2.2 CNS barriers and drug delivery
The presence of efflux drug transporters such as P-gp and BCRP at CNS
barriers, in addition to the TJ architecture, are known to limit the CNS
access of drugs, reducing their ability to reach their site of action
within the brain (Nicolazzo, Charman & Charman, 2006). Pharmacological
inhibition of P-gp has been trialled as an approach to improve CNS drug
delivery; however, this approach has not been clinically-translated due
to the undesirable effects associated with blanket suppression of P-gp
function (Davis, Sanchez-Covarubias & Tome, 2014). On the other hand,
influx transporters have been targeted to improve CNS drug delivery. For
example, drugs and prodrugs (e.g. L-DOPA, melphalan, and gabapentin)
have been designed to be recognised as substrates to LAT1 (Puris,
Gynther, Auriola & Huttunen, 2020), leading to improved brain uptake
and effectiveness.
While CNS barriers are considered a major barrier to drug delivery under
healthy conditions, it is becoming increasingly apparent that these
barriers are modulated in various diseases of the CNS, such as AD and PD
(Pan & Nicolazzo, 2018). This has been shown to lead to altered drug
access to the CNS, potentially resulting in a loss of desirable
pharmacological effects or an increased risk of CNS adverse effects.
While there has been significant focus on CNS barrier modifications in
AD and PD (Al-Bachari, Naish, Parker, Emsley & Parkes, 2020; Sweeney,
Sagare & Zlokovic, 2018), less studies have focused on modification to
the CNS barriers in ALS. Therefore, this review will (i) provide a
contemporary update on the status of the BBB and BSCB in ALS, (ii)
provide insight into the potential impact of these changes on CNS drug
exposure and medicine use in people with ALS, and (iii) suggest
recommendations for future research directions to ensure effective CNS
drug delivery and medicine use in ALS.
Modification of CNS barriers in ALS
Many of the studies reporting altered CNS barrier function in sporadic
ALS are based on observations using post mortem human tissues, while
transgenic rodent models expressing mutant genes, e.g. superoxide
dismutase 1 G93A (SOD1G93A) have significantly
contributed to our understanding of CNS barrier changes in familial ALS
(summarised in Table 1 , Table 2 and graphically
presented in Figure 2 ).