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).