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.