Central Nervous System Disease States Research Articles

Interleukin 1 receptor antagonist and neurodegenerative diseases: the future treatment strategy

Neurodegenerative disorders encompass a range of conditions affecting the central nervous system (CNS) in which alterations in the neuronal structure and cellular dysfunction lead to progressive deterioration. Activation of microglia and expression of the inflammatory cytokine interleukin-1 (IL-1) in the CNS have become almost synonymous with neuroinflammation. Additionally, the relentless activation of the IL-1 signalling pathway has been linked with the pathogenesis of various CNS disease states, ranging from Alzheimer disease (AD), Parkinson disease (PD) to amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Moreover, a growing body of evidence has inferred that impeding the IL-1 signalling either pharmacologically or genetically in various CNS disease models could reduce neuroinflammation or delay disease progression. This review will therefore aim to study the role of IL-1 in neurodegenerative diseases and highlight the key aspects that warrant IL-1Ra as a promising target for developing a novel treatment for various CNS conditions.

Mechanical actuators in microglia dynamics and function

Microglia are the most prominent immune resident cell population in the central nervous system (CNS). In the healthy CNS, microglia survey their surrounding microenvironment, through recurrent extension and retraction of filopodia-like membrane protrusions, without evident cell body displacement. Microglia undergo dramatic transcriptomic and shape changes upon brain insults or neurodegenerative disease states and adopt a classical immune effector function (producing an extensive array of inflammatory mediators such as cytokines, chemokines, and reactive oxygen species) to re-establish tissue homeostasis. While the biophysical principles underlying microglia morphological changes remain elusive, several recent studies have highlighted the pivotal role of the actin and non-muscle myosin II filamentous cytoskeleton in this process. In this work, we discuss how subcellular topological patterning of the actin and myosin cytoskeleton can control microglial cell shape dynamics and how it can potentially feedback on their functional specialization, which is of great importance to understanding the mechanisms of microglial action in homeostatic conditions and CNS disease states.

The Therapeutic Prospects of Targeting IL-1R1 for the Modulation of Neuroinflammation in Central Nervous System Disorders.

The interleukin-1 receptor type 1 (IL-1R1) holds pivotal roles in the immune system, as it is positioned at the “epicenter” of the inflammatory signaling networks. Increased levels of the cytokine IL-1 are a recognized feature of the immune response in the central nervous system (CNS) during injury and disease, i.e., neuroinflammation. Despite IL-1/IL-1R1 signaling within the CNS having been the subject of several studies, the roles of IL-1R1 in the CNS cellular milieu still cause controversy. Without much doubt, however, the persistent activation of the IL-1/IL-1R1 signaling pathway is intimately linked with the pathogenesis of a plethora of CNS disease states, ranging from Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), all the way to schizophrenia and prion diseases. Importantly, a growing body of evidence is showing that blocking IL-1R1 signaling via pharmacological or genetic means in different experimental models of said CNS diseases leads to reduced neuroinflammation and delayed disease progression. The aim of this paper is to review the recent progress in the study of the biological roles of IL-1R1, as well as to highlight key aspects that render IL-1R1 a promising target for the development of novel disease-modifying treatments for multiple CNS indications.

Perivascular and Perineural Pathways Involved in Brain Delivery and Distribution of Drugs after Intranasal Administration.

One of the most challenging aspects of treating disorders of the central nervous system (CNS) is the efficient delivery of drugs to their targets within the brain. Only a small fraction of drugs is able to cross the blood–brain barrier (BBB) under physiological conditions, and this observation has prompted investigation into the routes of administration that may potentially bypass the BBB and deliver drugs directly to the CNS. One such route is the intranasal (IN) route. Increasing evidence has suggested that intranasally-administered drugs are able to bypass the BBB and access the brain through anatomical pathways connecting the nasal cavity to the CNS. Though the exact mechanisms regulating the delivery of therapeutics following IN administration are not fully understood, current evidence suggests that the perineural and perivascular spaces of the olfactory and trigeminal nerves are involved in brain delivery and cerebral perivascular spaces are involved in widespread brain distribution. Here, we review evidence for these delivery and distribution pathways, and we address questions that should be resolved in order to optimize the IN route of administration as a viable strategy to treat CNS disease states.

Potential role of CSF cytokine profiles in discriminating infectious from non-infectious CNS disorders.

Current laboratory testing of cerebrospinal fluid (CSF) does not consistently discriminate between different central nervous system (CNS) disease states. Rapidly distinguishing CNS infections from other brain and spinal cord disorders that share a similar clinical presentation is critical. New approaches focusing on aspects of disease biology, such as immune response profiles that can have stimulus-specific attributes, may be helpful. We undertook this preliminary proof-of-concept study using multiplex ELISA to measure CSF cytokine levels in various CNS disorders (infections, autoimmune/demyelinating diseases, lymphomas, and gliomas) to determine the potential utility of cytokine patterns in differentiating CNS infections from other CNS diseases. Both agglomerative hierarchical clustering and mixture discriminant analyses revealed grouping of CNS disease types based on cytokine expression. To further investigate the ability of CSF cytokine levels to distinguish various CNS disease states, non-parametric statistical analysis was performed. Mann-Whitney test analysis demonstrated that CNS infections are characterized by significantly higher CSF lP-10/CXCL10 levels than the pooled non-infectious CNS disorders (p = 0.0001). Within the infection group, elevated levels of MDC/CCL22 distinguished non-viral from viral infections (p = 0.0048). Each disease group of the non-infectious CNS disorders independently showed IP-10/CXCL10 levels that are significantly lower than the infection group [(autoimmune /demyelinating disorders (p = 0.0005), lymphomas (p = 0.0487), gliomas (p = 0.0294), and controls (p = 0.0001)]. Additionally, of the non-infectious diseases, gliomas can be distinguished from lymphomas by higher levels of GRO/CXCL1 (p = 0.0476), IL-7 (p = 0.0119), and IL-8 (p = 0.0460). Gliomas can also be distinguished from autoimmune/demyelinating disorders by higher levels of GRO/CXCL1 (p = 0.0044), IL-7 (p = 0.0035) and IL-8 (p = 0.0176). Elevated CSF levels of PDGF-AA distinguish lymphomas from autoimmune/demyelinating cases (p = 0.0130). Interrogation of the above comparisons using receiver operator characteristic analysis demonstrated area under the curve (AUC) values (ranging from 0.8636–1.0) that signify good to excellent utility as potential diagnostic discriminators. In conclusion, our work indicates that upon formal validation, measurement of CSF cytokine levels may have clinical utility in both identifying a CNS disorder as infectious in etiology and, furthermore, in distinguishing viral from non-viral CNS infections.

RNA-sequencing reveals oligodendrocyte and neuronal transcripts in microglia relevant to central nervous system disease.

Expression profiling of distinct central nervous system (CNS) cell populations has been employed to facilitate disease classification and to provide insights into the molecular basis of brain pathology. One important cell type implicated in a wide variety of CNS disease states is the resident brain macrophage (microglia). In these studies, microglia are often isolated from dissociated brain tissue by flow sorting procedures [fluorescence-activated cell sorting (FACS)] or from postnatal glial cultures by mechanic isolation. Given the highly dynamic and state-dependent functions of these cells, the use of FACS or short-term culture methods may not accurately capture the biology of brain microglia. In the current study, we performed RNA-sequencing using Cx3cr1(+/GFP) labeled microglia isolated from the brainstem of 6-week-old mice to compare the transcriptomes of FACS-sorted versus laser capture microdissection (LCM). While both isolation techniques resulted in a large number of shared (common) transcripts, we identified transcripts unique to FACS-isolated and LCM-captured microglia. In particular, ∼50% of these LCM-isolated microglial transcripts represented genes typically associated with neurons and glia. While these transcripts clearly localized to microglia using complementary methods, they were not translated into protein. Following the induction of murine experimental autoimmune encephalomyelitis, increased oligodendrocyte and neuronal transcripts were detected in microglia, while only the myelin basic protein oligodendrocyte transcript was increased in microglia after traumatic brain injury. Collectively, these findings have implications for the design and interpretation of microglia transcriptome-based investigations.

Purkinje neuron physiology is altered by the inflammatory factor interleukin‐6

The cytokine interleukin-6 (IL-6) is produced by cells of the central nervous system (CNS) during a variety of neuroinflammatory states, in which it is thought to play a role in neuroprotection and/or neuropathology associated with neurological disease. In addition, CNS expression of IL-6 during non-pathological conditions may also occur, although the conditions for such IL-6 production remain elusive. Expression of IL-6 and its receptor and signal transducing elements by neurons and glia within the cerebellum implicate a role of IL-6 in modulating cerebellar function under normal conditions and in contributing to pathology and pathophysiology within the cerebellum during CNS disease states. Evidence for such a role of IL-6 comes from studies using transgenic mice that chronically express IL-6 within the CNS. These mice exhibit profound cerebellar pathology and significant alterations of Purkinje neuron electrical and synaptic activity. Additional evidence comes from in vitro studies using primary cultures of cerebellar cortex that have been chronically exposed to exogenously applied IL-6. Consistent with the IL-6 transgenic mice, chronic IL-6 treated Purkinje neurons in culture exhibit alterations of endogenous electrophysiological properties as well as changes in intracellular Ca2+ homeostasis and signaling. Despite these changes in Purkinje neuron physiology, chronic IL-6 does not affect the survival or morphology of Purkinje neurons in culture. Thus, by itself, IL-6 is able to modulate key components of cerebellar circuitry during periods of chronic expression, such as during neuroinflammation, and may be an important player in the movement disorders associated with a number of CNS disease states.

Minimally invasive neurosurgery: Anesthetic implications

late to new anesthettc challen~,es could be restated as New surgical procedures demand new anesthetic techniques. Neurosurgery has come a long way from the days of Harvey Cushing and Walter Dandy. Cushing was the pioneer of modern neurosurgery and, in the words of Sir William Osler, ° he opened a new chapter in the field of surgery. Cushing followed the principles of brain imaging, but it was based on his knowledge of neurophysiology and the patient's clinical features. Today, the scope of the available techniques in neuroimaging is vast. Apart from computed tomography (CT) and magnetic resonance imaging (MRI), there are other imaging modalities, such as magnetic resonance spectroscopy, magnetic resonance angiography, single photon emission contrast tomography, and positron emission tomography, to name a few. These techniques, besides providing precise neuroanatomical visualization of intracranial lesions, also have functional imaging capabilities, which give us physiological information about cerebral blood flow/metabolism, outline functional areas like the speech center and motor center and, in chronic pain patients, make it possible to visualize hyperactivity of the pain center in the thalamus, thus differentiating the psychological component from the somatic component of pain. Simultaneously, the field of endoscopy has come a long way, with the availability of video endoscopes and miniature cameras. Tools for endoscopic surgery have permitted surgical access to lesions previously considered inaccessible because of their location. Therefore, minimally invasive neurosurgery is the fulfillment of a long-felt need to develop surgical techniques with minimum potential for damage to the normal brain and a sequel to various technological innovations. The principle of primum nor nocire (do no harm), although important in medicine as a whole, has always been the guiding philosophy in neurosurgery. Preserving the integrity of normal tissue while maximizing the resection of a brain tumor is more effectively possible with the combination of available imaging techniques and a minimally invasive approach (endoscopic surgery). The availability of open MRI systems 2 allows real-time imaging intraoperatively, adding more precision to tumor localization and resection. Besides this, modern imaging technology is also being used for nonsurgical approaches to some of the central nervous system disease states, such as Parkinsonism, chronic pain, acoustic neurinoma, and arteriovenous malformation (AVM). This discussion will focus on 3 aspects of minimally invasive neurosurgery--endoscopic neurosurgery, brain imaging, and gamma knife surgery. NEUROENDOSCOPY History

Localization of the A 3 adenosine receptor gene (ADORA3) to human chromosome 1p

Adenosine modulates important physiologic functions involving the cardiovascular system, brain, kidneys, lungs, GI tract, and immune system. To date four adenosine receptors have been identified: A{sub 1}, A{sub 2a}, A{sub 2b}, and A{sub 3}. Activation of these receptors results in inhibition (A{sub 1} and A{sub 3}) or stimulation (A{sub 2a} and A{sub 2b}) of intracellular adenyl cyclase activity, stimulation of K{sup +} flux, inhibition of Ca{sup 2+} flux, and modulation of inositol phospholipid turnover. A{sub 3} receptors have been identified and sequenced in the testes, brain, lung, liver, kidney, and heart of various species, including the rat, mouse, and human. A{sub 3} receptor activation is responsible for release of inflammatory mediators from mast cells, which can cause allergic bronchoconstriction. In addition, they can produce systemic vasodilation and locomotor depression via activation of A{sub 3} receptors in the brain. Given the potential importance of A{sub 3} receptor activity in the pathogenesis of pulmonary, cardiovascular, and central nervous system disease states, we set out to localize the human A{sub 3} adenosine receptor gene (ADORA3). 9 refs., 1 fig.

Pediatric Brain Computed Tomography

Computed tomography today provides good anatomic depiction of the brain and its gross disease processes that have as a manifestation alteration of brain density, disturbance in blood-brain barrier, or mass effect. As such, computed tomography often provides valuable diagnostic information in the appropriate clinical setting. This article reviews many of the more common pediatric central nervous system disease states that have been demonstrated more easily as a result of computed tomography.

Aggravated CNS Depression With Urinary Retention Secondary to Baclofen Administration

A 74-year-old woman with a history of cerebrovascular disease developed profound central nervous system (CNS) and respiratory depression, generalized hypotonia, sinus bradycardia, and urinary retention following an increase in dose of baclofen, an antispasticity agent. Before receiving baclofen therapy the patient had had minor urinary dysfunction associated with a remote cerebrovascular accident but no urinary retention. Cessation of baclofen therapy and the relief of the urinary obstruction improved mental status and normalized motor function within 24 hours. A withdrawal syndrome of agitation, hallucinosis, and convulsive activity persisted for eight days following discontinuation of the baclofen. Our experience suggests that patients with various forms of CNS disease states may be at risk of serious CNS depression with even small therapeutic doses of baclofen.