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In this Review, Salter and Stevens discuss the role of microglia in CNS disorders such as autism, neurodegenerative disorders, Alzheimer’s disease, and chronic pain. There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.

Historically, the CNS has been considered immunologically privileged and separated from the peripheral immune system. In this Review, the authors highlight recent advances in our understanding of how the CNS interacts with peripheral immune cells in the context of health and disease. The CNS is protected by the immune system, including cells that reside directly within the CNS and help to ensure proper neural function, as well as cells that traffic into the CNS with disease. The CNS-resident immune system is comprised mainly of innate immune cells and operates under homeostatic conditions. These myeloid cells in the CNS parenchyma and at CNS–periphery interfaces are highly specialized but also extremely plastic cells that immediately react to any changes in CNS homeostasis and become reactive in the context of neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease. However, when the blood–brain barrier is impaired during CNS diseases such as multiple sclerosis or altered with cerebral ischemia, peripheral adaptive and innate immune cells, including monocytes, neutrophils, T cells and B cells, can enter the CNS, where they execute distinct cell-mediated effects. On the basis of these observations, we assess strategies for targeting peripheral immune cells to reduce CNS disease burden.

Key Points The blood–brain barriers (BBBs) are dynamic, adaptable, interactive monolayers of cells, including endothelial, ependymal and tanycytic cells, that participate in central nervous system (CNS) protection, are responsible for CNS nutrition and homeostasis, and facilitate serum-based brain–body communications. The cells forming the BBB are in communication with other cells of the CNS, thus forming the neurovascular unit. This communication informs the BBB of the needs of the CNS, allowing it to adapt to the needs of the CNS. The BBB also communicates with circulating immune cells and via blood-borne signals with the peripheral tissues. Through transport, secretion and other mechanisms, the BBB relays information between the periphery and the CNS. The complexity of the BBB complicates CNS drug delivery, but also provides many unique opportunities for drug delivery. Manipulation of transporters, secretory functions, the extracellular pathways, and adsorptive transcytosis are examples of promising approaches to drug development. The complexity of the BBB predisposes it to dysfunctions that can result in or promote disease. Such dysfunctions include BBB disruption as well as dysfunctions related to BBB transporters, neurovascular unit communication and secretion. Thus, the BBB itself can be a therapeutic target. Research on the blood–brain barrier (BBB) has led to the concept of a complex, dynamic interface between the central nervous system (CNS) and periphery. Banks considers how this new understanding can combine with classical concepts to inform CNS drug delivery strategies and promote BBB integrity in various diseases. One of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders is achieving sufficient blood–brain barrier (BBB) penetration. Research in the past few decades has revealed that the BBB is not only a substantial barrier for drug delivery to the CNS but also a complex, dynamic interface that adapts to the needs of the CNS, responds to physiological changes, and is affected by and can even promote disease. This complexity confounds simple strategies for drug delivery to the CNS, but provides a wealth of opportunities and approaches for drug development. Here, I review some of the most important areas that have recently redefined the BBB and discuss how they can be applied to the development of CNS therapeutics.

The eye is an extension of the CNS in terms of its development and anatomy, and in terms of its dialogue with the immune system. Many neurodegenerative disorders of the brain and spinal cord have manifestations in the eye, which are often evident before the emergence of clinical neurological symptoms. London et al . highlight how investigation of the eye represents a noninvasive approach to the detection and diagnosis of neurodegenerative disorders, and discuss how eye research could provide a valuable model to study CNS disorders. Philosophers defined the eye as a window to the soul long before scientists addressed this cliché to determine its scientific basis and clinical relevance. Anatomically and developmentally, the retina is known as an extension of the CNS; it consists of retinal ganglion cells, the axons of which form the optic nerve, whose fibres are, in effect, CNS axons. The eye has unique physical structures and a local array of surface molecules and cytokines, and is host to specialized immune responses similar to those in the brain and spinal cord. Several well-defined neurodegenerative conditions that affect the brain and spinal cord have manifestations in the eye, and ocular symptoms often precede conventional diagnosis of such CNS disorders. Furthermore, various eye-specific pathologies share characteristics of other CNS pathologies. In this Review, we summarize data that support examination of the eye as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS. Translation of eye research to CNS disease, and deciphering the role of immune cells in these two systems, could improve our understanding and, potentially, the treatment of neurodegenerative disorders. Key Points As an extension of the CNS, the retina displays similarities to the brain and spinal cord in terms of anatomy, functionality, response to insult, and immunology Several major neurodegenerative disorders have manifestations in the retina, suggesting that the eye is a 'window' into the brain Neurodegenerative processes that have been characterized in CNS disorders are also detected in some classic ocular pathologies The accessibility and organization of the retina makes it a convenient research tool with which to study processes in the CNS Advances in ocular imaging techniques support the potential of these approaches as effective aids in noninvasive diagnosis of CNS disorders Future research should be aimed at testing whether therapies that are beneficial in brain disorders could also alleviate diseases of the eye, and vice versa

Sex is a fundamentally important biological variable. Recent years have seen significant progress in the integration of sex in many aspects of basic and clinical research, including analyses of sex differences in brain function. Significant advances in the technology available for studying the endocrine and nervous systems are now coupled with a more sophisticated awareness of the interconnections of these two communication systems of the body. A thorough understanding of the current knowledge, conceptual approaches, methodological capabilities, and challenges is a prerequisite to continued progress in research and therapeutics in this interdisciplinary area. This book provides scientists with the basic tools for investigating sex differences in brain and behavior, and insight into areas where important progress in understanding physiologically relevant sex differences has already been made. The book is arranged in three parts. The first part of the book introduces the study of sex differences in the brain, with an overview of how the brain, stress systems, and pharmacogenetics differ in males and females and how this information is important for the study of behavior and neurobiology of both genders. The second part presents examples of sex differences in neurobiology and behavior from both basic and clinical research perspectives, covering both humans and nonhuman animals. The final part discusses sex differences in the neurobiology of disease and neurological disorders.

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions .

Magnesium is well known for its diverse actions within the human body. From a neurological standpoint, magnesium plays an essential role in nerve transmission and neuromuscular conduction. It also functions in a protective role against excessive excitation that can lead to neuronal cell death (excitotoxicity), and has been implicated in multiple neurological disorders. Due to these important functions within the nervous system, magnesium is a mineral of intense interest for the potential prevention and treatment of neurological disorders. Current literature is reviewed for migraine, chronic pain, epilepsy, Alzheimer’s, Parkinson’s, and stroke, as well as the commonly comorbid conditions of anxiety and depression. Previous reviews and meta-analyses are used to set the scene for magnesium research across neurological conditions, while current research is reviewed in greater detail to update the literature and demonstrate the progress (or lack thereof) in the field. There is strong data to suggest a role for magnesium in migraine and depression, and emerging data to suggest a protective effect of magnesium for chronic pain, anxiety, and stroke. More research is needed on magnesium as an adjunct treatment in epilepsy, and to further clarify its role in Alzheimer’s and Parkinson’s. Overall, the mechanistic attributes of magnesium in neurological diseases connote the macromineral as a potential target for neurological disease prevention and treatment.

The choroid plexus (CP) forming the blood–cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnostic methods and treatment of CP papilloma and carcinoma have recently been developed. This review describes and summarizes the current state of knowledge with regard to the roles of the CP and B-CSF barrier in the pathophysiology of various types of CNS diseases and sets up the foundation for further avenues of research.

Key Points Kynurenic acid has potentially neuroprotective actions, such as antagonism at NMDA ( N -methyl- D -aspartate) receptors, inhibition of glutamate release and free radical scavenging. Pharmacological manipulations to harness the beneficial effects of this blood–brain barrier-impermeable agent include increasing the availability of its precursor L -kynurenine, modulation of the kynurenine pathway enzymes towards the synthesis of kynurenic acid, as well as the systemic administration of kynurenic acid analogues that have improved pharmacokinetic characteristics. Most of the kynurenines are neuroactive; they have important roles in the functioning of glutamate receptors and in free radical production. NMDA receptor-mediated excitotoxicity and excessive free radical production are involved in neurodegenerative diseases such as Huntington's disease. The kynurenine pathway is altered in Huntington's disease to favour the production of toxic metabolites, and the possible therapeutic potential of its pharmacological modulation is currently under experimental investigation. Glutamatergic neurotransmission is essential for the spinal and trigeminal processing of pain. Kynurenic acid has several antiglutamatergic properties. Therefore, the elevation of kynurenic acid levels could have therapeutic value in pain syndromes, including migraine. In this disorder, increases in kynurenic acid levels could suppress trigeminal and higher-order nociceptive neurons, modulate migraine generator nuclei in the brainstem and inhibit cortical spreading depression. The activation of indoleamine 2,3-dioxygenase triggers a complex immunomodulatory response, which is involved in the mediation of physiological and pathological immune tolerance. The immunosuppressive effect of this enzyme is attributable to tryptophan depletion and the actions of downstream kynurenine metabolites. There is evidence to indicate that indoleamine 2,3-dioxygenase is activated in several inflammatory and autoimmune conditions, most probably serving as a self-protecting mechanism. Experimental and indirect evidence suggests that the kynurenine pathway is overactivated in multiple sclerosis. As most of the immunotolerogenic metabolites of the kynurenine pathway exert neurotoxic and/or oligotoxic properties, the influence of this phenomenon on the pathogenesis and progression of multiple sclerosis necessitates further investigation. In experimental models of multiple sclerosis, the activation of indoleamine 2,3-dioxygenase has shown beneficial effects; indeed, this mechanism may underlie the therapeutic potential of interferon-β in multiple sclerosis. Structurally similar synthetic derivatives of kynurenines have shown disease-modifying effects in recent clinical trials. The complex anti-inflammatory and neuroprotective properties of kynurenic acid and its analogues suggest that experimental screening of such compounds is warranted. Most metabolites of the kynurenine pathway — which metabolizes tryptophan — are neuroactive. This Review describes the role of the kynurenine pathway in the pathology of Huntington's disease, migraine and multiple sclerosis, and highlights the most promising compounds that could be of therapeutic value. Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington's disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.

Decades of research have revealed numerous differences in brain structure size, connectivity and metabolism between males and females. Sex differences in neurobehavioral and cognitive function after various forms of central nervous system (CNS) injury are observed in clinical practice and animal research studies. Sources of sex differences include early life exposure to gonadal hormones, chromosome compliment and adult hormonal modulation. It is becoming increasingly apparent that mitochondrial metabolism and cell death signaling are also sexually dimorphic. Mitochondrial metabolic dysfunction is a common feature of CNS injury. Evidence suggests males predominantly utilize proteins while females predominantly use lipids as a fuel source within mitochondria and that these differences may significantly affect cellular survival following injury. These fundamental biochemical differences have a profound impact on energy production and many cellular processes in health and disease. This review will focus on the accumulated evidence revealing sex differences in mitochondrial function and cellular signaling pathways in the context of CNS injury mechanisms and the potential implications for neuroprotective therapy development.