Maternal N-Acetyl-Cysteine Prevents Neonatal Hypoxia-Induced Brain Injury in a Rat Model

Abstract

Perinatal hypoxia is a major cause of infant brain damage, lifelong neurological disability, and infant mortality. N-Acetyl-Cysteine (NAC) is a powerful antioxidant that acts directly as a scavenger of free radicals. We hypothesized that maternal-antenatal and offspring-postnatal NAC can protect offspring brains from hypoxic brain damage.Sixty six newborn rats were randomized into four study groups. Group 1: Control (CON) received no hypoxic intervention. Group 2: Hypoxia (HYP)-received hypoxia protocol. Group 3: Hypoxia-NAC (HYP-NAC). received hypoxia protocol and treated with NAC following each hypoxia episode. Group 4: NAC Hypoxia (NAC-HYP) treated with NAC during pregnancy, pups subject to hypoxia protocol. Each group was evaluated for: neurological function (Righting reflex), serum proinflammatory IL-6 protein levels (ELISA), brain protein levels: NF-κB p65, neuronal nitric oxide synthase (nNOS), TNF-α, and IL-6 (Western blot) and neuronal apoptosis (histology evaluation with TUNEL stain). Hypoxia significantly increased pups brain protein levels compared to controls. NAC administration to dams or offspring demonstrated lower brain NF-κB p65, nNOS, TNF-α and IL-6 protein levels compared to hypoxia alone. Hypoxia significantly increased brain apoptosis as evidenced by higher grade of brain TUNEL reaction. NAC administration to dams or offspring significantly reduce this effect. Hypoxia induced acute sensorimotor dysfunction. NAC treatment to dams significantly attenuated hypoxia-induced acute sensorimotor dysfunction. Prophylactic NAC treatment of dams during pregnancy confers long-term protection to offspring with hypoxia associated brain injury, measured by several pathways of injury and correlated markers with pathology and behavior. This implies we may consider prophylactic NAC treatment for patients at risk for hypoxia during labor.

Intestine and brain TLR-4 modulation following N-acetyl-cysteine treatment in NEC rodent model

“…This finding is in accordance with the findings by Niño et al 9 . Although we did not evaluate behavior in the current study, we demonstrated in a previous study on a hypoxia model (not NEC model), that NAC treatment significantly attenuated sensorimotor dysfunction in neonatal rats exposed to hypoxia 13 . In another study, we found that NAC protected the brain from injury as compared to LPS group, as demonstrated by MRI at 30 days of age 25 .…”

“…The FDA suggests that a safe and effective dose of NAC for treating acetaminophen overdose is between 150 mg/kg and 300 mg/kg per day 12 . Studies in perinatology have used doses ranging from 300 mg/kg 13 to 1 g/kg 14 . In our current and previous research, we have utilized a dose of 300 mg/kg of NAC 15 , 16 .…”