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      Novel therapeutics for hydrocephalus: Insights from animal models

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          Abstract

          Hydrocephalus is a cerebrospinal fluid physiological disorder that causes ventricular dilation with normal or high intracranial pressure. The current regular treatment for hydrocephalus is cerebrospinal fluid shunting, which is frequently related to failure and complications. Meanwhile, considering that the current nonsurgical treatments of hydrocephalus can only relieve the symptoms but cannot eliminate this complication caused by primary brain injuries, the exploration of more effective therapies has become the focus for many researchers. In this article, the current research status and progress of nonsurgical treatment in animal models of hydrocephalus are reviewed to provide new orientations for animal research and clinical practice.

          Abstract

          Inflammation, fibrosis, iron overload, etc., play an important role in the development of hydrocephalus. By targeting these mechanisms, researchers have discovered a series of drugs that have therapeutic effects on hydrocephalus.

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          A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

          Jeffrey J. Iliff, Minghuan Wang, Yonghong Liao … (2012)
          Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
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            Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases

            Changshun Shao, Keli Liu, Qing Li … (2018)
            Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn's disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.
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              The Glymphatic System: A Beginner's Guide.

              Nadia Jessen, Anne Sofie Finmann Munk, Iben Lundgaard … (2015)
              The glymphatic system is a recently discovered macroscopic waste clearance system that utilizes a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system. Besides waste elimination, the glymphatic system also facilitates  brain-wide distribution of several compounds, including glucose, lipids, amino acids, growth factors, and neuromodulators. Intriguingly, the glymphatic system function mainly during sleep and is largely disengaged during wakefulness. The biological need for sleep across all species may therefore reflect that the brain must enter a state of activity that enables elimination of potentially neurotoxic waste products, including β-amyloid. Since the concept of the glymphatic system is relatively new, we will here review its basic structural elements, organization, regulation, and functions. We will also discuss recent studies indicating that glymphatic function is suppressed in various diseases and that failure of glymphatic function in turn might contribute to pathology in neurodegenerative disorders, traumatic brain injury and stroke.
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                Author and article information

                Contributors
                Gelei Xiao:
                ORCID: https://orcid.org/0000-0001-9234-0595
                xiaogelei@csu.edu.cn
                Journal
                Journal ID (nlm-ta): CNS Neurosci Ther
                Journal ID (iso-abbrev): CNS Neurosci Ther
                Journal ID (doi): 10.1111/(ISSN)1755-5949
                Journal ID (publisher-id): CNS
                Title: CNS Neuroscience & Therapeutics
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1755-5930
                ISSN (Electronic): 1755-5949
                Publication date (Electronic): 20 June 2021
                Publication date Collection: September 2021
                Volume: 27
                Issue: 9 ( doiID: 10.1002/cns.v27.9 )
                Pages: 1012-1022
                Affiliations
                [ 1 ] Department of Neurosurgery Xiangya Hospital Central South University Changsha Hunan China
                [ 2 ] Diagnosis and Treatment Center for Hydrocephalus Xiangya Hospital Central South University Changsha Hunan China
                [ 3 ] National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University Changsha Hunan China
                [ 4 ] Department of Pediatric Neurosurgery Xinhua Hospital Shanghai Jiaotong University School of Medicine Shanghai China
                [ 5 ] Department of Neurosurgery Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine Central South University Changsha Hunan China
                Author notes
                [*] [* ] Correspondence

                Gelei Xiao, Department of Neurosurgery, Xiangya Hospital, Central South University, No.87, Xiangya Road, Changsha, Hunan 410008, China.

                Email: xiaogelei@ 123456csu.edu.cn

                Author information
                https://orcid.org/0000-0001-9234-0595
                Article
                Publisher ID: CNS13695
                DOI: 10.1111/cns.13695
                PMC ID: 8339528
                PubMed ID: 34151523
                SO-VID: 2dfc1c4f-6137-42d5-80c7-99cdabdb8820
                Copyright statement: © 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date revision received : 09 May 2021
                Date received : 16 February 2021
                Date accepted : 02 June 2021
                Page count
                Figures: 2, Tables: 1, Pages: 11, Words: 9327
                Product
                Funding
                Funded by: Students Innovations in Central South University of China
                Award ID: S2020105330446
                Award ID: S2020105330521
                Funded by: Hunan Provincial Health Commission of China
                Award ID: B2019187
                Funded by: Natural Science Foundation of Hunan Province
                Award ID: 2019JJ50949
                Categories
                Subject: Review Article
                Subject: Review Articles
                Custom metadata
                source-schema-version-number 2.0
                cover-date September 2021
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:05.08.2021

                ScienceOpen disciplines: Neurosciences
                Keywords: animal models,cerebrospinal fluid,hydrocephalus,nonsurgical treatment,subarachnoid space
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: animal models, cerebrospinal fluid, hydrocephalus, nonsurgical treatment, subarachnoid space

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