Figure 2 . A summary of the modifications to TJ, adhesion
junctions and efflux transporter expression at ALS CNS barriers. The
abundance of TJ and adhesion proteins are generally reduced, leading to
a compromised junctional integrity and increase in paracellular
permeability. The basement membrane thickness is reported to either
increase as a reparative mechanism or decrease with reduced collagen and
laminin in ALS, with discrepancies reported in human tissues, while
being consistently decreased in animal models. The expression of P-gp
and BCRP are generally increased in ALS, which is expected to result in
reduced CNS exposure of drugs that are substrates for these efflux
transporters. ZO: zonula occludens, P-gp: P-glycoprotein, BCRP: breast
cancer resistance protein, JAM: junctional adhesion molecules.
Summary and future directions
Human and rodent studies have consistently demonstrated ultrastructural
abnormality, increased paracellular permeability and elevated P-gp (and
sometimes BCRP) expression and activity at the CNS barriers in ALS.
Based on the reports of reduced TJ function, it would be expected that
general CNS permeability to drugs would be elevated in ALS, however,
this may be counteracted especially if the drugs are substrates of P-gp
and/or BCRP. Furthermore, if there is indeed a thickening of the
cerebral or spinal microvasculature basement membrane, this could result
in lower brain and spinal cord access of drugs as has been reported in a
mouse model of AD with thickened cerebrovascular basement membrane
(Mehta, Short & Nicolazzo, 2013). Therefore, it is clear that a more
detailed functional analysis of transport processes of many drugs which
are trafficked via different mechanisms (i.e. paracellular,
transcellular, substrates of influx and efflux transporters) is required
so as to predict how CNS access of drugs indeed alters in ALS.
With disease progression, the expression and activity of P-gp and BCRP
generally increases, which may lead to suboptimal drug delivery, while
this yet to be confirmed in people with ALS, for example, by using PET
imaging. If this is validated in humans, specialised approaches can be
trialled to improve the CNS access of riluzole (and other CNS-acting
drugs) to improve therapeutic outcomes. This can be via pharmacological
manipulation of P-gp expression and activity or by transiently
disrupting the CNS barriers using emerging technology such as MR-guided
focused ultrasound (Abrahao et al., 2019).
Our current understanding of the CNS barriers in ALS is still limited.
The majority of studies have only investigated P-gp and BCRP expression.
Proteomic studies can be performed using microvessels isolated from
post-mortem ALS human brain/spinal cords or from transgenic ALS mice, to
generate a more detailed status of the ALS BBB and BSCB. A better
appreciation of the status of BBB/BSCB influx transporters in ALS can
assist in the design of new chemical entities that can specifically
target these influx transporters to enhance CNS exposure of otherwise
impermeable drugs. These studies will also highlight, based on their
affinity to transporters, which drugs not intended to reach the CNS have
increased CNS access in ALS, informing which drugs may require dosage
adjustment so as to avoid excessive CNS exposure. Ultimately, this will
guide optimum dosing in individuals for all medications consumed by
people with ALS to maximise effectiveness (when CNS access is required)
and minimise CNS toxicity (when CNS access is not desirable), overall
enhancing optimum use of medicines in individuals with ALS.