3.1.3 Increased expression of P-gp and BCRP
The cellular distribution and expression of P-gp and BCRP has been
assessed in the cervical spinal cord and motor cortex obtained from
individuals with ALS. Using immunohistochemistry, van Vliet et
al. has demonstrated a dramatic (~30-fold) increase in
P-gp abundance in cervical spinal cord and motor cortex astrocytes in
ALS tissues relative to control specimens, while P-gp abundance at the
endothelial cell lining of microvessels was comparable between control
and ALS spinal cord and motor cortex specimens (van Vliet et al., 2019).
A similar study was conducted by Jablonski et al. , who reported
an elevated P-gp abundance in microvessels from ALS lumbar spinal cord
(Jablonski et al., 2012). The discrepancies between these studies could
be due to different CNS regions assessed (cervical spinal cord, lumbar
spinal cord, and motor cortex). In terms of BCRP, microvasculature
expression was observed in both control and ALS specimens, and its
abundance did not differ between control and ALS in the cervical spinal
cord but was marginally increased in the ALS motor cortex (van Vliet et
al., 2019).
Further studies are required to confirm these findings and possibly
improve our understanding of CNS barriers protein expression in ALS,
i.e. beyond P-gp and BCRP. Specialised microvascular isolation
techniques can be implemented to obtain high purity of microvessels or
isolated endothelial cells, which can be analysed via proteomic
approaches. Such approaches may identify modified expression of efflux
and influx transporters in ALS, which can assist in (i) targeting
transporters to increase CNS exposure of otherwise impermeable compounds
and (ii) guiding dosage regimen design of medicines which are substrates
for such transporters to avoid potential CNS toxicity. Furthermore, the
functional consequence of these expression changes on CNS drug exposure
in humans is completely lacking, and could be confirmed using positron
emission tomography studies with 11C-verapamil (as a
substrate of P-gp) as has been undertaken in humans with AD and PD
(Bartels et al., 2008; Lubberink, van Assema, Hendrikse, Schuit,
Lammertsma & Van Berckel, 2010).