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.

N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats

“…Furthermore, NAC has been investigated as a safe neuroprotectant in animal models and human neonates with hypoxic ischemic injury, infection, and white matter injury. 22,34,37,38 In addition, we have demonstrated that NAC can significantly increase [GSH] in the basal ganglia of neonates 5 days after hypoxic ischemic birth, mitigating ongoing oxidative stress. 34 Cerebral oxidative stress has been well described during acute opioid withdrawal.…”

“…Phantom solutions (0.5-5 mM GSH, 5 mM DTT, 10 mM Choline, 25 mM Creatine, phosphate-buffered saline, pH 7.1) were used to validate [GSH], [Cr], and [Cho] quantification by MRS, using the water peak as a standard. 34 Quantification of GSH and Cr in phantoms by LCModel processing with our specialized basis set showed excellent correlation with known concentrations of these metabolites. 34 The phantom solution standard curves for [GSH], [Cho], and [Cr] are shown in Fig.…”

“…34 Quantification of GSH and Cr in phantoms by LCModel processing with our specialized basis set showed excellent correlation with known concentrations of these metabolites. 34 The phantom solution standard curves for [GSH], [Cho], and [Cr] are shown in Fig. 1b.…”

“…Adapted from Barr et al 29,33,34 N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS. .…”

“…We did not make partial volume corrections in these immature animals with small cerebrospinal fluid spaces and largely uniform brain matter. The following metabolites were analyzed for absolute concentrations in the right hemisphere using a validated basis set for LCModel 34,36 that included GSH (Glutathione), GLX (Glutamate+Glutamine), Cr (Phosphocreatine +Creatine), NAA (NAA+N-acetylaspartylglutamate), and Cho (Cho-line+Glycerophosphocholine). Major peaks for these metabolites are noted on a representative spectrum (Fig.…”