Postulated Role of Vasoactive Neuropeptide‐Related Immunopathology of the Blood Brain Barrier and Virchow‐Robin Spaces in the Aetiology of Neurological‐Related Conditions

Staines, Donald; Brenu, Ekua; Marshall‐Gradisnik, Sonya

doi:10.1155/2008/792428

Cited by 11 publications

(5 citation statements)

References 44 publications

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“…Other vasodilatory peptides, such as adrenomedullin, which causes vasodilation in the cerebral circulation, have been suggested to play an important role in the regulation of specific BBB properties as endothelium-derived autocrine/paracrine hormones [ 64 , 65 ]. Vasodilation is likely to increase BBB permeability [ 66 ]. The vasodilatory actions of VIP and PACAP in brain arteries have been demonstrated in the context of migraine.…”

Section: Discussionmentioning

confidence: 99%

VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage

Abad

Jayaram

Becquet

et al. 2016

J Neuroinflammation

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BackgroundVasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) are two highly homologous neuropeptides. In vitro and ex vivo experiments repeatedly demonstrate that these peptides exert pronounced immunomodulatory (primarily anti-inflammatory) actions which are mediated by common VPAC1 and VPAC2 G protein-coupled receptors. In agreement, we have shown that mice deficient in PACAP ligand or VPAC2 receptors exhibit exacerbated experimental autoimmune encephalomyelitis (EAE). However, we observed that VIP-deficient mice are unexpectedly resistant to EAE, suggesting a requirement for this peptide at some stage of disease development. Here, we investigated the involvement of VPAC1 in the development of EAE using a VPAC1-deficient mouse model.MethodsEAE was induced in wild-type (WT) and VPAC1 knockout (KO) mice using myelin oligodendrocyte glycoprotein 35–55 (MOG35–55), and clinical scores were assessed continuously over 30 days. Immune responses in the spinal cords were determined by histology, real-time PCR and immunofluorescence, and in the draining lymph nodes by antigen-recall assays. The contribution of VPAC1 expression in the immune system to the development of EAE was evaluated by means of adoptive transfer and bone marrow chimera experiments. In other experiments, VPAC1 receptor analogs were given to WT mice.ResultsMOG35–55-induced EAE was ameliorated in VPAC1 KO mice compared to WT mice. The EAE-resistant phenotype of VPAC1 KO mice correlated with reduced central nervous system (CNS) histopathology and cytokine expression in the spinal cord. The immunization phase of EAE appeared to be unimpaired because lymph node cells from EAE-induced VPAC1 KO mice stimulated in vitro with MOG exhibited robust proliferative and Th1/Th17 responses. Moreover, lymph node and spleen cells from KO mice were fully capable of inducing EAE upon transfer to WT recipients. In contrast, WT cells from MOG-immunized mice did not transfer the disease when administered to VPAC1 KO recipients, implicating a defect in the effector phase of the disease. Bone marrow chimera studies suggested that the resistance of VPAC1-deficient mice was only minimally dependent on the expression of this receptor in the immunogenic/hematopoietic compartment. Consistent with this, impaired spinal cord inductions of several chemokine mRNAs were observed in VPAC1 KO mice. Finally, treatment of WT mice with the VPAC1 receptor antagonist PG97-269 before, but not after, EAE induction mimicked the clinical phenotype of VPAC1 KO mice.ConclusionsVPAC1 gene loss impairs the development of EAE in part by preventing an upregulation of CNS chemokines and invasion of inflammatory cells into the CNS. Use of VPAC1 antagonists in WT mice prior to EAE induction also support a critical role for VPAC1 signaling for the development of EAE.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0626-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage

Abad

Jayaram

Becquet

et al. 2016

J Neuroinflammation

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“…Our finding that the ALG1 gene is highly upregulated by all three strains is in agreement with those previous findings. In addition, the finding that VIPR2 is modulated by all strains is quite interesting in terms of the postulated importance of VIP/PACAP in human brain diseases and its role in GABAergic transmission and possible role in schizophrenia (9,19,49). The finding that TAS2R39, a gene which encodes a taste receptor, is differentially regulated is also of potential interest.…”

Section: Discussionmentioning

confidence: 98%

Differential Effects of Three CanonicalToxoplasmaStrains on Gene Expression in Human Neuroepithelial Cells

Xiao¹,

Jones‐Brando²,

Talbot³

et al. 2011

Infect Immun

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Strain type is one of the key factors suspected to play a role in determining the outcome of Toxoplasma infection. In this study, we examined the transcriptional profile of human neuroepithelioma cells in response to representative strains of Toxoplasma by using microarray analysis to characterize the strain-specific host cell response. The study of neural cells is of interest in light of the ability of Toxoplasma to infect the brain and to establish persistent infection within the central nervous system. We found that the extents of the expression changes varied considerably among the three strains. Neuroepithelial cells infected with Toxoplasma type I exhibited the highest level of differential gene expression, whereas type II-infected cells had a substantially smaller number of genes which were differentially expressed. Cells infected with type III exhibited intermediate effects on gene expression. The three strains also differed in the individual genes and gene pathways which were altered following cellular infection. For example, gene ontology (GO) analysis indicated that type I infection largely affects genes related to the central nervous system, while type III infection largely alters genes which affect nucleotide metabolism; type II infection does not alter the expression of a clearly defined set of genes. Moreover, Ingenuity Pathways Analysis (IPA) suggests that the three lineages differ in the ability to manipulate their host; e.g., they employ different strategies to avoid, deflect, or subvert host defense mechanisms. These observed differences may explain some of the variation in the neurobiological effects of different strains of Toxoplasma on infected individuals.

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“…Thus, the USPIO‐SWI method could be an ideal imaging modality for studying the human glymphatic system if its detection sensitivity can be increased. Moreover, tube‐shaped PVSs are responsible for exchanges between interstitial fluid and cerebrospinal fluid, and play an important role in immunoregulation and signal transmission by a constant flux of waste, macrophages, and vasoactive neuropeptides . Clinically, PVS dilation and lacunar strokes are the most commonly observed histological correlates of signaling abnormalities .…”

Section: Discussionmentioning

confidence: 99%

The capability of detecting small vessels beyond the conventional MRI sensitivity using iron‐based contrast agent enhanced susceptibility weighted imaging

et al. 2020

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Imaging brain microvasculature is important in cerebrovascular diseases. However, there is still a lack of non-invasive, non-radiation, and whole-body imaging techniques to investigate them. The aim of this study is to develop an ultra-small superparamagnetic iron oxide (USPIO) enhanced susceptibility weighted imaging (SWI) method for imaging micro-vasculature in both animal (~10 μm in rat) and human brain. We hypothesized that the USPIO-SWI technique could improve the detection sensitivity of the diameter of small subpixel vessels 10-fold compared with conventional MRI methods.Computer simulations were first performed with a double-cylinder digital model to investigate the theoretical basis for this hypothesis. The theoretical results were verified using in vitro phantom studies and in vivo rat MRI studies (n = 6) with corresponding ex vivo histological examinations. Additionally, in vivo human studies (n = 3) were carried out to demonstrate the translational power of the USPIO-SWI method.By directly comparing the small vessel diameters of an in vivo rat using USPIO-SWI with the small vessel diameters of the corresponding histological slide using laser scanning confocal microscopy, 13.3-fold and 19.9-fold increases in SWI apparent diameter were obtained with 5.6 mg Fe/kg and 16.8 mg Fe/kg ferumoxytol, respectively. The USPIO-SWI method exhibited its excellent ability to detect small vessels down to about 10 μm diameter in rat brain. The in vivo human study unveiled hidden arterioles and venules and demonstrated its potential in clinical practice. Theoretical modeling simulations and in vitro phantom studies also confirmed a more than 10-fold increase in the USPIO-SWI apparent diameter compared with the actual small vessel diameter size.It is feasible to use SWI blooming effects induced by USPIO to detect small vessels (down to 10 μm in diameter for rat brain), well beyond the spatial resolution limit of conventional MRI methods. The USPIO-SWI method demonstrates higher potential in cerebrovascular disease investigations.Abbreviations: 3D, three dimensional; CA, contrast agent; CNR, contrast-to-noise ratio; FITC-dextran, fluorescein isothiocyanate-dextran; FOV, field of view; IV, intravenous; LSCM, laser scanning confocal microscopy; MRA, magnetic resonance angiography; PVS, para-vascular space; SNR, signal-to-noise ratio; SWI, susceptibility weighted imaging; T 2 *W, T 2 * weighted; USPIO, ultra-small superparamagnetic iron oxide; Δχ, susceptibility difference of adjacent materials.

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Postulated Role of Vasoactive Neuropeptide‐Related Immunopathology of the Blood Brain Barrier and Virchow‐Robin Spaces in the Aetiology of Neurological‐Related Conditions

Cited by 11 publications

References 44 publications

VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage

VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage

Differential Effects of Three CanonicalToxoplasmaStrains on Gene Expression in Human Neuroepithelial Cells

The capability of detecting small vessels beyond the conventional MRI sensitivity using iron‐based contrast agent enhanced susceptibility weighted imaging

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