NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes.

Dorothea D Jenkins,Milad Yazdani,Paolo Montaldo,Maximo Vento,Julia Kuligowski,Truman R Brown,Carol Wagner,Bruce W Hollis,Donald B Wiest,Hunter G Moss,Sudhin Thayyil

doi:10.3390/antiox10091344

Abstract

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.

Highlights

We previously demonstrated that NAC plus hypothermia improved outcomes over hypothermia alone in neonatal female, but not male, rats subjected to severe HI [37]
In a previous rapid communication, we reported our validation of MR spectroscopy (MRS) quantification of GSH in this cohort of convalescing hypoxic ischemic encephalopathy (HIE) infants, with mean basal ganglia (BG) [GSH] of 1.6 ± 0.2 mM
In neonates with moderate and severe HIE, oxidative stress continues for days after completion of therapeutic hypothermia, as reflected in low concentrations of reduced glutathione in the basal ganglia before NVD dosing on day of life (DOL) 5–6

Summary

Introduction

Therapeutic hypothermia provides significant neuroprotection for half of neonates with uncomplicated hypoxic ischemic encephalopathy (HIE), but not in more severe HIE or HIE complicated by chorioamnionitis [1,2,3,4,5,6]. Oxidative stress is both an early and persistent contributor to pathology in HIE [7,8,9,10,11]. Evidence in animal models and humans indicate that oxidative stress depletes reduced Glutathione (GSH) is the major intracellular antioxidant which scavenges reactive oxygen species (ROS) and is essential for cell survival [12,13].

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Results

Discussion

Conclusion