The Grasshopper: A Novel Model for Assessing Vertebrate Brain Uptake

@article{Andersson2013TheGA,
  title={The Grasshopper: A Novel Model for Assessing Vertebrate Brain Uptake},
  author={Olga Andersson and Steen Honor{\'e} Hansen and Karin Hellman and Line R{\o}rb{\ae}k Olsen and Gunnar Andersson and Lassina Badolo and Niels Svenstrup and Peter Aadal Nielsen},
  journal={The Journal of Pharmacology and Experimental Therapeutics},
  year={2013},
  volume={346},
  pages={211 - 218}
}
The aim of the present study was to develop a blood-brain barrier (BBB) permeability model that is applicable in the drug discovery phase. The BBB ensures proper neural function, but it restricts many drugs from entering the brain, and this complicates the development of new drugs against central nervous system diseases. Many in vitro models have been developed to predict BBB permeability, but the permeability characteristics of the human BBB are notoriously complex and hard to predict… 
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References

SHOWING 1-10 OF 37 REFERENCES
Novel models for assessing blood–brain barrier drug permeation
TLDR
This focused review covers novel models which have been developed or are in the process of being developed which can be used in modeling BBB and the main model organisms covered here are the grasshopper, fruit fly and zebrafish.
Assays to predict drug permeation across the blood-brain barrier, and distribution to brain.
TLDR
In combination with in silico and in vivo models, the portfolio of methods establishing and predicting CNS drug PK is now very powerful, allowing much more accurate iterative feedback to chemists to optimise compound profiles through the drug discovery and development programme.
Evolutionary Conservation of Vertebrate Blood–Brain Barrier Chemoprotective Mechanisms in Drosophila
TLDR
The Drosophila melanogaster (Dm) humoral/CNS barrier conserves the xenobiotic exclusion properties found in the vertebrate vascular endothelium and this data indicates that the ancient origins of CNS chemoprotection extend to both conserved molecular means and functionally analogous anatomic spaces that together promote CNS selective drug partition.
In vitro models of the blood-brain barrier.
TLDR
The in vitro BBB model is characterized by high transendothelial electrical resistance (TEER regularily above 200 Ohm x cm(2), low permeability and expression of several transporters, which has proven that the model is suitable for basic research and for testing the interaction between the BBB and potential drug candidates (toxicity, permeability, interaction with effluxTransporters) as well.
Models for predicting blood-brain barrier permeation.
Progress in Brain Penetration Evaluation in Drug Discovery and Development
TLDR
This review discusses strategies to optimize brain penetration from the perspective of drug discovery and development and proposes the following strategies for addressing drug transporters at the blood-brain barrier.
P-glycoprotein deficient mouse in situ blood-brain barrier permeability and its prediction using an in combo PAMPA model.
In vivo, in vitro and in silico methods for small molecule transfer across the BBB.
TLDR
This review gives a comprehensive overview of different approaches currently considered in drug discovery to circumvent the lack of small molecule transfer through the BBB, together with their inherent advantages and disadvantages.
Structure and function of the blood–brain barrier
Physiologic and anatomic characterization of the brain surface glia barrier of Drosophila
TLDR
It is concluded that many unique BBB physiologies are conserved across phyla and suggest new methods for modeling CNS physiology and disease.
...
1
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3
4
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