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It is now well accepted that astrocytes are essential in all major nervous system functions of the rodent brain, including neurotransmission, energy metabolism, modulation of blood flow, ion and water homeostasis, and, indeed, higher cognitive functions, although the contribution of astrocytes in cognition is still in early stages of study. Here we review the most current research findings on human astrocytes, including their structure, molecular characterization, and functional properties. We also highlight novel tools that have been established for translational approaches to the comparative study of astrocytes from humans and experimental animals. Understanding the differences in astrocytes is essential to elucidate the contribution of astrocytes to normal physiology, cognitive processing and diverse pathologies of the central nervous system. [ABSTRACT FROM AUTHOR]

Astroglial perisynaptic sheath covers the majority of synapses in the central nervous system. This glial coverage evolved as a part of the synaptic structure in which elements directly responsible for neurotransmission (exocytotic machinery and appropriate receptors) concentrate in neuronal membranes, whereas multiple molecules imperative for homeostatic maintenance of the synapse (transporters for neurotransmitters, ions, amino acids, etc.) are shifted to glial membranes that have substantially larger surface area. The astrocytic perisynaptic processes act as an 'astroglial cradle' essential for synaptogenesis, maturation, isolation and maintenance of synapses, representing the fundamental mechanism contributing to synaptic connectivity, synaptic plasticity and information processing in the nervous system. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) flows through the central nervous system (CNS) via the glymphatic pathway to clear the interstitium of metabolic waste. In preclinical studies, glymphatic fluid flow rate increases with low central noradrenergic tone and slow-wave activity during natural sleep and general anesthesia. By contrast, sleep deprivation reduces glymphatic clearance and leads to intracerebral accumulation of metabolic waste, suggesting an underlying mechanism linking sleep disturbances with neurodegenerative diseases. The selective α 2 -adrenergic agonist dexmedetomidine is a sedative drug that induces slow waves in the electroencephalogram, suppresses central noradrenergic tone, and preserves glymphatic outflow. As recently developed dexmedetomidine formulations enable self-administration, we suggest that dexmedetomidine could serve as a sedative-hypnotic drug to enhance clearance of harmful waste from the brain of those vulnerable to neurodegeneration. The brain clears itself of harmful metabolic waste through the glymphatic system to several egress routes, including the meningeal lymphatic vessels, and onward to cervical lymph nodes. In rodents, glymphatic flow declines in the awake state and increases with slow-wave activity in electroencephalography during non-rapid eye movement (NREM) sleep. Declining glymphatic function could be an underlying link between chronic sleep disturbance and neurodegeneration. Dexmedetomidine is a widely used and studied sedative agent that promotes NREM sleep in humans. Further, it has neuroprotective and anti-neuroinflammatory properties. In rodents, dexmedetomidine enhances the glymphatic clearance of intraparenchymal tracers from the rodent brain. Due to its mechanisms of action, safety, and ease of use through several noninvasive administration routes, dexmedetomidine should be studied as a self-administered sedative-hypnotic drug in outpatient care. It may be the best available sedative glymphatic enhancer and may prove to attenuate neurodegeneration in long-term use. [ABSTRACT FROM AUTHOR]

Focuses on the study published in the 'Proceedings of the National Academy of Science USA,' that suggests erythropoietin (EPO), recognized as a potent neuroprotective cytokine, as a potential treatment for spinal cord injury. Functional improvement made under the EPO treatment; Neuroprotective effects of EPO; Features of EPO.

The glymphatic concept along with the discovery of meningeal lymphatic vessels have, in recent years, highlighted that fluid is directionally transported within the central nervous system (CNS). Imaging studies, as well as manipulations of fluid transport, point to a key role of the glymphatic–lymphatic system in clearance of amyloid-β and other proteins. As such, the glymphatic–lymphatic system represents a new target in combating neurodegenerative diseases. Not unexpectedly, introduction of a new plumbing system in the brain has stirred controversies. This opinion article will highlight what we know about the brain's fluid transport systems, where experimental data are lacking, and what is still debated. Several global models of brain fluid transport have been proposed. When assessing these models, it is imperative that they are based on observations in live animals. Cerebrospinal fluid (CSF) tracer distribution in histological sections mostly reflects nonphysiological events triggered after death. The literature suggests that diffusion and convective flow both contribute to clearance of CNS solutes. Experiments that are aimed at defining the relative contribution of diffusion versus convection are difficult to interpret because minor changes in physiological variables, such as body posture or respiratory rate, can significantly affect both pathways. Invasive procedures, such as tracer injection, will primarily suppress convective flow. The glymphatic system drives CSF into the brain along periarterial spaces and interstitial fluid (ISF) out along perivenous spaces. Aquaporin-4 (AQP4) water channels, densely expressed at the vascular endfeet of astrocytes, facilitate glymphatic transport, based on all studies on this topic (with one exception). Glymphatic–lymphatic efflux of amyloid-β contributes to diurnal variations in amyloid-β concentration in murine Alzheimer's disease models and represents a potential therapeutic target for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111 In-radiolabelled gold nanoparticles (AuNPs; 10–15 nm) via intra- cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs. [Display omitted] • Brain access of intrathecally administered nanoparticles has been considered sparse. • Glymphatic-assisted CNS drug delivery has emerged as a new CNS drug delivery system. • We studied the brain distribution of 111In-labelled small gold nanoparticles (AuNPs). • Systemic hypertonic solution markedly increased brainwide AuNP delivery. • MRI of Gd-AuNPs visualizes their periarterial flow towards deep brain structures. [ABSTRACT FROM AUTHOR]

The central nervous system is lined by meninges, classically known as dura, arachnoid, and pia mater. We show the existence of a fourth meningeal layer that compartmentalizes the subarachnoid space in the mouse and human brain, designated the subarachnoid lymphatic-like membrane (SLYM). SLYM is morpho- and immunophenotypically similar to the mesothelial membrane lining of peripheral organs and body cavities, and it encases blood vessels and harbors immune cells. Functionally, the close apposition of SLYM with the endothelial lining of the meningeal venous sinus permits direct exchange of small solutes between cerebrospinal fluid and venous blood, thus representing the mouse equivalent of the arachnoid granulations. The functional characterization of SLYM provides fundamental insights into brain immune barriers and fluid transport. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) is an essential and critical component of the central nervous system (CNS). According to the concept of the "third circulation" originally proposed by Cushing, CSF is mainly produced by the choroid plexus and subsequently leaves the cerebral ventricles via the foramen of Magendie and Luschka. CSF then fills the subarachnoid space from whence it disperses to all parts of the CNS, including the forebrain and spinal cord. CSF provides buoyancy to the submerged brain, thus protecting it against mechanical injury. CSF is also transported via the glymphatic pathway to reach deep interstitial brain regions along perivascular channels; this CSF clearance pathway promotes transport of energy metabolites and signaling molecules, and the clearance of metabolic waste. In particular, CSF is now intensively studied as a carrier for the removal of proteins implicated in neurodegeneration, such as amyloid-β and tau. Despite this key function of CSF, there is little information about its production rate, the factors controlling CSF production, and the impact of diseases on CSF flux. Therefore, we consider it to be a matter of paramount importance to quantify better the rate of CSF production, thereby obtaining a better understanding of CSF dynamics. To this end, we now review the existing methods developed to measure CSF production, including invasive, noninvasive, direct, and indirect methods, and MRI-based techniques. Depending on the methodology, estimates of CSF production rates in a given species can extend over a ten-fold range. Throughout this review, we interrogate the technical details of CSF measurement methods and discuss the consequences of minor experimental modifications on estimates of production rate. Our aim is to highlight the gaps in our knowledge and inspire the development of more accurate, reproducible, and less invasive techniques for quantitation of CSF production. [ABSTRACT FROM AUTHOR]

The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: The classical view of cerebrospinal fluid (CSF) production posits the choroid plexus as its major source. Although previous studies indicate that part of CSF production occurs in the subarachnoid space (SAS), the mechanisms underlying extra-choroidal CSF production remain elusive. We here investigated the distributions of aquaporin 1 (AQP1) and Na+/K+/2Cl− cotransporter 1 (NKCC1), key proteins for choroidal CSF production, in the adult rodent brain and spinal cord. Methods: We have accessed AQP1 distribution in the intact brain using uDISCO tissue clearing technique and by Western blot. AQP1 and NKCC1 cellular localization were accessed by immunohistochemistry in brain and spinal cord obtained from adult rodents. Imaging was performed using light-sheet, confocal and bright field light microscopy. Results: We determined that AQP1 is widely distributed in the leptomeningeal vasculature of the intact brain and that its glycosylated isoform is the most prominent in different brain regions. Moreover, AQP1 and NKCC1 show specific distributions in the smooth muscle cell layer of penetrating arterioles and veins in the brain and spinal cord, and in the endothelia of capillaries and venules, restricted to the SAS vasculature. Conclusions: Our results shed light on the molecular framework that may underlie extra-choroidal CSF production and we propose that AQP1 and NKCC1 within the leptomeningeal vasculature, specifically at the capillary level, are poised to play a role in CSF production throughout the central nervous system. [ABSTRACT FROM AUTHOR]

Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brain-barrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used α 2 -adrenergic agonist dexmedetomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics. Unlabelled Image • The glymphatic system drives cerebrospinal fluid influx into brain tissue. • Glymphatic flow is increased by drugs that decrease brain noradrenergic tone. • Dexmedetomidine is a clinically used α 2 -adrenergic agonist sedative. • Dexmedetomidine increases the brain delivery of intrathecally administered drugs. • Glymphatic flow can be manipulated to enhance the CNS delivery of intrathecal therapeutics. [ABSTRACT FROM AUTHOR]

Cerebral small vessel diseases (SVDs) range broadly in etiology but share remarkably overlapping pathology. Features of SVD including enlarged perivascular spaces (EPVS) and formation of abluminal protein deposits cannot be completely explained by the putative pathophysiology. The recently discovered glymphatic system provides a new perspective to potentially address these gaps. This work provides a comprehensive review of the known factors that regulate glymphatic function and the disease mechanisms underlying glymphatic impairment emphasizing the role that aquaporin-4 (AQP4)-lined perivascular spaces (PVSs), cerebrovascular pulsatility, and metabolite clearance play in normal CNS physiology. This review also discusses the implications that glymphatic impairment may have on SVD inception and progression with the aim of exploring novel therapeutic targets and highlighting the key questions that remain to be answered. [ABSTRACT FROM AUTHOR]

Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems. [ABSTRACT FROM AUTHOR]

Microglia are involved in synaptic pruning both in development and in the mature CNS. In this study, we investigated whether microglia might further contribute to circuit plasticity by modulating neuronal recruitment from the neurogenic subventricular zone (SVZ) of the adult mouse striatum. We found that microglia residing in the SVZ and adjacent rostral migratory stream (RMS) comprise a morphologically and antigenically distinct phenotype of immune effectors. Whereas exhibiting characteristics of alternatively activated microglia, the SVZ/RMS microglia were clearly distinguished by their low expression of purinoceptors and lack of ATP-elicitable chemotaxis. Furthermore, the in vivo depletion of these microglia hampered the survival and migration of newly generated neuroblasts through the RMS to the olfactory bulb. SVZ and RMS microglia thus appear to comprise a functionally distinct class that is selectively adapted to the support and direction of neuronal integration into the olfactory circuitry. Therefore, this unique microglial subpopulation may serve as a novel target with which to modulate cellular addition from endogenous neural stem and progenitor cells of the adult brain. [ABSTRACT FROM AUTHOR]

Microglia constitute as much as 10-15% of all cells in the mammalian central nervous system (CNS) and are the only glial cells that do not arise from the neuroectoderm. As the principal CNS immune cells, microglial cells represent the first line of defence in response to exogenous threats. Past studies have largely been dedicated to defining the complex immune functions of microglial cells. However, our understanding of the roles of microglia has expanded radically over the past years. It is now clear that microglia are critically involved in shaping neural circuits in both the developing and adult CNS, and in modulating synaptic transmission in the adult brain. Intriguingly, microglial cells appear to use the same sets of tools, including cytokine and chemokine release aswell as phagocytosis, whether modulating neural function or mediating the brain's innate immune responses. This review will discuss recent developments that have broadened our views of neuro-glial signalling to include the contribution of microglial cells. [ABSTRACT FROM AUTHOR]

The presence of a glymphatic pathway in the optic nerve and the theory that a dysfunctional glymphatic system may be involved in the pathogenesis of glaucoma were first proposed by Wostyn et al. (2015). The central nervous system (CNS) is largely devoid of functional lymphatic vessels, apart from within the meningeal lining (Louveau et al. 2015). Can we develop diagnostic tracers to study this pathway in a clinical setting and modulate transport to delay or prevent optic nerve diseases like glaucoma?. [Extracted from the article]

Abstract: Activation of glial cells and neuro–glial interactions are emerging as key mechanisms underlying chronic pain. Accumulating evidence has implicated 3 types of glial cells in the development and maintenance of chronic pain: microglia and astrocytes of the central nervous system (CNS), and satellite glial cells of the dorsal root and trigeminal ganglia. Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. Although widely detected in chronic pain resulting from nerve trauma, inflammation, cancer, and chemotherapy in rodents, and more recently, human immunodeficiency virus-associated neuropathy in human beings, glial reaction (activation state 1) is not thought to mediate pain sensitivity directly. Instead, activation states 2 to 4 have been demonstrated to enhance pain sensitivity via a number of synergistic neuro–glial interactions. Glial mediators have been shown to powerfully modulate excitatory and inhibitory synaptic transmission at presynaptic, postsynaptic, and extrasynaptic sites. Glial activation also occurs in acute pain conditions, and acute opioid treatment activates peripheral glia to mask opioid analgesia. Thus, chronic pain could be a result of “gliopathy,” that is, dysregulation of glial functions in the central and peripheral nervous system. In this review, we provide an update on recent advances and discuss remaining questions. [Copyright &y& Elsevier]

Traumatic spinal cord injury is characterized by an immediate. irreversible loss of tissue at the lesion site, as well as a secondary expansion of tissue damage overtime. Although secondary injury should, in principle, be preventable, no effective treatment options currently exist for patients with acute spinal cord injury (Sd). Excessive release of ATP by the traumatized tissue, followed by activation of high-affinity P2X7 receptors, has previously been implicated in secondary injury, but no clinically relevant strategy by which to antagonize P2X7 receptors has yet, to the best of our knowledge, been reported. Here we have tested the neuroprotective effects of a systemically administered P2X7R antagonist, Brilliant blue G (BBG), in a weight-drop model of thoracic Sd in rats. Administration of BBG 15 mm after injury reduced spinal cord anatomic damage and improved motor recovery without evident toxicity. Moreover, BBG treatment directly reduced local activation of astrocytes and microglia, as well as neutrophil infiltration. These observations suggest that BBG not only protected spinal cord neurons from purinergic excitotoxicity, but also reduced local inflammatory responses. Importantly, BBG is a derivative of a commonly used blue food color (FD&C blue No. 1), which crosses the blood-brain barrier. Systemic administration of BBG may thus comprise a readily feasible approach by which to treat traumatic SCI in humans. [ABSTRACT FROM AUTHOR]

Summary: There is a paucity of therapies for most neurological disorders—from rare lysosomal storage diseases to major public health concerns such as stroke and Alzheimer''s disease. Advances in the targeting of drugs to the CNS are essential for the future success of neurotherapeutics; however, the delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by the blood–brain barrier, the blood–CSF barrier, or other specialised CNS barriers. These brain barriers are now recognised as a major obstacle to the treatment of most brain disorders. The challenge to deliver therapies to the CNS is formidable, and the solution will require concerted international efforts among academia, government, and industry. At a recent meeting of expert panels, essential and high-priority recommendations to propel brain barrier research forward in six topical areas were developed and these recommendations are presented here. [Copyright &y& Elsevier]

Protoplasmic astrocytes are critically important to energy metabolism in the CNS. Our current understanding of the metabolic interactions between neurons and glia is based on studies using cultured cells, from which mainly inferential conclusions have been drawn as to the relative roles of neurons and glia in brain metabolism. In this study, we used functional genomics to establish the relative compartmentalization of neuronal and astrocytic metabolic pathways in the adult brain. To this end, fluorescence-activated cell sorting was used to directly isolate neurons and protoplasmic astrocytes from the cortex of adult mice. Microarray analysis showed that astrocytes and neurons each express transcripts predicting individual self-sufficiency in both glycolysis and oxidative metabolism. Surprisingly, most enzymes in the tricarboxylic acid (TCA) cycle were expressed at higher relative levels in astrocytes than in neurons. Mass spectrometric analysis of the TCA cycle intermediates confirmed that freshly isolated adult astrocytes maintained an active TCA cycle, whereas immuno-electron microscopy revealed that fine astrocytic processes encompassing synapses contained a higher density of mitochondria than surrounding cells. These observations indicate that astrocytes exhibit robust oxidative metabolism in the intact adult brain and suggest a prominent contribution of astrocytic metabolism to functional brain imaging, including BOLD (blood-oxygen level-dependent) functional magnetic resonance imaging signals. [ABSTRACT FROM AUTHOR]

Abstract: Human embryonic stem (hES) cells may generate all major somatic cell types, yet no neuronal subtype has yet been specifically generated in useful purity from hES culture. We report here the selective induction and isolation of functional spinal motor neurons (MNs) from human ES cells. hES cells of the H1 line were transfected with plasmids encoding GFP placed under the control of an MN-specifying enhancer within the 5′-regulatory region of the gene encoding the transcription factor Hb9 and treated with sonic hedgehog (Shh) and retinoic acid (RA). As MNs were induced under the influence of Shh and RA, they activated Hb9-driven GFP expression, permitting their isolation by fluorescence-activated cell sorting (FACS). The MNs thereby generated and isolated became cholinergic and achieved functional maturation in vitro, as evidenced by their fast sodium currents and action potentials on whole-cell patch-clamp and α-bungarotoxin-identified clustering of AChR receptors on co-cultured skeletal myoblasts. The serial combination of these two approaches, motor neuron phenotypic induction followed by Hb9 enhancer-based FACS, permitted the high-efficiency induction and isolation of functional motor neurons from hES cells. These results suggest the utility of promoter/enhancer-based FACS for the isolation of specific phenotypes from hES cell populations as a means of purifying clinically appropriate vectors for cell therapy. [Copyright &y& Elsevier]