scholarly journals Evaluation of molecular target of ademol by chemoinformatic method

2021 ◽  
Vol 17 (7) ◽  
pp. 37-41
Author(s):  
S.I. Semenenko ◽  
A.I. Semenenko ◽  
R.G. Redkin ◽  
I.F. Semenenko
Keyword(s):  
Surface Area ◽  
Blood Brain Barrier ◽  
Software Package ◽  
Brain Barrier ◽  
Glutamate Excitotoxicity ◽  
Polar Surface Area ◽  
Polar Surface ◽  
Computing Platform ◽  
Blood Brain ◽  
Β Blockers

Background. Glutamate excitotoxicity and intracranial hypertension are potential targets for possible developments of pathogenetic therapy of brain lesions, in particular those associated with high intracranial pressure. The purpose of the work: using chemoinformatic methods to justify the intravenous use of ademol, to detect the ability of ademol to block β-adrenergic receptors, as well as to assess the possibility of its passage through the blood-brain barrier in terms of drug-likeness and bioavailability criteria. Materials and methods. All calculations of molecular descriptors were made using the software package SIB Swiss Institute of Bioinformatics, computing platform and Molinspiration Cheminformatics v2016.09, available online. Results. The molecular weight of ademol does not exceed 500, the average lipophilicity value calculated using software package is in the acceptable range for the above compounds. For ademol, the value of LogP is 2,736, which is higher than that of rimantadine (2,456), but lower than that of propranolol (2,967). The total polar surface area is calculated based on the methodology developed by Ertl et al. in the form of contributions of the sum of the planes of O- and N-atoms etc., as a part of the functional groups of polar fragments. To predict ademol pe-netration through the blood-brain barrier, descriptors calculated in silico were used — average lipophilicity, which appeared to be close to previously described lipophilicity coefficient in a mixture of octanol and phosphate buffer, and the total polar surface area of mo-lecules. Affinity correlation (LogKi, nM) with polarity for known β-blockers and ademol is described as a second-degree parabolic polynomial function. Conclusions. A model of affinity correlation with lipophilicity for a number of β-blockers was created and the affinity of ademol is predicted, which is close to that of high-affi-nity non-selective β-blockers.

Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer’s Disease

2019 ◽  
Vol 16 (9) ◽  
pp. 821-833 ◽  
Author(s):  
Martina Kaniakova ◽  
Eugenie Nepovimova ◽  
Lenka Kleteckova ◽  
Kristyna Skrenkova ◽  
Kristina Holubova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Parent Compound ◽  
Brain Barrier ◽  
Glutamate Excitotoxicity ◽  
Unknown Etiology ◽  
Ache Inhibitors ◽  
Blood Brain

Background: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N–methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called “multi-targeting" approach has been established. Objectives: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. Methods: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. Results: novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. Conclusion: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.

Transfer of nonelectrolytes from blood into peripheral nerve endoneurium

1987 ◽  
Vol 252 (6) ◽  
pp. H1175-H1182 ◽  
Author(s):  
E. Rechthand ◽  
Q. R. Smith ◽  
S. I. Rapoport
Keyword(s):  
Surface Area ◽  
Blood Brain Barrier ◽  
Lipid Membranes ◽  
Brain Barrier ◽  
Solute Flux ◽  
Injection Technique ◽  
Lipid Solubility ◽  
Permeability Coefficients ◽  
Blood Brain

Permeability-surface area (PA) products were determined for the transfer of seven nonelectrolytes across the blood-nerve barrier (BNB) of rat tibial nerve using a quantitative in vivo injection technique. PA values at the BNB for slowly penetrating nonelectrolytes such as urea, mannitol, L-glucose, and sucrose differed by less than threefold from values at the blood-brain barrier in the same animals. Permeability coefficients for transfer across the BNB were calculated assuming both endoneurial capillaries and perineurium contribute to solute flux into endoneurium. Total BNB surface area was determined as 175 cm2/g with morphometric techniques. Calculated permeability coefficients for slowly penetrating nonelectrolytes ranged from 7 X 10(-8) cm/s for sucrose to 4 X 10(-7) cm/s for urea and were directly proportional to solute lipid solubility as measured by the octanol-water partition coefficient. BNB permeability coefficients for sucrose, mannitol, L-glucose, and urea were within 60% of values at cerebral capillaries, of the same order of magnitude as values at aporous lipid membranes, and 100-1,000 times less than values at most nonneural capillaries, such as in skeletal muscle. These results demonstrate that the BNB markedly restricts the transfer of hydrophilic nonelectrolytes between plasma and endoneurium and that diffusion restriction of the BNB is comparable to that of the blood-brain barrier.

Protective Effects of Indole-3-Carbinol-Loaded Poly(lactic-co-glycolic acid) Nanoparticles Against Glutamate-Induced Neurotoxicity

2015 ◽  
Vol 15 (10) ◽  
pp. 7922-7928 ◽  
Author(s):  
Ji Heun Jeong ◽  
Jwa-Jin Kim ◽  
Dong Ho Bak ◽  
Kwang Sik Yu ◽  
Je Hun Lee ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Glycolic Acid ◽  
Neuronal Cells ◽  
Survival Rates ◽  
Brain Barrier ◽  
Glutamate Excitotoxicity ◽  
Protective Effects ◽  
Ros Scavenging ◽  
Neuroprotective Effects ◽  
Blood Brain

Indole-3-carbinol (I3C) has anti-oxidant and anti-inflammatory properties. Nonetheless, the potential of I3C to treat neurodegenerative diseases remains unclear because of its poor ability to penetrate the blood-brain barrier (BBB). Because polymer-based drug delivery systems stabilized by surfactants have been intensively utilized as a strategy to cross the blood-brain barrier, we prepared I3C-loaded poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) that were stabilized by Tween 80 (T80) (I3C-PLGA-T80-NPs) and examined their neuroprotective potential in vitro. We prepared I3C-PLGA-T80-NPs with an oil-in-water (o/w) emulsion solvent evaporation technique and confirmed their successful synthesis with both transmission electron microscopy and Fourier transform-infrared spectroscopy. I3C-PLGA-T80-NPs were then used to treat PC12 neuronal cells injured by glutamate excitotoxicity (GE) and examined the resulting survival rates compared with PC12 cells treated with I3C only. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay revealed higher survival rates in I3C-PLGA-T80-NPs-treated cells after GE injury compared with those treated with I3C only. Furthermore, I3C-PLGA-T80-NPs decreased the levels of reactive oxygen species (ROS) and apoptosis-related enzymes (Caspase-3 and -8) in GE-damaged neuronal cells. Taken together, I3C-PLGA-T80-NPs might possess neuroprotective effects against GE through ROS scavenging and subsequent apoptosis blockage.

scholarly journals Hyperammonaemia causes many of the changes found after portacaval shunting

1990 ◽  
Vol 272 (2) ◽  
pp. 311-317 ◽  
Author(s):  
J Jessy ◽  
A M Mans ◽  
M R DeJoseph ◽  
R A Hawkins
Keyword(s):  
Amino Acid ◽  
Surface Area ◽  
Blood Brain Barrier ◽  
High Energy ◽  
Brain Barrier ◽  
Brain Glucose ◽  
Metabolic Alterations ◽  
Portacaval Shunting ◽  
Blood Brain ◽  
Area Product

1. Portacaval shunting in rats results in several metabolic alterations similar to those seen in patients with hepatic encephalopathy. The characteristic changes include: (a) diminution of cerebral function; (b) raised plasma ammonia and brain glutamine levels; (c) increased neutral amino acid transport across the blood-brain barrier; (d) altered brain and plasma amino acid levels; and (e) changes in brain neurotransmitter content. The aetiology of these abnormalities remains unknown. 2. To study the degree to which ammonia could be responsible, rats were made hyperammonaemic by administering 40 units of urease/kg body weight every 12 h and killing the rats 48 h after the first injection. 3. The changes observed in the urease-treated rats were: (a) whole-brain glucose use was significantly depressed, whereas the levels of high-energy phosphates remained unchanged; (b) the permeability of the blood-brain to barrier to two large neutral amino acids, tryptophan and leucine, was increased; (c) blood-brain barrier integrity was maintained, as indicated by the unchanged permeability-to-surface-area product for acetate; (d) plasma and brain amino acid concentrations were altered; and (e) dopamine, 5-hydroxytryptamine (serotonin) and noradrenaline levels in brain were unchanged, but 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-hydroxytryptamine, was elevated. 4. The depressed brain glucose use, increased tryptophan permeability-to-surface-area product, elevated brain tryptophan content and rise in the level of cerebral 5-HIAA were closely correlated with the observed rise in brain glutamine content. 5. These results suggest that many of the metabolic alterations seen in rats with portacaval shunts could be due to elevated ammonia levels. Furthermore, the synthesis or accumulation of glutamine may be closely linked to cerebral dysfunction in hyperammonaemia.

Computerassisted models for Blood Brain Barrier permeation of 1, 5-Benzodiazepines

2020 ◽  
Vol 16 ◽  
Author(s):  
Rakesh P. Dhavale ◽  
Praffula B. Choudhari ◽  
Manish S. Bhatia
Keyword(s):  
Surface Area ◽  
Predictive Models ◽  
Molecular Descriptors ◽  
Structure Property ◽  
Polar Surface Area ◽  
Qspr Model ◽  
Polar Surface ◽  
Blood Brain ◽  
Bbb Permeability

Aim: To generate and validate predictive models for blood brain permeation (BBB) of CNS molecules using QSPR approach. Background: Prediction of molecules crossing BBB remain a challenge in drug delivery. Predictive models are designed for evaluation of set of preclinical drugs which may serve as alternatives for determining BBB permeation by experimentation. Objective: The objective of present study was to generate QSPR models for permeation of CNS molecules across BBB and its validation using existing in-house leads. Method: The present study envisaged the determination of set of molecular descriptors which are considered significant correlative factors for BBB permeation property. Quantitative Structure Property Relationship (QSPR) approach was followed to describe the correlation between identified descriptors for 45 molecules and highest, moderate and least BBB permeation data. The molecular descriptors were selected based on drug likeness, hydrophilicity, hydrophobicity, polar surface area, etc. of molecules which served highest correlation with BBB permeation. The experimental data in terms of logBB were collected from available literature, subjected for 2D-QSPR model generation using regression analysis method like Multiple Linear Regression (MLR). Result: The best QSPR model (Model 3) exhibited regression coefficient as R2= 0.89, F = 36; Q2= 0.7805 and properties such as polar surface area, hydrophobic hydrophilic distance, electronegativity etc., which were considered key parameters in determination of the BBB permeability. The developed QSPR models were validated with in-house 1,5-benzodiazepines molecules and correlation studies were conducted between experimental and predicted BBB permeability. Conclusion: The QSPR model 3showed predictive results in good agreements with experimental results for blood brain permeation. Thus, this model was found to be satisfactory in achieving goodcorrelation between selected descriptors and BBB permeation for benzodiazepines and tricyclic compounds.

scholarly journals Blood—Brain Barrier to Ammonia in Humans

1984 ◽  
Vol 4 (4) ◽  
pp. 516-522 ◽  
Author(s):  
Alan H. Lockwood ◽  
Leonard Bolomey ◽  
Franz Napoleon
Keyword(s):  
White Matter ◽  
Surface Area ◽  
Blood Brain Barrier ◽  
Brain Dysfunction ◽  
Brain Barrier ◽  
Surface Area Ratio ◽  
Blood Brain ◽  
Positron Emission ◽  
Normal Humans ◽  
Cerebral Capillary

We have developed a method to evaluate the diffusion of ammonia across the blood–brain barrier (BBB) in normal humans, based on measures of CBF and the regional cerebral metabolic rate for ammonia, obtained by positron emission tomography. The extraction fraction for ammonia passing through the cerebral capillary bed was a reciprocal function of CBF. The product of the BBB surface area and ammonia permeability, calculated from the Renkin-Crone model, was 0.32 ± 0.19 cm3 g−1 min−1 (±SD) in gray matter and 0.24 ± 0.16 cm3 g−1 min−1 in white matter. From literature values of the expected capillary surface area ratio, a gray-to-white matter ammonia permeability ratio of 0.37:1.0 was calculated. We speculate that astrocytes may mediate this unexpected difference in permeability, and that the permeability of the BBB to ammonia may be important in the pathogenesis of hyperammonemic brain dysfunction.

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