title: Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid.
abstract: N-acetyl cysteine (NAC) supports the synthesis of glutathione (GSH), an essential substrate for fast, enzymatically catalyzed oxidant scavenging and protein repair processes. NAC is entering clinical trials for adrenoleukodystrophy, Parkinson's disease, schizophrenia, and other disorders in which oxidative stress may contribute to disease progression. However, these trials are hampered by uncertainty about the dose of NAC required to achieve biological effects in human brain. Here we describe an approach to this issue in which mice are used to establish the levels of NAC in cerebrospinal fluid (CSF) required to affect brain neurons. NAC dosing in humans can then be calibrated to achieve these NAC levels in human CSF. The mice were treated with NAC over a range of doses, followed by assessments of neuronal GSH levels and neuronal antioxidant capacity in ex vivo brain slices. Neuronal GSH levels and antioxidant capacity were augmented at NAC doses that produced peak CSF NAC concentrations of ≥50 nM. Oral NAC administration to humans produced CSF concentrations of up to 10 μM, thus demonstrating that oral NAC administration can surpass the levels required for biological activity in brain. Variations of this approach may similarly facilitate and rationalize drug dosing for other agents targeting central nervous system disorders.
authors.affiliation: Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA, 94121, USA.|The Department of Neurology, University of California, San Francisco Medical Center, San Francisco, CA, USA.
authors.forename: Reno C
authors.initials: RC
authors.lastname: Reyes
authors.affiliation: Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA, 94121, USA.|The Department of Neurology, University of California, San Francisco Medical Center, San Francisco, CA, USA.|Programa de Pós Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil.|Science Without Borders, CNPq, Brasilia, Brazil.
authors.forename: Giordano Fabricio
authors.initials: GF
authors.lastname: Cittolin-Santos
authors.affiliation: Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA, 94121, USA.|The Department of Neurology, University of California, San Francisco Medical Center, San Francisco, CA, USA.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA, 94121, USA.|The Department of Neurology, University of California, San Francisco Medical Center, San Francisco, CA, USA.
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.affiliation: Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA, 94121, USA.|The Department of Neurology, University of California, San Francisco Medical Center, San Francisco, CA, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Brennan-Minnella
authors.affiliation: Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA, 94121, USA.|The Department of Neurology, University of California, San Francisco Medical Center, San Francisco, CA, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Katz
authors.affiliation: Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA, 94121, USA.|The Department of Neurology, University of California, San Francisco Medical Center, San Francisco, CA, USA.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Glass
authors.affiliation: Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA, 94121, USA. raymond.swanson@ucsf.edu.|The Department of Neurology, University of California, San Francisco Medical Center, San Francisco, CA, USA. raymond.swanson@ucsf.edu.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Swanson
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage* / Q000134:cerebrospinal fluid; D000818:Animals; D000975:Antioxidants / Q000032:analysis; D001923:Brain Chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000134:cerebrospinal fluid*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; D005978:Glutathione; D000111:Acetylcysteine
keywords: Cysteine; Parkinson’s disease; cerebrospinal fluid; human; oxidative stress; target engagement