scholarly journals Heterogeneous incidence and propagation of spreading depolarizations

2016 ◽  
Vol 37 (5) ◽  
pp. 1748-1762 ◽  
Author(s):  
Dan Kaufmann ◽  
Jeremy J Theriot ◽  
Jekaterina Zyuzin ◽  
C Austin Service ◽  
Joshua C Chang ◽  
...  
Keyword(s):  
Nervous System ◽  
Great Variability ◽  
Neurologic Disease ◽  
Neurologic Diseases ◽  
Present Evidence ◽  
System Activity ◽  
Nervous System Activity ◽  
The Brain

Spreading depolarizations are implicated in a diverse set of neurologic diseases. They are unusual forms of nervous system activity in that they propagate very slowly and approximately concentrically, apparently not respecting the anatomic, synaptic, functional, or vascular architecture of the brain. However, there is evidence that spreading depolarizations are not truly concentric, isotropic, or homogeneous, either in space or in time. Here we present evidence from KCl-induced spreading depolarizations, in mouse and rat, in vivo and in vitro, showing the great variability that these depolarizations can exhibit. This variability can help inform the mechanistic understanding of spreading depolarizations, and it has implications for their phenomenology in neurologic disease.

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 The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites

2018 ◽  
Vol 4 (1) ◽  
pp. 00127-2017 ◽  
Author(s):  
Elena K. Schneider ◽  
Rachel M. McQuade ◽  
Vincenzo C. Carbone ◽  
Felisa Reyes-Ortega ◽  
John W. Wilson ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Radioligand Binding ◽  
Forced Swim Test ◽  
Treated Group ◽  
System Activity ◽  
Nervous System Activity ◽  
Central Nervous System Activity

Ivacaftor–lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators.The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1) and ivacaftorcarboxylate (iva-M6) with neurotransmitter receptors were investigated in radioligand binding assays.Ivacaftor displayed significant affinity to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT2Creceptor (pKi=6.06±0.03), β3-adrenergic receptor (pKi=5.71±0.07), δ-opioid receptor (pKi=5.59±0.06) and the dopamine transporter (pKi=5.50±0.20); iva-M1 displayed significant affinity to the 5-HT2Creceptor (pKi=5.81±0.04) and the muscarinic M3 receptor (pKi=5.70±0.10); iva-M6 displayed significant affinity to the 5-HT2Areceptor (pKi=7.33±0.05). Thein vivocentral nervous system activity of ivacaftor (40 mg·kg−1intraperitoneally for 21 days) was assessed in a chronic mouse model of depression. In the forced swim test, the ivacaftor-treated group displayed decreased immobility (52.8±7.6 s), similarly to fluoxetine (33.8±11.0 s), and increased climbing/swimming activity (181.5±9.2 s). In the open field test, ivacaftor produced higher locomotor activity than the fluoxetine group, measured both as mean number of paw touches (ivacaftor 81.1±9.6versusfluoxetine 57.9±9.5) and total distance travelled (ivacaftor 120.6±16.8 cmversusfluoxetine 84.5±16.0 cm) in 600 s. Treatment of 23 cystic fibrosis patients with ivacaftor–lumacaftor resulted in significant improvements in quality of life (including anxiety) in all five domains of the AweScoreCF questionnaire (p=0.092–0.096).Our findings suggest ivacaftor displays potential clinical anxiolytic and stimulating properties, and may have beneficial effects on mood.

scholarly journals The Significance of Anoxæmia in Modern Psychiatric Treatment

1939 ◽  
Vol 32 (8) ◽  
pp. 951-958 ◽  
Author(s):  
J. H. Quastel
Keyword(s):  
Nervous System ◽  
Glucose Oxidation ◽  
Psychiatric Treatment ◽  
Venous Blood ◽  
In Vivo Studies ◽  
Venous Blood Flow ◽  
And Function ◽  
The Brain

Blood in its passage through the brain loses oxygen and glucose at relatively high rates, the amount of oxygen disappearing being approximately equivalent to the amount of glucose consumed, calculating on the basis that the sugar is completely oxidized. The respiratory quotient of brain in vivo is unity. These facts point to the dominance of carbohydrate oxidation in brain respiration in vivo and are similar to those found in studies of brain in vitro. Various factors influence glucose oxidation in brain, e.g. changes in the ionic environment of the cells, vitamin B1, or the presence of narcotics. The latter bring about inhibitions of glucose oxidation in brain tissue which may in most cases be shown to be reversible in vitro. Glucose is not only important for the maintenance of respiration of brain but for enabling certain synthetic processes to occur. One of these is the formation of acetylcholine whose physiological significance is now well known and whose synthesis seems to be confined to the nervous system. This synthesis depends not only on the presence of glucose but on that of oxygen. The influence of glucose has been observed also in investigations on cortical potentials. An important feature of the nerve cell is its vulnerability to the lack of oxygen. Reversibility depends on the degree and duration of the anoxæmia. During insulin shock treatment studies of brain in vivo show lowered oxygen consumption and glucose utilization, these depending on the degree of hypoglycæmia. In cardiazol treatment, in vivo studies show that the oxygen content of the blood may fall to 42%. During the convulsion there is a greatly lowered arterial and venous blood-flow through the brain and cerebral anæmia becomes a marked feature. In narcosis treatment both in vitro and in vivo studies show a diminished ability of the brain to consume oxygen. It is suggested that the most significant facts to be taken into account are (1) the importance of glucose and oxygen for the metabolism and function of the nervous system, (2) the vulnerability and varying sensitivities of nerve cells to lack of oxygen and glucose, (3) the occurrence of varying degrees of cerebral anoxæmia in narcosis, insulin and cardiazol treatments.

Cyclosporin A, a P-gp Inhibitor, Augments the Anti-Central Nervous System Ph+ Leukemia Effects of INNO-406.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 834-834
Author(s):  
Asumi Yokota ◽  
Shinya Kimura ◽  
Satohiro Masuda ◽  
Eishi Ashihara ◽  
Yoshimasa Urasaki ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cyclosporin A ◽  
Leukemic Cells ◽  
Wild Type ◽  
Intracellular Accumulation ◽  
Cns Relapse ◽  
The Brain

Abstract Central nervous system (CNS) relapse accompanying prolonged administration of imatinib mesylate, an Abl-specific tyrosine kinase inhibitor, has recently become apparent as an impediment to the therapy of Philadelphia-chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib into the cerebrospinal fluid due to presence of P-glycoprotein (P-gp) at blood-brain barrier. To overcome imatinib-resistance mechanisms such as bcr-abl gene amplification, point mutations within ABL kinase domain, and activation of Lyn, we recently developed a specific dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25–55 times more potent than imatinib in vitro and at least 10 times more potent in vivo (Blood106: 3948–3954, 2005). The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. The intracellular accumulation of [14C]INNO-406 in P-gp overexpressing LLC-GA5-COL150 cells was much less than that in parental LLC-PK1 cells. The addition of 10 mM cyclosporin A (CsA) increased the intracellular accumulation of [14C]INNO-406 in both LLC-PK1 cells and LLC-GA5-COL150 cells. The peak concentration of INNO-406 in the brain when 30 mg/kg INNO-406 was administered p.o. was 50 ng/ g (87 nM), representing only 10% of plasma drug level. These findings suggested that INNO-406 is also a substrate of P-gp, as is imatinib. However, the residual concentration of INNO-406 in the CNS was enough to inhibit the growth of Ph+ leukemic cells according to the in vitro data. To increase the concentration of INNO-406 in CNS, we next examined the combined effects of CsA. In the brain, the concentration of INNO-406 was doubled following prior administration of 50 mg/kg CsA. Since pharmacokinetic studies suggested the possible effects of INNO-406 against CNS Ph+ leukemia, we investigated in vivo anti-CNS Ph+ leukemia effects of INNO-406 alone and combination of INNO-406 and CsA using immunodeficient mice (nude or NOD/SCID) which received Ph+ leukemic cells into the cerebral ventricle. INNO-406 alone inhibited growth of leukemic cells harboring either wild type or mutated BCR-ABL such as E255K and M351T in CNS. Furthermore, CsA significantly enhanced anti-CNS Ph+ leukemia effects of INNO-406 in vivo not only against cells harboring wild type BCR-ABL but also against cells harboring BCR-ABL/M351T (Figure). In conclusion, INNO-406 was found to inhibit Ph+ leukemic cell growth in CNS in spite of efflux of the compound by P-gp, and CsA augmented the anti-CNS Ph+ leukemia effects of INNO-406. Phase I clinical study on INNO-406 was initiated in the U.S.A. in July 2006. The efficacy and safety of INNO-406 in the treatment of leukemias is expected to be verified by early-phase clinical trials. Figure Figure

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

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