N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury

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, th...

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Bibliographic Details
Published in:Neurotherapeutics 2023-10, Vol.20 (6), p.1529-1537
Main Authors: Clark, Robert S. B., Empey, Philip E., Kochanek, Patrick M., Bell, Michael J.
Format: Article
Language:English
Subjects:
Acetylcysteine
Acetylcysteine - pharmacology
Acetylcysteine - therapeutic use
Adjuvant therapy
Adjuvants
Biomedical and Life Sciences
Biomedicine
Blood-Brain Barrier
Brain
Brain Injuries, Traumatic - drug therapy
Child
Humans
Membrane permeability
Neurobiology
Neurology
Neurosciences
Neurosurgery
Organic acids
Permeability
Pilot Projects
Probenecid - pharmacology
Probenecid - therapeutic use
Review
Traumatic brain injury
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Summary: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.
ISSN:1933-7213
1878-7479
1878-7479
DOI:10.1007/s13311-023-01422-z