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On the other hand, lipid-soluble antioxidants as vitamin E cross the BBB slowly and may require prolonged exposure to achieve meaningful brain concentrations, where none of the vitamin-based AMS trials assessed these agents reach the relevant target tissues, this evident limitation strongly constrains interpretation of clinical outcomes and underscores the PK-PD disconnect between theoretical neuroprotective effect and observed efficacy (Table 3)

Unresolved inflammation can result in sustained and the production of multiple factors that contribute to decreased TJ expression and increased BBB permeability, including interleukin (IL)-1, tumor necrosis factor alpha (TNF-), IL-6, nuclear factor kappa B (NF-B), matrix metalloproteinase (MMP)-9, advanced glycation end-products (AGEs), and reactive oxygen species (ROS) (Hofmann et al., 1999

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