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.
Highlights
IntroductionPerinatal hypoxia is a major cause of infant brain damage, lifelong neurological disability, and infant mortality [1]
P65 and nNOSlevels compared to controls
We demonstrated that perinatal hypoxic brain damage is mediated by inflammation, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and neuronal nitric oxide synthase (nNOS) pathways, and brain apoptosis as described in other models [10,11,12,13,14,15,16,17]
Summary
Perinatal hypoxia is a major cause of infant brain damage, lifelong neurological disability, and infant mortality [1]. Severe hypoxic ischemic stress may cause cellular energy failure, loss of mitochondrial function, brain edema, and increased release of neurotransmitters and intracellular calcium [1,2,3]. These changes trigger pathological cascades activating microglia, which generate oxidative stress, pro-inflammatory cytokine release, and glutamate toxicity. Together, these factors lead to a vulnerability of preoligodendrocytes, especially during the preterm period, with resulting impairment of
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