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.

N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E2 to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

“…51 As we plan to try to avoid these enormous challenges in moving our studies of NAC forward for ICH, we will need to develop a good biomarker for NAC's therapeutic effect in humans. Almost all studies chose doses of NAC that are safe, but without clear elucidation of the dose required to induce a therapeutic effect.…”

“…Cerebrospinal fluid measurements could improve fidelity of glutathione measurements, but a threshold level of increase of glutathione has yet to be elucidated in any paradigm. 51 As we plan to try to avoid these enormous challenges in moving our studies of NAC forward for ICH, we will need to develop a good biomarker for NAC's therapeutic effect in humans. Given the ability of PGE 2 to synergize with NAC in mice to induce functional recovery, it is our hypothesis that understanding precisely how this combination is effective will provide the best chances of neuroprotection with the widest therapeutic window in humans, once a good biomarker for NAC efficacy (possibly an ALOX5 metabolite) is identified.…”

Opposite in vivo effects of agents that stimulate or inhibit the glutamate/cysteine exchanger system on the inhibition of hippocampal LTP by Aß

“…Yet, any increased glutamate extrusion caused by stimulation of system by NAC was clearly insufficient to inhibit LTP at either 1 or 12 h after injection on its own. Interestingly, the relative ability of NAC to increase intracellular GSH and extracellular glutamate concentrations is state‐dependent (Baker et al, ; Choy et al, ; Kupchik et al, ; Reyes et al, ). An alternative or additional explanation for the delayed beneficial action of NAC is that it may trigger a gradual increase in the expression of amino acid transporters that mediate glutamate uptake, and thereby promote the clearance of excess glutamate from the extracellular space.…”

“…NAC has been found to increase GSH synthesis in brain both directly and indirectly (Holmay et al, 2013;Zhou et al, 2015). Although the extent of blood brain barrier permeability of NAC is somewhat controversial, available evidence indicates that the levels in CSF increase rapidly and transiently, peaking 20 min after acute injection (Reyes et al, 2016), consistent with NAC's short elimination half-life (30 min in mice, Zhou et al, 2015). In contrast, NAC has been found to elicit a more gradual increase in brain GSH synthesis, reaching a plateau within 3-6 h after acute administration (Holmay et al, 2013;Zhou et al, 2015).…”

Disrupting pathogenic interactions between α-synuclein, c-Abl, and redox stress

“…2A). The H 2 O 2 -induced c-Abl activation was suppressed by N-acetyl-cysteine (NAC), a thiol agent previously shown to support neuronal glutathione synthesis 28,31 and to have salutary effects in animal models of PD 28,32,33 . We next evaluated the effect of redox stress on c-Abl activation in vivo, using EAAC1 -/mice.…”