N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy

Abstract

Persistent oxidative stress depletes reduced glutathione (GSH), an intracellular antioxidant and an important determinant of CNS injury after hypoxia ischemia. We used standard, short echo time Stimulated Echo Acquisition Mode (STEAM) to detect GSH by magnetic resonance spectroscopy (MRS) in 24 term neonates with hypoxic-ischemic encephalopathy (HIE), on day of life 5-6, after rewarming from therapeutic hypothermia. MRS demonstrated reliable, consistent GSH of 1·64 ± 0·20 mM in the basal ganglia immediately before intravenous infusion of N-acetylcysteine. N-acetylcysteine resulted in a rapid and significant GSH increase to 1·93 ± 0.23 mM within 12-30 min after completion of infusion ( n = 21, p < 0.0001, paired t-test), compared with those who did not receive N-acetylcysteine ( n = 3, GSH = 1.66 ± 0.06 mM and 1.64 ± 0.09 mM). In one perinatal stroke patient, GSH in the diffusion-restricted stroke area was 1.0 mM, indicating significant compromise of intracellular redox potential, which also improved after N-acetylcysteine. For comparison, GSH in healthy term neonates has been reported at 2.5 ± 0.9 mM in the thalamus. This is the first report to show persistent oxidative stress reflected in GSH during the subacute phase in neonates with HIE and rapid response to N-acetylcysteine, using a short echo MRS sequence that is available on all clinical scanners without spectral editing.

Keywords: Glutathione; N-acetylcysteine; hypoxic-ischemic encephalopathy; magnetic resonance spectroscopy; vitamin D.

Figures

Figure 1.

LCModel quantification of [GSH] in phantom solutions.

Figure 2.

MR spectra using STEAM 20 ms, with peaks for GSH, NAA, Cr, and Cho noted (left). Spectral fitting with LCModel with (blue) and without (red) GSH cysteinyl peak at ∼2.95 ppm included in basis set (right).

Figure 3.

Representative voxel placement in the basal ganglia of near-term and term neonates with HIE.

Figure 4.

(a) [GSH] in the basal ganglia (except as noted) immediately before and after NAC* alone or NAC + calcitriol in HIE neonates on DOL 5–6 (n = 21). NVD 14, 17, 29 had NAC infusions paused due to pump malfunction, but did receive NAC prior to second MRS. An additional ROI was obtained in NVD 26 with voxel placement in left parietal stroke area, which was adjacent to the BG voxel placement. (b) GSH concentration in basal ganglia of HIE neonates, on DOL 5–6, for whom infusion of *NAC alone or NAC + calcitriol could not be completed prior to second MRS. Little change between pre- and post-infusion [GSH] values is noted. Mean and SD of individual GSH concentrations before and after NAC + calcitriol/NAC infusion are noted with black diamonds and error bars.

Figure 5.

Diffusion-weighted images showing ADC (a) and trace (b) parametric maps with clear stroke lesion delineation, (c) voxel placement in left parietal stroke area.