scholarly journals Interaction of Cucurbit[7]uril with Oxime K027, Atropine, and Paraoxon: Risky or Advantageous Delivery System?

2020 ◽  
Vol 21 (21) ◽  
pp. 7883
Author(s):  
Jana Zdarova Karasova ◽  
Martin Mzik ◽  
Tomas Kucera ◽  
Zbynek Vecera ◽  
Jiri Kassa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Delivery System ◽  
Treatment Effectiveness ◽  
Free Fraction ◽  
Umbrella Sampling ◽  
Potential Risks ◽  
Acetylcholinesterase Reactivation ◽  
The Brain

Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood–brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC—pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.

scholarly journals Chemical Delivery System of MIBG to the Central Nervous System: Synthesis, 11C-Radiosynthesis, and in Vivo Evaluation

2019 ◽  
Vol 10 (3) ◽  
pp. 352-357 ◽  
Author(s):  
Fabienne Gourand ◽  
Delphine Patin ◽  
Axelle Henry ◽  
Méziane Ibazizène ◽  
Martine Dhilly ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Delivery System ◽  
In Vivo Evaluation ◽  
System Synthesis ◽  
Chemical Delivery System ◽  
The Central Nervous System

scholarly journals Drug Penetration into the Central Nervous System: Pharmacokinetic Concepts and In Vitro Model Systems

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1542
Author(s):  
Felix Neumaier ◽  
Boris D. Zlatopolskiy ◽  
Bernd Neumaier
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Model Systems ◽  
Pharmacokinetic Parameters ◽  
Special Focus ◽  
Drug Penetration ◽  
The Central Nervous System ◽  
The Brain

Delivery of most drugs into the central nervous system (CNS) is restricted by the blood–brain barrier (BBB), which remains a significant bottleneck for development of novel CNS-targeted therapeutics or molecular tracers for neuroimaging. Consistent failure to reliably predict drug efficiency based on single measures for the rate or extent of brain penetration has led to the emergence of a more holistic framework that integrates data from various in vivo, in situ and in vitro assays to obtain a comprehensive description of drug delivery to and distribution within the brain. Coupled with ongoing development of suitable in vitro BBB models, this integrated approach promises to reduce the incidence of costly late-stage failures in CNS drug development, and could help to overcome some of the technical, economic and ethical issues associated with in vivo studies in animal models. Here, we provide an overview of BBB structure and function in vivo, and a summary of the pharmacokinetic parameters that can be used to determine and predict the rate and extent of drug penetration into the brain. We also review different in vitro models with regard to their inherent shortcomings and potential usefulness for development of fast-acting drugs or neurotracers labeled with short-lived radionuclides. In this regard, a special focus has been set on those systems that are sufficiently well established to be used in laboratories without significant bioengineering expertise.

scholarly journals Brain Targeting of anti-HIV Nucleosides: in vitro and in vivo Evaluation of 6-chloro-2′,3′-dideoxypurine, a Lipophilic Prodrug of 2′,3′-dideoxyinosine

1994 ◽  
Vol 5 (5) ◽  
pp. 304-311 ◽  
Author(s):  
K. J. Doshi ◽  
F. D. Boudinot ◽  
J. M. Gallo ◽  
R. F. Schinazi ◽  
C. K. Chu
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Oral Administration ◽  
Intravenous Administration ◽  
Brain Targeting ◽  
The Central Nervous System ◽  
Intravenous And Oral Administration ◽  
The Brain

Lipophilic 6-halo-2′,3′-dideoxypurine nucleosides may be useful prodrugs for the targeting of 2′,3′-dideoxyinosine (ddl) to the central nervous system. The purpose of this study was to evaluate the potential effectiveness of 6-chloro-2′,3′-dideoxypurine (6-CI-ddP) for the targeting of ddl to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-CI-ddP to ddl was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-CI-ddP and ddl was assessed in vivo in mice following intravenous and oral administration of the prodrug or parent drug. Brain concentrations of ddl were similar after intravenous administration of 6-CI-ddP or ddl. However, after oral administration of the 6-CI-ddP prodrug, significantly greater concentrations of ddl were seen in the brain compared to those found after oral administration of ddl. The brain:serum AUG ratio (expressed as a percentage) of ddl after intravenous administration of 50 mg kg−1 of the active nucleoside was 3%. Following oral administration of 250 mg kg−1 ddl, low concentrations of ddl were detected in the brain. Brain:serum AUC ratios following intravenous and oral administration of the prodrug 6-CI-ddP were 19–25%. Thus, brain:serum AUC ratios were 6- to 8-fold higher after prodrug administration than those obtained after administration of the parent nucleoside. Oral administration of 6-CI-ddP yielded concentrations of ddl in the brain similar to those obtained following intravenous administration. The results of this study provide further evidence that 6-CI-ddP may be a useful prodrug for delivering ddl to the central nervous system, particularly after oral administration.

scholarly journals Coordinated Regulation and Widespread Cellular Expression of Interferon-Stimulated Genes (ISG) ISG-49, ISG-54, and ISG-56 in the Central Nervous System after Infection with Distinct Viruses

2006 ◽  
Vol 81 (2) ◽  
pp. 860-871 ◽  
Author(s):  
Christie Wacher ◽  
Marcus Müller ◽  
Markus J. Hofer ◽  
Daniel R. Getts ◽  
Regina Zabaras ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Dominant Role ◽  
Lymphocytic Choriomeningitis ◽  
Wild Type ◽  
Cellular Expression ◽  
The Central Nervous System ◽  
The Brain ◽  
Lcmv Infection

ABSTRACT The interferon (IFN)-stimulated genes (ISGs) ISG-49, ISG-54, and ISG-56 are highly responsive to viral infection, yet the regulation and function of these genes in vivo are unknown. We examined the simultaneous regulation of these ISGs in the brains of mice during infection with either lymphocytic choriomeningitis virus (LCMV) or West Nile virus (WNV). Expression of the ISG-49 and ISG-56 genes increased significantly during LCMV infection, being widespread and localized predominantly to common as well as distinct neuronal populations. Expression of the ISG-54 gene also increased but to lower levels and with a more restricted distribution. Although expression of the ISG-49, ISG-54, and ISG-56 genes was increased in the brains of LCMV-infected STAT1 and STAT2 knockout (KO) mice, this was blunted, delayed, and restricted to the choroid plexus, meninges, and endothelium. ISG-56 protein was regulated in parallel with the corresponding RNA transcript in the brain during LCMV infection in wild-type and STAT KO mice. Similar changes in ISG-49, ISG-54, and ISG-56 RNA levels and ISG-56 protein levels were observed in the brains of wild-type mice following infection with WNV. Thus, the ISG-49, ISG-54, and ISG-56 genes are coordinately upregulated in the brain during LCMV and WNV infection; this upregulation, in the case of LCMV, was totally (neurons) or partially (non-neurons) dependent on the IFN-signaling molecules STAT1 and STAT2. These findings suggest a dominant role for the ISG-49, ISG-54, and ISG-56 genes in the host response to different viruses in the central nervous system, where, particularly in neurons, these genes may have nonredundant functions.

scholarly journals Clinical Trials for Gene Therapy in Lysosomal Diseases With CNS Involvement

2021 ◽  
Vol 8 ◽  
Author(s):  
Caroline Sevin ◽  
Kumaran Deiva
Keyword(s):  
Gene Therapy ◽  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Ex Vivo ◽  
Central Nervous System Involvement ◽  
Large Animal ◽  
Hematopoietic Stem ◽  
The Brain

There are over 70 known lysosomal storage disorders (LSDs), most caused by mutations in genes encoding lysosomal hydrolases. Central nervous system involvement is a hallmark of the majority of LSDs and, if present, generally determines the prognosis of the disease. Nonetheless, brain disease is currently poorly targeted by available therapies, including systemic enzyme replacement therapy, mostly (but not only) due to the presence of the blood–brain barrier that restricts the access of orally or parenterally administered large molecules into the brain. Thus, one of the greatest and most exciting challenges over coming years will be to succeed in developing effective therapies for the treatment of central nervous system manifestations in LSDs. Over recent years, gene therapy (GT) has emerged as a promising therapeutic strategy for a variety of inherited neurodegenerative diseases. In LSDs, the ability of genetically corrected cells to cross-correct adjacent lysosomal enzyme-deficient cells in the brain after gene transfer might enhance the diffusion of the recombinant enzyme, making this group of diseases a strong candidate for such an approach. Both in vivo (using the administration of recombinant adeno-associated viral vectors) and ex vivo (auto-transplantation of lentiviral vector-modified hematopoietic stem cells-HSCs) strategies are feasible. Promising results have been obtained in an ever-increasing number of preclinical studies in rodents and large animal models of LSDs, and these give great hope of GT successfully correcting neurological defects, once translated to clinical practice. We are now at the stage of treating patients, and various clinical trials are underway, to assess the safety and efficacy of in vivo and ex vivo GT in several neuropathic LSDs. In this review, we summarize different approaches being developed and review the current clinical trials related to neuropathic LSDs, their results (if any), and their limitations. We will also discuss the pitfalls and the remaining challenges.

scholarly journals Glial Cells Promote Myelin Formation and Elimination

2021 ◽  
Vol 9 ◽  
Author(s):  
Alexandria N. Hughes
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glial Cells ◽  
Cell Types ◽  
Brain Functions ◽  
Myelin Sheaths ◽  
Local Signaling ◽  
The Brain ◽  
Vertebrate Central Nervous System

Building a functional nervous system requires the coordinated actions of many glial cells. In the vertebrate central nervous system (CNS), oligodendrocytes myelinate neuronal axons to increase conduction velocity and provide trophic support. Myelination can be modified by local signaling at the axon-myelin interface, potentially adapting sheaths to support the metabolic needs and physiology of individual neurons. However, neurons and oligodendrocytes are not wholly responsible for crafting the myelination patterns seen in vivo. Other cell types of the CNS, including microglia and astrocytes, modify myelination. In this review, I cover the contributions of non-neuronal, non-oligodendroglial cells to the formation, maintenance, and pruning of myelin sheaths. I address ways that these cell types interact with the oligodendrocyte lineage throughout development to modify myelination. Additionally, I discuss mechanisms by which these cells may indirectly tune myelination by regulating neuronal activity. Understanding how glial-glial interactions regulate myelination is essential for understanding how the brain functions as a whole and for developing strategies to repair myelin in disease.

scholarly journals The Interferon-Stimulated GeneIfitm3Restricts West Nile Virus Infection and Pathogenesis

2016 ◽  
Vol 90 (18) ◽  
pp. 8212-8225 ◽  
Author(s):  
Matthew J. Gorman ◽  
Subhajit Poddar ◽  
Michael Farzan ◽  
Michael S. Diamond
Keyword(s):  
Central Nervous System ◽  
Cell Culture ◽  
T Cells ◽  
Nervous System ◽  
West Nile Virus ◽  
Transmembrane Protein ◽  
Viral Pathogenesis ◽  
West Nile ◽  
The Brain

ABSTRACTThe interferon-induced transmembrane protein (IFITM) family of proteins inhibit infection of several different enveloped viruses in cell culture by virtue of their ability to restrict entry and fusion from late endosomes. As few studies have evaluated the importance ofIfitm3 in vivoin restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice.Ifitm3−/−mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. As no difference in viral burden in the brain or spinal cord was observed after direct intracranial inoculation, Ifitm3 likely functions as an antiviral protein in nonneuronal cells. Consistent with this,Ifitm3−/−fibroblasts but not dendritic cells resulted in higher yields of WNV in multistep growth analyses. Moreover, transcomplementation experiments showed that Ifitm3 inhibited WNV infection independently of Ifitm1, Ifitm2, Ifitm5, and Ifitm6. Beyond a direct effect on viral infection in cells, analysis of the immune response in WNV-infectedIfitm3−/−mice showed decreases in the total number of B cells, CD4+T cells, and antigen-specific CD8+T cells. Finally, bone marrow chimera experiments demonstrated that Ifitm3 functioned in both radioresistant and radiosensitive cells, as higher levels of WNV were observed in the brain only when Ifitm3 was absent from both compartments. Our analyses suggest that Ifitm3 restricts WNV pathogenesis likely through multiple mechanisms, including the direct control of infection in subsets of cells.IMPORTANCEAs part of the mammalian host response to viral infections, hundreds of interferon-stimulated genes (ISGs) are induced. The inhibitory activity of individual ISGs varies depending on the specific cell type and viral pathogen. Among ISGs, the genes encoding interferon-induced transmembrane protein (IFITM) have been reported to inhibit multiple families of viruses in cell culture. However, few reports have evaluated the impact ofIFITMgenes on viral pathogenesisin vivo. In this study, we characterized the antiviral activity of Ifitm3 against West Nile virus (WNV), an encephalitic flavivirus, using mice with a targeted gene deletion ofIfitm3. Based on extensive virological and immunological analyses, we determined that Ifitm3 protects mice from WNV-induced mortality by restricting virus accumulation in peripheral organs and, subsequently, in central nervous system tissues. Our data suggest that Ifitm3 restricts WNV pathogenesis by multiple mechanisms and functions in part by controlling infection in different cell types.

Comparison on Reactivity of Fe(III) and AI(III) Compounds in the Presence of Hydrogen Peroxide: Its Relevance to Possible Origin for Central Nervous System Toxicity by Aluminum Ion

1995 ◽  
Vol 50 (7-8) ◽  
pp. 571-577 ◽  
Author(s):  
Yuzo Nishida ◽  
Sayo Ito
Keyword(s):  
Hydrogen Peroxide ◽  
Central Nervous System ◽  
Nervous System ◽  
High Activity ◽  
Furan Ring ◽  
Nitrilotriacetic Acid ◽  
Central Nervous System Toxicity ◽  
The Brain ◽  
System Toxicity

Abstract The iron(III) compounds with several aminocarboxylate chelates containing an aryl or furan substituent exhibit high activity in enhancement of the reactivity of hydrogen peroxide, leading to facile hydroxylation at benzene ring, and to degradation of furan ring, but no such activity was observed for the corresponding Al(III) compounds. These results were inter­preted in terms of the molecular orbital consideration, and lack of the activity of the Al(III) complexes was attributed to lack of electrophilic nature of the peroxide adduct due to the absence of a d-orbital: this may explain the fact that there were no tumors in Al-NTA (nitrilotriacetic acid)-treated rats. Based on the facts observed in this study, the decreased function of iron(III) ions for synthesizing neurotransmitters in the brain was assumed to be one of the possible origin for the neurotoxicity by injection of the Al(III) salts in vivo.

scholarly journals All Central Nervous System Neuro- and Vascular-Communication Channels Are Surrounded With Cerebrospinal Fluid

2021 ◽  
Vol 12 ◽  
Author(s):  
Lara M. Fahmy ◽  
Yongsheng Chen ◽  
Stephanie Xuan ◽  
E. Mark Haacke ◽  
Jiani Hu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Critical Role ◽  
Communication Channels ◽  
Brain Parenchyma ◽  
Spinal Nerves ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

Background: Recent emerging evidence has highlighted the potential critical role of cerebrospinal fluid (CSF) in cerebral waste clearance and immunomodulation. It is already very well-established that the central nervous system (CNS) is completely submerged in CSF on a macro-level; but to what extent is this true on a micro-level? Specifically, within the peri-neural and peri-vascular spaces within the CNS parenchyma. Therefore, the objective of this study was to use magnetic resonance imaging (MRI) to simultaneously map the presence of CSF within all peri-neural (cranial and spinal nerves) and peri-vascular spaces in vivo in humans. Four MRI protocols each with five participants were used to image the CSF in the brain and spinal cord. Our findings indicated that all CNS neuro- and vascular-communication channels are surrounded with CSF. In other words, all peri-neural spaces surrounding the cranial and spinal nerves as well as all peri-vascular spaces surrounding MRI-visible vasculature were filled with CSF. These findings suggest that anatomically, substance exchange between the brain parenchyma and outside tissues including lymphatic ones can only occur through CSF pathways and/or vascular pathways, warranting further investigation into its implications in cerebral waste clearance and immunity.

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