Here we summarize three aspects of our understanding of the interactions
of cytokines and neurotrophic peptides/proteins with the blood-brain and bloodspinal
cord barriers (BBB): (a) pharmacokinetic analysis that has been reported for
native cytokines and neurotrophic peptides/proteins; (b) landmark work on
conjugated proteins to enhance their delivery across the normal BBB; and (c)
regulatory changes under pathophysiological conditions in rodents, particularly after
spinal cord injury (SCI). First, though the BBB restricts the permeation of large
proteins, some cytokines and neurotrophic peptides/proteins in the periphery can
reach the central nervous system (CNS) by specific transport systems. Moreover,
SCI and some other disease processes may regulate these transport systems. The
significance of studies of the transport systems is obvious because of the biological impact of these
molecules on the CNS in health and disease. We have characterized the pharmacokinetic characteristics
of some stable cytokines and neurotrophic peptides/proteins in mice after intravenous administration
and also in the setting of in situ brain perfusion. In the particular case of SCI, there are time- and regionspecific
changes of BBB permeability and transport systems. Tumor necrosis factor-α, a cytokine with
dual actions in regeneration of the spinal cord, has a slow basal influx into the brain and spinal cord.
After SCI, the increase in the entry of tumor necrosis factor-α to the CNS differs from leakage after
BBB disruption and is related to upregulation of the transport system in a unique temporal and regional
pattern. Overall, the permeation of cytokines across the BBB can be mediated by specific transport
systems. The regulation of transport in pathophysiological conditions affects the extent of
neuroinflammation and is implicated in neuroregeneration.
Keywords: Blood-brain barrier, blood-spinal cord barrier, cytokines, neurodegeneration, neurotrophins, tumor necrosis factor.
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