Invertebrate models for CNS drug discovery


The blood brain barrier (BBB) provides an added challenge to successful neuroscience drug discovery programs. The presence of metabolising enzymes, tight junctions and efflux transporters in the BBB are effective at preventing the passage of xenobiotics into the central nervous system (CNS).

In response to this extra barrier, a variety of in silico, in vivo and in vitro models have been generated to try to understand and assess BBB permeability at earlier stages in the drug discovery process reviewed in depth by Abbott.[1] In general the majority in vitro models lack the structural and functional complexity of the BBB and require multiple assays for an adequate prediction of permeability. In vivo models on the other hand are reflective of the real situation of the BBB, but unfortunately are both low through put and resource intensive, making them inadequate for screening larger sets of compounds needed at the early stages of a drug discovery project.

This year I attended a conference (ISNTD-d3 2015), where I saw a presentation by Dr Peter Nielsen from the company N2MO, on an ex vivo insect brain model for assessing BBB permeability. (Presentation found here: http://www.isntd.org/#/isntd-d-2015-nielsen/4589881601). The model itself provides medium throughput (~6 compounds a day) method of assessing BBB permeability of a compound. The advantage this model provides is that the insect BBB is similar in structure to the mammalian BBB. Tight junctions, high content of lipids and similar ABC and SLC transporters are all present in the insect brain,[2] suggesting reasons for why the model correlates well to rat perfusion models, where in vitro models fail. The model also provides the opportunity to measure the kinetics of permeability, as well as generating a figure of total uptake, paracellular diffusion and transcellular transport can also be discriminated.[3] Overall the extent of data generated from this model provides an adequate platform for the early assessment of BBB permeability, a bonus considering that these assays can be run with the first research batch of compound as requirement of material is low.[4] A model well worth considering for neuroscience drug discovery projects.

N2MO company website – http://n2mo.co/

Blog written by Ryan West

[1]         N. J. Abbott, Drug Discov. Today Technol. 2004, 407–416.

[2]         S. Al-qadi, M. Schiøtt, S. Honoré, P. Aadal, L. Badolo, BBA – Gen. Subj. 2015, 1850, 2439–2451.

[3]         K. Hellman, P. A. Nielsen, L. R. Olsen, R. Verdonck, N. J. Abbott, J. Vanden Broeck, G. Andersson, Pharmacol. Res. Perspect. 2014, 2, 1–12.

[4]         P. A. Nielsen, O. Andersson, S. Honore, G. Andersson, Drug Discov. Today 2011, 16, 12–15.

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