title: Autophagy in neonatal hypoxia ischemic brain is associated with oxidative stress.
abstract: Autophagy is activated when the neonatal brain exposed to hypoxia ischemia (HI), but the mechanisms underlying its activation and its role in the neuronal cell death associated with HI is unclear. We have previously shown that reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase play an important role in HI-mediated neuronal cell death. Thus, the aim of this study was to determine if ROS is involved in the activation of autophagy in HI-mediated neonatal brain injury and to determine if this is a protective or deleterious pathway. Initial electron microscopy data demonstrated that autophagosome formation is elevated in P7 hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD). This corresponded with increased levels of LC3II mRNA and protein. The autophagy inhibitor, 3-methyladenine (3-MA) effectively reduced LC3II levels and autophagosome formation in hippocampal slice cultures exposed to OGD. Neuronal cell death was significantly attenuated. Finally, we found that the pharmacologic inhibition of NADPH oxidase using apocynin or gp91ds-tat decreased autophagy in hippocampal slice cultures and the rat brain respectively. Thus, our results suggest that an activation of autophagy contributes to neonatal HI brain injury this is oxidative stress dependent.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Harris
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Sanjv
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Pharmacy Practice & Science, Department of Medicine, The University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Mansour
authors.affiliation: Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona, Tucson, AZ 85724, USA. Electronic address: steveblack@email.arizona.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D046509:Tissue Culture Techniques
chemical_list: D000098:Acetophenones; C056165:acetovanillone; D019255:NADPH Oxidases
keywords: Autophagy; Hypoxia–ischemia; NADPH oxidase; Neonatal brain; Neuronal cell death