Blood–brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins

Verbeken, Mathieu; Wynendaele, Evelien; Mauchauffée, Elodie; Bracke, Nathalie; Stalmans, Sofie; Bojnik, Engin; Benyhe, Sándor; Peremans, Kathelijne; Polis, Ingeborgh; Burvenich, Christian; Gjedde, Albert; Hernandez, Jean Franc ̧ois; Spiegeleer, Bart De

doi:10.1016/j.peptides.2014.10.010

Cited by 9 publications

(9 citation statements)

References 63 publications

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“…The exposure time is calculated as the integral of the arterial serum radioactivity over time divided by the radioactivity at time t. The integral is calculated through the trapezoidal rule of the log-transformed data [ 73 ]. In the linear part of the curve, assuming a two-compartmental BBB model, data can be fitted using a linear model from which the unidirectional influx rate (K in ), also referred to as unidirectional blood to brain clearance K 1 [ 46 ], and the initial brain distribution volume (V i ) can be determined using the following equation according to Gjedde and Patlak [ 37 – 40 ]: …”

Section: Methodsmentioning

confidence: 99%

“…If during the experimental time frame the curve deviates from linearity due to a significant efflux out of the brain resulting in a transition from unidirectional to net transfer, the following expansion of the Gjedde-Patlak plot, a model of biphasic blood-brain transfer as derived from [ 42 ], was used to fit the uptake: with K 1 is the unidirectional clearance, K is the net clearance, V g the brain tissue distribution volume, and V 0 the vascular brain distribution volume, experimentally determined as the brain distribution volume of radioiodinated BSA [ 46 , 74 ].…”

Section: Methodsmentioning

confidence: 99%

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Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo

et al. 2015

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Cell-penetrating peptides (CPPs) are a group of peptides, which have the ability to cross cell membrane bilayers. CPPs themselves can exert biological activity and can be formed endogenously. Fragmentary studies demonstrate their ability to enhance transport of different cargoes across the blood-brain barrier (BBB). However, comparative, quantitative data on the BBB permeability of different CPPs are currently lacking. Therefore, the in vivo BBB transport characteristics of five chemically diverse CPPs, i.e. pVEC, SynB3, Tat 47–57, transportan 10 (TP10) and TP10-2, were determined. The results of the multiple time regression (MTR) analysis revealed that CPPs show divergent BBB influx properties: Tat 47–57, SynB3, and especially pVEC showed very high unidirectional influx rates of 4.73 μl/(g × min), 5.63 μl/(g × min) and 6.02 μl/(g × min), respectively, while the transportan analogs showed a negligible to low brain influx. Using capillary depletion, it was found that 80% of the influxed peptides effectively reached the brain parenchyma. Except for pVEC, all peptides showed a significant efflux out of the brain. Co-injection of pVEC with radioiodinated bovine serum albumin (BSA) did not enhance the brain influx of radiodionated BSA, indicating that pVEC does not itself significantly alter the BBB properties. A saturable mechanism could not be demonstrated by co-injecting an excess dose of non-radiolabeled CPP. No significant regional differences in brain influx were observed, with the exception for pVEC, for which the regional variations were only marginal. The observed BBB influx transport properties cannot be correlated with their cell-penetrating ability, and therefore, good CPP properties do not imply efficient brain influx.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo

et al. 2015

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“…which is a commonly used unit to report brain influx (Banks et al, 1990Dogrukol-Ak et al, 2003;Hsuchou et al, 2010;Verbeken et al, 2015;Wynendaele et al, 2015). The obtained brain/serum activity (μL/g) was plotted in function of exposure time (min), applying the vascular brain distribution volume of BSA (V0 = 14.8 µL/g), and curve fitting was done using the biphasic model mentioned above.…”

Section: Blood-to-brain Transportmentioning

confidence: 99%

“…passive diffusion) or by a saturable, active or facilitated, transport mechanism, or both (Banks and Kastin, 1988;Verbeken et al, 2015;Wynendaele et al, 2015). Moreover, the BBB is an important biological barrier with declining functionality in ageing (De Spiegeleer et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Blood-brain barrier transport kinetics of the cyclic depsipeptide mycotoxins beauvericin and enniatins

et al. 2016

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“…Guanidines are present in a large variety of natural products with potent biological activities in many fields [10][11][12][13] and more specifically in the central nervous system area. 14,15 This approach was exemplified by preparing the guanidine derivative "Tic-guanidine" and its derivatives (2 to 13) in order to evaluate the affinity of this new series on the adenosine receptor A2AR. 16 In fact, in addition to its affinity towards sigma-1 receptor, Tic-H 1 showed a promising affinity constant towards adenosine receptor A2A (Ki = 44 µM).…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of fused tetrahydroisoquinoline-iminoimidazolines

Moas-Héloire

Renault

Batalha³

et al. 2015

European Journal of Medicinal Chemistry

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In the aim of identifying new privileged structures, we describe the 5-steps synthesis of cyclic guanidine compounds "tetrahydroisoquinoline-iminoimidazolines" derived from tetrahydroisoquinoline-hydantoin core. In order to evaluate this new minimal structure and the impact of replacing a carbonyle by a guanidine moiety, their affinity towards adenosine receptor A2A was evaluated and compared to those of tetrahydroisoquinoline-hydantoin compounds.

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Blood–brain transfer and antinociception of linear and cyclic N-methyl-guanidine and thiourea-enkephalins

Cited by 9 publications

References 63 publications

Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo

Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo

Blood-brain barrier transport kinetics of the cyclic depsipeptide mycotoxins beauvericin and enniatins

Design and synthesis of fused tetrahydroisoquinoline-iminoimidazolines

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