NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats

• Main Authors: Lauren E. Adams (Author), Hunter G. Moss (Author), Danielle W. Lowe (Author), Truman Brown (Author), Donald B. Wiest (Author), Bruce W. Hollis (Author), Inderjit Singh (Author), Dorothea D. Jenkins (Author)
• Format: Book
• Published: MDPI AG, 2021-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antiox10030489; 2076-3921
• Keywords: glutathione; glutamate; oxidative stress; hypoxia ischemia; endotoxin; magnetic resonance spectroscopy; Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 10, Iss 3, p 489 (2021)

Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O₂), followed by hypothermia alone or with <i>N</i>-acetylcysteine (25 mg/kg) and vitamin D (1,25(OH)₂D₃, 0.05 μg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was significantly decreased in all LPS-HI rats compared with baseline and sham controls. Two hours of hypothermia alone did not improve GSH and allowed glutamate + glutamine (GLX) to increase. Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection.