural antigens in stroke and discuss their potential contribution to the functional outcome of stroke.
- Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts. [JOURNAL ARTICLE]
- Neurotherapeutics 2016 Aug 8.
Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman's drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk-benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.
- Heterogeneity of B Cell Functions in Stroke-Related Risk, Prevention, Injury, and Repair. [REVIEW, JOURNAL ARTICLE]
- Neurotherapeutics 2016 Aug 4.
It is well established that post-stroke inflammation contributes to neurovascular injury, blood-brain barrier disruption, and poor functional recovery in both animal and clinical studies. However, recent studies also suggest that several leukocyte subsets, activated during the post-stroke immune response, can exhibit both pro-injury and pro-recovery phenotypes. In accordance with these findings, B lymphocytes, or B cells, play a heterogeneous role in the adaptive immune response to stroke. This review highlights what is currently understood about the various roles of B cells, with an emphasis on stroke risk factors, as well as post-stroke injury and repair. This includes an overview of B cell functions, such as antibody production, cytokine secretion, and contribution to the immune response as antigen presenting cells. Next, evidence for B cell-mediated mechanisms in stroke-related risk factors, including hypertension, diabetes, and atherosclerosis, is outlined, followed by studies that focus on B cells during endogenous protection from stroke. Subsequently, animal studies that investigate the role of B cells in post-stroke injury and repair are summarized, and the final section describes current B cell-related clinical trials for stroke, as well as other central nervous system diseases. This review reveals the complex role of B cells in stroke, with a focus on areas for potential clinical intervention for a disease that affects millions of people globally each year.
- Microglia and Monocyte-Derived Macrophages in Stroke. [REVIEW, JOURNAL ARTICLE]
- Neurotherapeutics 2016 Aug 2.
Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.
- Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy. [JOURNAL ARTICLE]
- Neurotherapeutics 2016 Aug 2.
Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.
- Prophylactic Antibiotic Therapy for Preventing Poststroke Infection. [REVIEW, JOURNAL ARTICLE]
- Neurotherapeutics 2016 Aug 2.
Infections, in particular pneumonia, are common complications in patients with acute stroke and are associated with a less favorable neurologic and functional outcome. Patients with severe stroke and dysphagia are at highest risk of infection. Experimental and clinical data suggest stroke-induced immunodeficiency as a major factor contributing to the high incidence of infection after stroke. Preclinical studies support the potential benefit of preventive antibiotic therapy in acute stroke for lowering the incidence of infection and improving clinical outcome. Several smaller clinical trials on preventive antibiotic therapy in patients with stroke conducted during the last 10 years yielded inconclusive results. Recently, 2 large, open-label, controlled trials failed to demonstrate an improved clinical outcome after preventive antibiotic therapy in patients with acute stroke treated in specialized stroke units. In the "Preventive Antibiotics in Stroke Study", antibiotic therapy lowered the rate of infection but did not influence outcome. In the STROKE-INF study, performed in patients with dysphagia after stroke, antibiotic therapy did not lower the incidence of pneumonia and had no prognostic significance. At present, preventive antibiotic therapy cannot be recommended as a therapeutic option for acute stroke.
- Is Immunomodulation a Principal Mechanism Underlying How Cell-Based Therapies Enhance Stroke Recovery? [REVIEW, JOURNAL ARTICLE]
- Neurotherapeutics 2016 Aug 2.
Inflammation within the brain and in peripheral tissues contributes to brain injury following ischemic stroke. Therapeutic modulation of the inflammatory response has been actively pursued as a novel stroke treatment approach for decades, without success. In recent years, extensive studies support the high potential for cell-based therapies to become a new treatment modality for stroke and other neurological disorders. In this review, we explore different types of cellular therapies and discuss how they modulate central and peripheral inflammatory processes after stroke. Apart from identifying potential targets for cell therapy, we also discuss paracrine and immunomodulatory mechanisms of cell therapy.