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Paths to Successful Translation of New Therapies for Severe Traumatic Brain Injury in the Golden Age of Traumatic Brain Injury Research: A Pittsburgh Vision

“…Recently, our translational TBI research group in Pittsburgh used another type of pharmacodynamics/response biomarker, namely, cerebrospinal fluid (CSF) pharmacometabolomics to assess the impact of treatment with the combination of the antioxidant, N-acetylcysteine (NAC), and the drug transport inhibitor, probenecid, on its key target, namely the glutathione pathway after severe TBI in children. 5,82 Although NAC crosses the BBB, 83 the CSF concentrations that are achieved are only a tiny fraction (<0.1%) of those achieved in blood. 5,83 This is partly because NAC is rapidly transported back into blood by the organic acid transporters 1 and 3.…”

“…5,82 Although NAC crosses the BBB, 83 the CSF concentrations that are achieved are only a tiny fraction (<0.1%) of those achieved in blood. 5,83 This is partly because NAC is rapidly transported back into blood by the organic acid transporters 1 and 3. Probenecid inhibits those transporters and thus enhances brain exposure of NAC to levels measurable in human CSF.…”

“…Probenecid inhibits those transporters and thus enhances brain exposure of NAC to levels measurable in human CSF. 83 NAC serves both as a direct antioxidant and a source for the synthesis of glutathione. Treatment with probenecid and NAC produced a significant alteration in the CSF metabolomic signature of TBI.…”

“…Relative glutathione levels were increased >600-fold after treatment with NAC plus probenecid, and both pathway and network analyses showed that biochemical processes involving detoxification with glutathione and glutathione recycling were enriched by treatment verifying target engagement. 5,83 CSF metabolomics, in severe TBI-where CSF is often available-thus has potential to serve as a pharmacodynamics/response monitor of target engagement by a given therapy in severe TBI. Not only can the primary target and its metabolites be assessed, but also other off-target and/or unanticipated effects can be interrogated.…”