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N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury

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Neurotherapeutics

Abstract

N-Acetylcysteine (NAC) has shown promise as a putative neurotherapeutic for traumatic brain injury (TBI). Yet, many such promising compounds have limited ability to cross the blood–brain barrier (BBB), achieve therapeutic concentrations in brain, demonstrate target engagement, among other things, that have hampered successful translation. A pharmacologic strategy for overcoming poor BBB permeability and/or efflux out of the brain of organic acid-based, small molecule therapeutics such as NAC is co-administration with a targeted or nonselective membrane transporter inhibitor. Probenecid is a classic ATP-binding cassette and solute carrier inhibitor that blocks transport of organic acids, including NAC. Accordingly, combination therapy using probenecid as an adjuvant with NAC represents a logical neurotherapeutic strategy for treatment of TBI (and other CNS diseases). We have completed a proof-of-concept pilot study using this drug combination in children with severe TBI—the Pro-NAC Trial (ClinicalTrials.gov NCT01322009). In this review, we will discuss the background and rationale for combination therapy with probenecid and NAC in TBI, providing justification for further clinical investigation.

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Acknowledgements

The Pro-NAC trial and pharmacometabolomic study were supported by R01 NS069247 (RSBC, PEE, PMK, MJB). PMK is supported by the Ake Grenvik Endowment.

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Authors and Affiliations

  1. Departments of Critical Care Medicine and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Robert S. B. Clark

  2. Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA

    Robert S. B. Clark & Patrick M. Kochanek

  3. UPMC Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA

    Robert S. B. Clark & Patrick M. Kochanek

  4. Department of Pharmacy & Therapeutics, Center for Clinical Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Philip E. Empey

  5. Departments of Critical Care Medicine, Anesthesiology, and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Patrick M. Kochanek

  6. Division of Critical Care Medicine, Department of Pediatrics, Children’s National Medical Center, Washington, DC, USA

    Michael J. Bell

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  1. Robert S. B. Clark
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Clark, R.S.B., Empey, P.E., Kochanek, P.M. et al. N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury. Neurotherapeutics 20, 1529–1537 (2023). https://doi.org/10.1007/s13311-023-01422-z

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