scholarly journals Small molecules as central nervous system therapeutics: old challenges, new directions, and a philosophic divide

2019 ◽  
Vol 11 (6) ◽  
pp. 489-493 ◽  
Author(s):  
William A Banks ◽  
Nigel H Greig
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Small Molecules ◽  
New Directions

Glial Function in Homeostasis of the Neuronal Microenvironment

Physiology ◽  
1994 ◽  
Vol 9 (6) ◽  
pp. 265-267
Author(s):  
RK Orkand ◽  
SC Opava
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Small Molecules ◽  
Transport Systems ◽  
Large Area ◽  
Glial Function ◽  
The Central Nervous System ◽  
Glial Membrane ◽  
Membrane Transport Systems ◽  
Specific Membrane

Neuroglia buffer changes in the concentrations of ions and small molecules in the tortuous network of narrow extracellular clefts that constitutes the functional environment of neurons in the central nervous system. The large area of glial membrane bordering this space exhibits specific membrane transport systems for homeostasis.

scholarly journals MiR-124 and Small Molecules Synergistically Regulate the Direct Generation of Neuronal Cells from Rat Cortical Reactive Astrocytes

2020 ◽  
Author(s):  
Yangyang Zheng ◽  
Zhehao Huang ◽  
Jinying Xu ◽  
Kun Hou ◽  
Yifei Yu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Small Molecules ◽  
Expression Patterns ◽  
Cholinergic Neurons ◽  
Reactive Astrocytes ◽  
Neurological Dysfunction ◽  
Neuronal Regeneration ◽  
Neuronal Markers ◽  
Hes1 Expression

Abstract Background：Irreversible neuron loss caused by central nervous system injuries usually lead to persistent neurological dysfunction. Reactive astrocytes, because of their high proliferative capacity, proximity to neuronal lineage, and significant involvement in glial scarring, are ideal starting cells for neuronal regeneration. Having previously identified several small molecules as important regulators of astrocyte-to-neuron reprogramming, our aim in this study was to explore whether other small molecules and miR-124, a key neural differentiation mediator, could co-regulate reactive astrocyte-to-neuron conversion.Methods: MiR-124, ruxolitinib, SB203580, and forskolin were used to induce postnatal rat cortex reactive astrocytes, and the neuronal phenotype of the induced cells was characterised. To understand the genetic changes, RNA-sequencing analyses were performed on reactive astrocytes, induced neurons, and rat neurons, and the mechanisms underlying the regulatory role of miR-124 during the neuronal conversion was explored.Results：MiR-124, ruxolitinib, SB203580, and forskolin could co-convert rat cortical reactive astrocytes into neurons. The induced cells had reduced astroglial properties, displayed typical neuronal morphologies, and expressed neuronal markers, reflecting 25.9% of cholinergic neurons and 22.3% of glutamatergic neurons. Gene analysis revealed that induced neuron gene expression patterns were more similar to that of primary neurons than of initial reactive astrocytes. On the molecular level, miR-124-driven neuronal differentiation of reactive astrocytes was via targeting of the SOX9-NFIA-HES1 axis to inhibit HES1 expression.Conclusions：Providing a novel approach for inducing endogenous rat cortical reactive astrocytes into neurons by co-regulation involving miR-124 and three small molecules, our research has potential implications for inhibiting glial scar formation and promoting neuronal regeneration after central nervous system injury or disease.

scholarly journals Pathways for Small Molecule Delivery to the Central Nervous System across the Blood-Brain Barrier

2014 ◽  
Vol 6 ◽  
pp. PMC.S13384 ◽  
Author(s):  
John L. Mikitsh ◽  
Ann-Marie Chacko
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Nervous System ◽  
Small Molecules ◽  
Blood Brain Barrier ◽  
Small Molecule ◽  
Drug Uptake ◽  
Brain Barrier ◽  
Blood Brain ◽  
Imaging Probes

The treatment of central nervous system (CNS) disease has long been difficult due to the ineffectiveness of drug delivery across the blood-brain barrier (BBB). This review summarizes important concepts of the BBB in normal versus pathophysiology and how this physical, enzymatic, and efflux barrier provides necessary protection to the CNS during drug delivery, and consequently treatment challenging. Small molecules account for the vast majority of available CNS drugs primarily due to their ability to penetrate the phospholipid membrane of the BBB by passive or carrier-mediated mechanisms. Physiochemical and biological factors relevant for designing small molecules with optimal capabilities for BBB permeability are discussed, as well as the most promising classes of transporters suitable for small-molecule drug delivery. Clinically translatable imaging methodologies for detecting and quantifying drug uptake and targeting in the brain are discussed as a means of further understanding and refining delivery parameters for both drugs and imaging probes in preclinical and clinical domains. This information can be used as a guide to design drugs with preserved drug action and better delivery profiles for improved treatment outcomes over existing therapeutic approaches.

Quantifying orientational regeneration of injured neurons by natural product concentration gradients in a 3D microfluidic device

Lab on a Chip ◽  
2018 ◽  
Vol 18 (6) ◽  
pp. 971-978 ◽  
Author(s):  
Yun Tang ◽  
Quan-Fa Qiu ◽  
Fu-Li Zhang ◽  
Min Xie ◽  
Wei-Hua Huang
Keyword(s):  
Central Nervous System ◽  
Extracellular Matrix ◽  
Nervous System ◽  
Small Molecules ◽  
Natural Product ◽  
Microfluidic Device ◽  
Concentration Gradients ◽  
Product Concentration

We developed a microfluidic device which can provide multiple adjustable gradients in a 3D extracellular matrix to investigate regeneration of injured central nervous system neurons in response to natural small molecules.

Treatment of Primary Central Nervous System Lymphoma: From Chemotherapy to Small Molecules

2018 ◽  
pp. 604-615 ◽  
Author(s):  
Joe S. Mendez ◽  
Christian Grommes
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Small Molecules ◽  
Checkpoint Inhibitors ◽  
Central Nervous System Lymphoma ◽  
Phase Iii ◽  
High Dose ◽  
First Line ◽  
The Past ◽  
Systemic Spread

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that is typically confined to the brain, eyes, and cerebrospinal fluid (CSF) without evidence of systemic spread. PCNSL is an uncommon tumor, and only four randomized trials and one phase III trial have been completed so far, all in the first-line setting. The prognosis of patients with PCNSL has improved during the past few decades with the introduction of high-dose methotrexate (HD-MTX), which now serves as the backbone of all first-line treatment regimens. Despite recent progress, results after treatment are durable in half of patients, and therapy can be associated with late neurotoxicity. Novel insights into the pathophysiology of PCNSL have identified the B-cell receptor (BCR) pathway as a key mechanism in the pathogenesis of PCNSL. The use of novel agents targeting components of the BCR pathway, namely the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, and immunomodulatory drugs (IMIDs) like lenalidomide and pomalidomide, has so far been limited to patients who have recurrent/refractory PCNSL with promising high response rates. Within the past 5 years, there has been a peak in clinical trials investigating small molecules and novel reagents in the recurrent/refractory setting, including immune checkpoint inhibitors, IMIDs, and BTK and PI3K/AKT/mTOR inhibitors.

scholarly journals Application progress of RVG peptides to facilitate the delivery of therapeutic agents into the central nervous system

RSC Advances ◽  
2021 ◽  
Vol 11 (15) ◽  
pp. 8505-8515
Author(s):  
Qinghua Wang ◽  
Shang Cheng ◽  
Fen Qin ◽  
Ailing Fu ◽  
Chen Fu
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Nervous System ◽  
Small Molecules ◽  
Rabies Virus ◽  
Drug Delivery Systems ◽  
Therapeutic Agents ◽  
System P ◽  
The Central Nervous System ◽  
Almost All

Rabies virus glycoprotein (RVG) peptides have been developed to deliver drugs for CNS diseases. In the present review, RVG-mediated drug delivery systems are summarised, which can deliver almost all small molecules and macromolecule agents.

scholarly journals MiR-124 and small molecules synergistically regulate the direct generation of neuronal cells from rat cortical reactive astrocytes

2020 ◽  
Author(s):  
Yangyang Zheng ◽  
Zhehao Huang ◽  
Jinying Xu ◽  
Kun Hou ◽  
Yifei Yu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Small Molecules ◽  
Expression Patterns ◽  
Cholinergic Neurons ◽  
Reactive Astrocytes ◽  
Neurological Dysfunction ◽  
Neuronal Regeneration ◽  
Neuronal Markers ◽  
Hes1 Expression

Abstract Background：Irreversible neuron loss caused by central nervous system injuries usually lead to persistent neurological dysfunction. Reactive astrocytes, because of their high proliferative capacity, proximity to neuronal lineage, and significant involvement in glial scarring, are ideal starting cells for neuronal regeneration. Having previously identified several small molecules as important regulators of astrocyte-to-neuron reprogramming, our aim in this study was to explore whether other small molecules and miR-124, a key neural differentiation mediator, could co-regulate reactive astrocyte-to-neuron conversion.Methods: MiR-124, ruxolitinib, SB203580, and forskolin were used to induce postnatal rat cortex reactive astrocytes, and the neuronal phenotype of the induced cells was characterised. To understand the genetic changes, RNA-sequencing analyses were performed on reactive astrocytes, induced neurons, and rat neurons, and the mechanisms underlying the regulatory role of miR-124 during the neuronal conversion was explored.Results：MiR-124, ruxolitinib, SB203580, and forskolin could co-convert rat cortical reactive astrocytes into neurons. The induced cells had reduced astroglial properties, displayed typical neuronal morphologies, and expressed neuronal markers, reflecting 25.9% of cholinergic neurons. Gene analysis revealed that induced neuron gene expression patterns were more similar to that of primary neurons than of initial reactive astrocytes. On the molecular level, miR-124-driven neuronal differentiation of reactive astrocytes was via targeting of the SOX9-NFIA-HES1 axis to inhibit HES1 expression.Conclusions：Providing a novel approach for inducing endogenous rat cortical reactive astrocytes into neurons by co-regulation involving miR-124 and three small molecules, our research has potential implications for inhibiting glial scar formation and promoting neuronal regeneration after central nervous system injury or disease.

Neurotropic enteroviruses co-opt “fair-weather-friend” commensal gut microbiota to drive host infection and central nervous system disturbances

2019 ◽  
Vol 42 ◽  
Author(s):  
Kevin B. Clark
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gut Bacteria ◽  
Infection Cycle ◽  
Fair Weather ◽  
Host Health ◽  
Microbe Interactions ◽  
Animal Hosts ◽  
Host Infection ◽  
Neuropsychiatric Conditions

Abstract Some neurotropic enteroviruses hijack Trojan horse/raft commensal gut bacteria to render devastating biomimicking cryptic attacks on human/animal hosts. Such virus-microbe interactions manipulate hosts’ gut-brain axes with accompanying infection-cycle-optimizing central nervous system (CNS) disturbances, including severe neurodevelopmental, neuromotor, and neuropsychiatric conditions. Co-opted bacteria thus indirectly influence host health, development, behavior, and mind as possible “fair-weather-friend” symbionts, switching from commensal to context-dependent pathogen-like strategies benefiting gut-bacteria fitness.

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