3.2.4 Leaky CNS barriers
An increased paracellular permeability of the BSCB was clearly
demonstrated by intravenous injection of Evans Blue, a tracer used to
assess barrier disruption, in SOD1G93A mice
(Garbuzova-Davis et al., 2007). Vascular leakage (indicated by Evans
Blue extravasation) was observed in lumbar spinal cord, and cervical
spinal cord from 13 weeks of age in SOD1G93A mice.
Considerable vessel permeability was observed in early as well as late
stage symptomatic SOD1G93A mice. Notably, more
vascular leakage was detected in the lumbar spinal cord than cervical
spinal cord at the late stage of disease. Using Evans Blue again, vessel
leakiness has been demonstrated in the spinal cord and brain stem, but
not the brain, of SOD1G93A rats at symptomatic stages
(Nicaise et al., 2009). However, using a sensitive magnetic resonance
imaging approach, increased BBB permeability was demonstrated in the
brains of SOD1G93A rats (Andjus et al., 2009).
Overall, these studies demonstrate increased permeability of CNS
barriers in rodent models of ALS, which is expected based on reduced TJ
expression in these models. However, whether such changes lead to
altered drug penetration into the spinal cord or brain of ALS mice
remains to be investigated. It would be hypothesised that drug
penetration would increase in mouse models of ALS based on the reported
TJ dysfunction and paracellular, however, the modifications in efflux
transporter expression (described below) may counteract this leakiness,
and indeed reduce CNS exposure of drugs.