Application of an in vivo brain microdialysis technique to studies of drug transport across the blood-brain barrier.
TL;DR: The results from the successful application of the in vivo brain microdialysis technique to BBB drug transport studies are reviewed, which include novel and CNS-active peptides, some agents that are actively removed from the brain ISF across the BBB, and a brain-directed prodrug.
Abstract: There is a wide range of methods available for studying the transport of drugs across the blood-brain barrier (BBB) which is equipped with several systems to transport drugs as well as endogenous nutrients and waste products. The in vivo brain microdialysis technique, which allows direct sampling of the brain interstitial fluid (ISF), is a powerful means of characterizing influx and efflux transport across the BBB. In this paper, we review our results from the successful application of this technique to BBB drug transport studies. The drugs investigated include novel and CNS-active peptides, some agents that are actively removed from the brain ISF across the BBB, and a brain-directed prodrug.
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TL;DR: The extent to which a substance in the circulation gains access to the CNS needs to be determined for potential neuropharmaceuticals as well as for drug candidates with primary targets in the periphery.
Abstract: The extent to which a substance in the circulation gains access to the CNS needs to be determined for potential neuropharmaceuticals as well as for drug candidates with primary targets in the periphery. Characteristics of thein vivo methods, ranging from classical pharmacokinetic techniques (intravenous administration and tissue sampling) over brain perfusions to microdialysis and imaging techniques, are highlighted.In vivo measurements remain unmatched with respect to sensitivity and for the characterization of carrier-mediated uptake, receptor-mediated transport, and active efflux. Isolated microvessels are valuable tools for molecular characterization of transporters. Endothelial cell culture models of the blood-brain barrier (BBB) are pursued asin vitro systems suitable for screening procedures. Recent applications of conditionally immortalized cell lines indicate that a particular weakness of culture models because of downregulation of BBB-specific transporter systems can be overcome.In silico approaches are being developed with the goal of predicting brain uptake from molecular structure at early stages of drug development. Currently, the predictive capability is limited to passive, diffusional uptake and predominantly relies on few molecular descriptors related to lipophilicity, hydrogen bonding capacity, charge, and molecular weight. A caveat with most present strategies is their reliance on surrogates of BBB transport, like CNS activity/inactivity or brain-to-blood partitioning rather than actual BBB permeability data.
188 citations
Cites background or methods from "Application of an in vivo brain mic..."
...The microdialysis technique has gained increasing popularity over the last decade for studying drug distribution to the CNS.40,41 This method requires stereotaxic probe implantation under anesthesia, which is an invasive procedure causing acute traumatic injury.42 Once the probe is implanted, microdialysis offers the advantage of allowing repeated or continuous sampling in freely moving animals....
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...These include the retrodialysis method, the zero-net-flux approaches,(44) and the reference method.(40) Moreover, the underlying pharmacokinetic principles need to be considered in the interpretation when microdialysis is used to analyze BBB permeability....
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...Brain microdialysis The microdialysis technique has gained increasing popularity over the last decade for studying drug distribution to the CNS.(40,41) This method requires stereotaxic probe implantation under anesthesia, which is an invasive procedure causing acute traumatic injury....
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...to be known, which requires the separate measurement of total tissue concentrations.(40,47) Erroneous conclusions...
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TL;DR: The rate of Mn efflux from the brain is consistent with diffusion, and injection of Mn ion or Mn citrate into the brain would be expected to result in rapid formation of the same Mn species in brain extracellular fluid.
Abstract: There is concern about manganese (Mn) neurotoxicity Mn can enter the brain by carrier-mediated influx There have been no previous reports of investigation of Mn efflux from the brain We used an established method that determines the rate of efflux out of the brain across the blood-brain barrier (BBB) from the product of the brain distribution volume (Vbrain) and the apparent elimination rate constant (Kel) Vbrain is determined as 54Mn uptake into rat parietal brain slices versus time Kel is determined from the percentage of 54Mn remaining in the brain at various times after its discrete injection into the parietal cortex, compared to a reference compound which is expected to very slowly diffuse out of the brain The Mn ion, Mn citrate and Mn transferrin (Mn Tf) were studied 14C-sucrose and 14C-dextran were used as reference compounds The volume of distribution of the Mn species in brain slices was approximately 3-5 ml/g, indicating concentrative uptake Mn, as the Mn ion or Mn citrate, was injected into the brain with sucrose or dextran to determine Kel Based on the rapid exchange rate of Mn with ligands and on thermodynamic calculations, injection of Mn ion or Mn citrate into the brain would be expected to result in rapid formation of the same Mn species, predominantly the Mn ion, Mn citrates and Mn phosphate, in brain extracellular fluid After injection into the brain Mn did not efflux from the brain more rapidly than sucrose or dextran, which diffuse across the BBB Brain capillary diffusion of the Mn ion and Mn citrate would be expected to be slower than sucrose or dextran The rate of Mn efflux from the brain is consistent with diffusion
101 citations
Cites background from "Application of an in vivo brain mic..."
..., 1991) and microdialysis (Yokel, 2001; Deguchi and Morimoto, 2001)....
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01 Jan 2004
TL;DR: In situ rat brain perfusion was used to study influx across the blood-brain barrier of three predominant plasma Mn species available to enter the brain, suggesting transporter-mediated uptake of these species and suggesting that diffusion mediates distribution from rat brain to blood.
Abstract: Increased manganese (Mn) use in manufacturing and in gasoline has raised concern about Mn-induced parkinsonism. Previous research indicated carrier-mediated brain entry but did not assess brain efflux. Using in situ rat brain perfusion, we studied influx across the blood-brain barrier (BBB*) of three predominant plasma Mn species available to enter the brain: Mn2+, Mn citrate, and Mn transferrin. Our results suggested transporter-mediated uptake of these species. The uptake rate was greatest for Mn citrate. Our results using the brain efflux index method suggested that diffusion mediates distribution from rat brain to blood. To characterize the carriers mediating brain Mn uptake, we used rat erythrocytes, an immortalized murine BBB cell line (b.End5), primary bovine brain endothelial cells (bBMECs), and Sprague Dawley and Belgrade rats. Studies with bBMECs and b.End5 cells suggested concentrative brain Mn2+ and Mn citrate uptake, respectively, consistent with carrier-mediated uptake. Mn2+ uptake positively correlated with pH, suggesting mediation by an electromotive force. Mn2+ uptake was not inhibited by iron or the absence of divalent metal transporter 1 (DMT-1) expression, suggesting an iron-transporter-independent mechanism. Mn2+ uptake inversely correlated with calcium and was affected by calcium channel modulators, suggesting a role for calcium channels. Rat erythrocyte results suggested monocarboxylate transporter 1 (MCT1) and anion exchange transporters do not mediate Mn citrate brain uptake. Considering carrier-mediated brain influx (but not efflux), repeated excessive Mn exposure should produce brain accumulation. Further work is necessary to identify the specific transporter or transporters mediating Mn distribution across the BBB.
60 citations
Cites methods from "Application of an in vivo brain mic..."
...Whole-animal techniques have included measuring the decrease in brain content over time after a bolus intracarotid injection (Oldendorf et al 1982; Cornford et al 1985); comparing the ratios of coinjected substances over time (Leininger et al 1991); and microdialysis (Deguchi and Morimoto 2001; Yokel 2001)....
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TL;DR: The present review will give comprehensive details of extensive research being done in field of nanostructured carriers to transport the drugs through the BBB in a safe and effective manner to give an insight to the researchers working on neurodegenerative and non-neurodegeneration diseases of the CNS including brain tumor.
Abstract: Context: It is well-known fact that blood brain barrier (BBB) hinders the penetrance and access of many pharmacotherapeutic agents to central nervous system (CNS). Many diseases of the CNS remain undertreated and the inability to treat most CNS disorders is not due to the lack of effective CNS drug discovery, rather, it is due to the ineffective CNS delivery. Therefore, a number of nanostructured drug delivery carriers have been developed and explored over the past couple of years to transport the drugs to brain. Objective: The present review will give comprehensive details of extensive research being done in field of nanostructured carriers to transport the drugs through the BBB in a safe and effective manner. Methods: The method includes both the polymeric- and lipid-based nanocarriers with emphasis on their utility, methodology, advantages, and the drugs which have been worked on using a particular approach to provide a noninvasive method to improve the drug transport through BBB. Results: Polymeric- a...
51 citations
TL;DR: It appears that the observed behavioural effects of 2-PMPA may not be mediated by NAAG nor, in turn, by mGluR3 receptors, and the NAAg concentration in the ECF did not reach levels which are likely to have an impact on any known target.
41 citations