scholarly journals Neurotropic Lineage III Strains of Listeria monocytogenes Disseminate to the Brain without Reaching High Titer in the Blood

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Taylor E. Senay ◽  
Jessica L. Ferrell ◽  
Filip G. Garrett ◽  
Taylor M. Albrecht ◽  
Jooyoung Cho ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Mouse Model ◽  
Brain Stem ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Neurological Deficits ◽  
Content Type ◽  
Phylogenetic Lineage ◽  
Blood Brain ◽  
The Brain

ABSTRACT Listeria monocytogenes is thought to colonize the brain using one of three mechanisms: direct invasion of the blood-brain barrier, transportation across the barrier by infected monocytes, and axonal migration to the brain stem. The first two pathways seem to occur following unrestricted bacterial growth in the blood and thus have been linked to immunocompromise. In contrast, cell-to-cell spread within nerves is thought to be mediated by a particular subset of neurotropic L. monocytogenes strains. In this study, we used a mouse model of foodborne transmission to evaluate the neurotropism of several L. monocytogenes isolates. Two strains preferentially colonized the brain stems of BALB/cByJ mice 5 days postinfection and were not detectable in blood at that time point. In contrast, infection with other strains resulted in robust systemic infection of the viscera but no dissemination to the brain. Both neurotropic strains (L2010-2198, a human rhombencephalitis isolate, and UKVDL9, a sheep brain isolate) typed as phylogenetic lineage III, the least characterized group of L. monocytogenes. Neither of these strains encodes InlF, an internalin-like protein that was recently shown to promote invasion of the blood-brain barrier. Acute neurologic deficits were observed in mice infected with the neurotropic strains, and milder symptoms persisted for up to 16 days in some animals. These results demonstrate that neurotropic L. monocytogenes strains are not restricted to any one particular lineage and suggest that the foodborne mouse model of listeriosis can be used to investigate the pathogenic mechanisms that allow L. monocytogenes to invade the brain stem. IMPORTANCE Progress in understanding the two naturally occurring central nervous system (CNS) manifestations of listeriosis (meningitis/meningoencephalitis and rhombencephalitis) has been limited by the lack of small animal models that can readily distinguish between these distinct infections. We report here that certain neurotropic strains of Listeria monocytogenes can spread to the brains of young otherwise healthy mice and cause neurological deficits without causing a fatal bacteremia. The novel strains described here fall within phylogenetic lineage III, a small collection of L. monocytogenes isolates that have not been well characterized to date. The animal model reported here mimics many features of human rhombencephalitis and will be useful for studying the mechanisms that allow L. monocytogenes to disseminate to the brain stem following natural foodborne transmission.

scholarly journals Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 909
Author(s):  
Yurii A. Zolotarev ◽  
Vladimir A. Mitkevich ◽  
Stanislav I. Shram ◽  
Alexei A. Adzhubei ◽  
Anna P. Tolstova ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Mouse Model ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Laboratory Animals ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Bolus Administration ◽  
Blood Brain ◽  
The Brain

One of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35–38 region of the α4 subunit of α4β2 nicotinic acetylcholine receptor and specifically binds to the 11–14 site of Aβ, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood–brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aβ species directly in the brain.

Quantitative autoradiographic measurements of blood-brain barrier permeability in the rat glioma model

1982 ◽  
Vol 57 (3) ◽  
pp. 394-398 ◽  
Author(s):  
Kazuo Yamada ◽  
Yukitaka Ushio ◽  
Toru Hayakawa ◽  
Amami Kato ◽  
Noriko Yamada ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Chemotherapeutic Drugs ◽  
Content Type ◽  
Rat Glioma ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Bbb Permeability ◽  
Autoradiographic Technique ◽  
The Brain

✓ Quantitative autoradiographic technique was applied in measuring blood-brain barrier (BBB) permeability of autochthonous gliomas in rats. In small tumors (less than 2 mm in diameter), no increase in BBB permeability was noted. As the tumor grew and neovascularization occurred, BBB permeability increased in the center of the tumor, and it was suggested that the BBB was partly disrupted in the neovascularized vessels. In the fully grown tumors, BBB permeability was markedly increased in the viable part of the tumor to levels similar to the choroid plexus. Yet, the BBB was partly preserved at the periphery of the tumor and in the brain adjacent to the tumor. The heterogeneity of the BBB phenomenon according to the stage of tumor growth may be a major obstacle for uptake of chemotherapeutic drugs that do not cross the BBB easily.

scholarly journals Systemic Immune Deficiency Necessary for Cytomegalovirus Invasion of the Mature Brain

2004 ◽  
Vol 78 (3) ◽  
pp. 1473-1487 ◽  
Author(s):  
Jon D. Reuter ◽  
Daniel L. Gomez ◽  
Jean H. Wilson ◽  
Anthony N. van den Pol
Keyword(s):  
Blood Brain Barrier ◽  
Mononuclear Cells ◽  
Regional Distribution ◽  
Brain Barrier ◽  
Neurological Deficits ◽  
Ependymal Cells ◽  
Cns Infection ◽  
Immunodeficient Mice ◽  
Blood Brain ◽  
The Brain

ABSTRACT Cytomegalovirus (CMV) is a significant opportunistic pathogen associated with AIDS and immunosuppressive therapy. Infection of the mature central nervous system (CNS) can cause significant pathology with associated neurological deficits, mental disorders, and cognitive impairment and may have potentially fatal consequences. Using genetically immunocompromised mice, we studied mechanisms of CMV invasion into, and behavior within, the CNS. Adult immunodeficient (nude and SCID) and control mice were peripherally infected with recombinant mouse CMV expressing a green fluorescent protein reporter gene. Control mice actively eliminated acute peripheral infection and were resistant to invasion of CMV into the brain. In contrast, virus infected brains of immunodeficient mice but only after a minimum of 21 days postinoculation. After inoculation, CMV was found in circulating leukocytes (MAC-3/CD45+) and in leukocytes within the brain, suggesting these cells as a possible source of CMV entry into the CNS. CNS infection was observed in many different cell types, including neurons, glial cells, meninges, ependymal cells, and cells of cerebral vessels. Infection foci progressively expanded locally to adjacent cells, resulting in meningitis, choroiditis, encephalitis, vasculitis, and necrosis; clear indication of axonal transport of CMV was not found. Regional distribution of CMV was unique in each brain, consisting of randomly distributed, unilateral foci. Testing whether CMV gained access to brain through nonspecific vascular disruption, vascular injections of a tracer molecule revealed no obvious disruption of the blood brain barrier in mice with CMV in the brain. Results indicate the importance of host adaptive immunity (particularly T cells) in controlling entry and dissemination of CMV into the brain and are consistent with the view that virus may be carried into the brain by circulating mononuclear cells that traffic through the blood brain barrier.

Disruption of the blood-brain barrier in cerebrum and brain stem during acute hypertension

1986 ◽  
Vol 251 (6) ◽  
pp. H1171-H1175 ◽  
Author(s):  
W. G. Mayhan ◽  
F. M. Faraci ◽  
D. D. Heistad
Keyword(s):  
Arterial Pressure ◽  
Brain Stem ◽  
Blood Brain Barrier ◽  
Venous Pressure ◽  
Fluorescent Microscopy ◽  
Systemic Arterial Pressure ◽  
Brain Barrier ◽  
Acute Hypertension ◽  
Blood Brain ◽  
The Brain

The purpose of this study was to examine hemodynamic mechanisms of protection of the blood-brain barrier in the brain stem during acute hypertension. We used a new method to examine the microcirculation of the brain stem. Intravital fluorescent microscopy and fluorescein-labeled dextran were used to evaluate disruption of the blood-brain barrier during acute hypertension in rats. During control conditions, pressure (servo null) in arterioles (60 microns in diameter) was 50 +/- 2% (mean +/- SE) of systemic arterial pressure in the cerebrum and 67 +/- 1% of systemic arterial pressure in the brain stem (P less than 0.05 vs. cerebrum). In the cerebrum, pial venous pressure increased from 7 +/- 1 to 25 +/- 2 mmHg during acute hypertension, and there was marked disruption of the blood-brain barrier in venules (26 +/- 2 leaky sites). In contrast, in the brain stem, pial venous pressure increased from 4 +/- 1 to only 8 +/- 1 mmHg (P less than 0.05 vs. cerebrum), and there was minimal disruption of the blood-brain barrier in venules (1.5 +/- 0.6 leaky sites, P less than 0.05 vs. cerebrum). During acute hypertension, increases in blood flow (microspheres) were less in brain stem than in cerebrum. The findings suggest distribution of vascular resistance differs in the brain stem and cerebrum under control conditions, whereas large arteries account for a greater fraction of resistance in cerebrum; pial venous pressure increases less in brain stem than cerebrum during acute hypertension, so that the blood-brain barrier is protected.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity of brain blood flow and permeability during acute hypertension

1985 ◽  
Vol 249 (3) ◽  
pp. H629-H637 ◽  
Author(s):  
G. L. Baumbach ◽  
D. D. Heistad
Keyword(s):  
Blood Flow ◽  
Brain Stem ◽  
Blood Brain Barrier ◽  
Regional Differences ◽  
Severe Hypertension ◽  
Brain Barrier ◽  
Acute Hypertension ◽  
Blood Brain ◽  
The Brain ◽  
Increased Blood Flow

The purpose of this study was to examine regional autoregulation of blood flow in the brain during acute hypertension. In anesthetized cats severe hypertension increased blood flow more in cerebrum (159%) and cerebellum (106%) than brain stem (58%). In contrast to the heterogeneous autoregulatory response, hypocapnia produced uniform vasoconstriction in the brain. We also compared vasodilatation during severe hypertension with vasodilatation during hypercapnia. During hypercapnia, blood flow increased as much in brain stem, as in cerebrum and cerebellum. Thus regional differences in autoregulation appear to be specific for autoregulatory stimulus and are not secondary to nonspecific differences in vasoconstrictor or vasodilator capacity. To determine whether the blood-brain barrier is more susceptible to hypertensive disruption in regions with less effective autoregulation, permeability of the barrier was quantitated with 125I-albumin. Severe hypertension produced disruption of the barrier in cerebrum but not in brain stem. Thus there are parallel differences in effectiveness of autoregulation and susceptibility to disruption of the blood-brain barrier in different regions of the brain.

scholarly journals SCIDOT-14. ENHANCING BRAIN RETENTION OF A KIF11 INHIBITOR SIGNIFICANTLY IMPROVES ITS EFFICACY IN A MOUSE MODEL OF GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi274-vi274
Author(s):  
Gautham Gampa ◽  
Rajappa Kenchappa ◽  
Afroz Mohammad ◽  
Karen Parrish ◽  
Minjee Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Blood Brain ◽  
Clinical Investigations ◽  
Molecule Inhibitor ◽  
Cellular Components ◽  
The Brain

Abstract Glioblastoma, the most common and lethal of brain tumors, is both highly invasive and proliferative. This allows tumor cells to infiltrate into regions of the brain with an intact blood brain barrier and be protected from effective therapeutics. Thus, an ideal glioblastoma therapy needs to target cellular components that drive both invasion and proliferation, with inhibitors that penetrate the blood brain barrier. The mitotic kinesin KIF11 meets these criteria and it can be targeted with ispinesib, a highly specific small molecule inhibitor. However, to be effective, ispinesib needs to cross the blood brain barrier and be retained within brain long enough to target glioblastoma cells when they are vulnerable, during mitosis.. We have examined the factors that affect distribution of ispinesib to both brain and glioblastoma. We find that delivery of ispinesib is limited by P-gp and Bcrp-mediated drug efflux at the blood brain barrier. Consequently, ispinesib levels are significantly lower in the infiltrative tumor margin relative to the tumor core, where the blood brain barrier is defective. We also show that elacridar—an inhibitor of the P-gp and Brcp efflux transporters—enhances delivery of ispinesib, and that co-administration of ispinesib with elacridar markedly slows tumor proliferation and prolongs survival in a mouse model of this disease. These results demonstrate the feasibility and efficacy of combining a potentially ideal therapeutic with a compound that enhances brain retention of this therapeutic, and provides support for utilizing this approach in clinical investigations of KIF11 inhibitors in GBM.

scholarly journals Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

2013 ◽  
Vol 57 (9) ◽  
pp. 4336-4342 ◽  
Author(s):  
Liang Jin ◽  
Roger L. Nation ◽  
Jian Li ◽  
Joseph A. Nicolazzo
Keyword(s):  
Blood Brain Barrier ◽  
Bacterial Species ◽  
Specific Effect ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Blood Brain ◽  
The Impact ◽  
The Brain

ABSTRACTThe aim of this study was to usein vitroandin vivomodels to assess the impact of lipopolysaccharide (LPS) from two different bacterial species on blood-brain barrier (BBB) integrity and brain uptake of colistin. Following repeated administration of LPS fromPseudomonas aeruginosa, the brain-to-plasma ratio of [14C]sucrose in Swiss outbred mice was not significantly increased. Furthermore, while the brain uptake of colistin in mice increased 3-fold following administration of LPS fromSalmonella enterica, LPS fromP. aeruginosahad no significant effect on colistin brain uptake. This apparent species-dependent effect did not appear to correlate with differences in plasma cytokine levels, as the concentrations of tumor necrosis factor alpha and interleukin-6 following administration of each LPS were not different (P> 0.05). To clarify whether this species-specific effect of LPS was due to direct effects on the BBB, human brain capillary endothelial (hCMEC/D3) cells were treated with LPS fromP. aeruginosaorS. entericaand claudin-5 expression was measured by Western blotting.S. entericaLPS significantly (P< 0.05) reduced claudin-5 expression at a concentration of 7.5 μg/ml. In contrast,P. aeruginosaLPS decreased (P< 0.05) claudin-5 expression only at the highest concentration tested (i.e., 30 μg/ml). Coadministration of therapeutic concentrations of colistin ameliorated theS. entericaLPS-induced reduction in claudin-5 expression in hCMEC/D3 cells and the perturbation in BBB function in mice. This study demonstrates that BBB disruption induced by LPS is species dependent, at least betweenP. aeruginosaandS. enterica, and can be ameliorated by colistin.

Blood—brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain

2004 ◽  
Vol 101 (2) ◽  
pp. 303-309 ◽  
Author(s):  
David Yarnitsky ◽  
Yossi Gross ◽  
Adi Lorian ◽  
Alon Shalev ◽  
Itschak Lamensdorf ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Sphenopalatine Ganglion ◽  
Parasympathetic Innervation ◽  
Content Type ◽  
Blood Brain ◽  
The Brain ◽  
Fine Print ◽  
Stimulation Of

Object. Drug delivery across the blood—brain barrier remains a significant challenge. Based on earlier findings, the authors hypothesized that parasympathetic innervation of the brain vasculature could be used to augment drug delivery to the brain. Methods. Using a craniotomy—cerebrospinal fluid superfusate paradigm in rats with an intravenous injection of tracer the authors demonstrated that stimulation of the postganglionic parasympathetic fibers of the sphenopalatine ganglion (SPG) increased the concentration of fluorescein isothiocyanate—dextran (4–250 kD) in the superfusate by two- to sixfold. A histological examination indicated the presence of dextran in the parenchyma. In another experiment the amount of Evans blue dye in the brain following SPG activation was similarly significantly elevated. The chemotherapeutic agents anti-HER2 monoclonal antibody and etoposide were also delivered to the brain and reached therapeutic concentrations. Brain homeostasis was not disturbed by this procedure; a measurement of nicotinamide adenine dinucleotide reduction did not show a decrease in the tissue metabolic state and brain water content did not increase significantly. Conclusions. Sphenopalatine ganglion activation demonstrates a promising potential for clinical use in the delivery of small and large molecules to the brain.

scholarly journals The Primary Target Organ of Cryptococcus gattii Is Different from That of Cryptococcus neoformans in a Murine Model

mBio ◽  
2012 ◽  
Vol 3 (3) ◽  
Author(s):  
Popchai Ngamskulrungroj ◽  
Yun Chang ◽  
Edward Sionov ◽  
Kyung J. Kwon-Chung
Keyword(s):  
Cryptococcus Neoformans ◽  
Blood Brain Barrier ◽  
Opportunistic Pathogen ◽  
Lung Infection ◽  
Cryptococcus Gattii ◽  
Brain Barrier ◽  
Hiv Patients ◽  
Content Type ◽  
Blood Brain ◽  
The Brain

ABSTRACTCryptococcosis is caused by the opportunistic pathogenCryptococcus neoformansor by the primary pathogenCryptococcus gattii. Epidemiological studies suggest that patients infected withC. gattiimainly present with pulmonary disease, while those infected withC. neoformanscommonly manifest meningoencephalitis. We compared the pathogenesis of the two species using theC. neoformansH99 andC. gattiiR265 strains in a murine inhalation model.C. neoformansgrew faster in the brain and caused death by meningoencephalitis, whileC. gattiigrew faster in the lungs and caused death without producing fulminating meningoencephalitis. Despite the consistent failure to recover R265 cells from blood, a fraction of the R265 population was detected in the extrapulmonary organs, including the brain. Upon intravenous (i.v. ) inoculation of 104cells via the tail vein, however,C. gattiiproduced severe meningoencephalitis, demonstrating thatC. gattiicells can efficiently cross the blood-brain barrier. Interestingly, i.v. inoculation with five cells caused brain infection in only 10% ofC. gattii-infected mice, compared to 60% of mice infected withC. neoformans. In mice that had been initially inoculated via the pulmonary route and subsequently challenged intravenously, a protective effect was observed only in mice infected withC. gattii.C. neoformanscells grew 10 to 100 times faster thanC. gattiicells in blood or serum collected from naive mice. The paucity of meningoencephalitis upon inhalation ofC. gattii, therefore, may be partly due to an unknown factor(s) in the host’s blood coupled with immune protection that reduces dissemination to the brain and fosters lung infection.IMPORTANCEWhileCryptococcus neoformansis the most common cause of fatal meningoencephalitis, especially in HIV patients,Cryptococcus gattiicauses disease mainly in non-HIV patients. Clinical studies revealed that most patients infected withC. gattiiVGII strains have lung infections with minimal brain involvement. Despite extensive clinicopathological studies on cryptococcosis in animal models, only a few have includedC. gattii. We compared the pathogenesis of the two species in mice using an inhalation model. Similar to infection in humans, even thoughC. gattiican cross the blood-brain barrier, it failed to cause fatal meningoencephalitis but caused fatal lung infection. We show that growth ofC. gattiiin mouse blood is significantly slower than that ofC. neoformansand that a secondary protective phenomenon, though weak, manifests itself only inC. gattiiinfection. Our study provides a model for understanding the clinicopathological differences between these two closely genetically related pathogens.

scholarly journals In VitroandIn VivoEvidence for Amphotericin B as a P-Glycoprotein Substrate on the Blood-Brain Barrier

2014 ◽  
Vol 58 (8) ◽  
pp. 4464-4469 ◽  
Author(s):  
Ji-Qin Wu ◽  
Kun Shao ◽  
Xuan Wang ◽  
Rui-Ying Wang ◽  
Ya-Hui Cao ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Blood Brain Barrier ◽  
Fungal Infections ◽  
Brain Barrier ◽  
Content Type ◽  
P Glycoprotein ◽  
Blood Brain ◽  
The Impact ◽  
The Brain

ABSTRACTAmphotericin B (AMB) has been a mainstay therapy for fungal infections of the central nervous system, but its use has been limited by its poor penetration into the brain, the mechanism of which remains unclear. In this study, we aimed to investigate the role of P-glycoprotein (P-gp) in AMB crossing the blood-brain barrier (BBB). The uptake of AMB by primary brain capillary endothelial cellsin vitrowas significantly enhanced after inhibition of P-gp by verapamil. The impact of two model P-gp inhibitors, verapamil and itraconazole, on brain/plasma ratios of AMB was examined in both uninfected CD-1 mice and those intracerebrally infected withCryptococcus neoformans. In uninfected mice, the brain/plasma ratios of AMB were increased 15 min (3.5 versus 2.0;P< 0.05) and 30 min (5.2 versus 2.8;P< 0.05) after administration of verapamil or 45 min (6.0 versus 3.9;P< 0.05) and 60 min (5.4 versus 3.8;P< 0.05) after itraconazole administration. The increases in brain/plasma ratios were also observed in infected mice treated with AMB and P-gp inhibitors. The brain tissue fungal CFU in infected mice were significantly lower in AMB-plus-itraconazole or verapamil groups than in the untreated group (P< 0.005), but none of the treatments protected the mice from succumbing to the infection. In conclusion, we demonstrated that P-gp inhibitors can enhance the uptake of AMB through the BBB, suggesting that AMB is a P-gp substrate.

Sign in / Sign up

Export Citation Format

Share Document