Abstract
Autophagy is a self-degradative process that involves turnover and recycling of cytoplasmic components in healthy and diseased tissue. Autophagy has been shown to be protective at the early stages of programmed cell death but it can also promote apoptosis under certain conditions. Earlier we demonstrated that oxygen contributes to the pathogenesis of neonatal brain damage, which can be ameliorated by intervention with recombinant human erythropoietin (rhEpo). Extrinsic- and intrinsic apoptotic pathways are involved in oxygen induced neurotoxicity but the role of autophagy in this model is unclear. We analyzed the expression of autophagy activity markers in the immature rodent brain after exposure to elevated oxygen concentrations. We observed a hyperoxia-exposure dependent regulation of autophagy-related gene (Atg) proteins Atg3, 5, 12, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3), LC3A-II, and LC3B-II which are all key autophagy activity proteins. Interestingly, a single injection with rhEpo at the onset of hyperoxia counteracted these oxygen-mediated effects. Our results indicate that rhEpo generates its protective effect by modifying the key autophagy activity proteins.
Highlights
Toxic levels of oxidative stress and reactive oxygen species (ROS) are a common pathway in many neurodegenerative disorders
Due to the neuro-protective ability of recombinant human erythropoietin (rhEpo) in different neonatal brain injury models [31,33,34,35,36], we investigated the effect of rhEpo on key autophagy activity proteins in hyperoxia-mediated neonatal brain injury
On account of the processing of light chain 3 (LC3) proteins involved in the formation and elongation of the autophagosome [20], we further investigated the effect of hyperoxia and concomitant rhEpo-treatment in the developing rat brain
Summary
Toxic levels of oxidative stress and reactive oxygen species (ROS) are a common pathway in many neurodegenerative disorders. Autophagy is a complex cellular process that involves digestion and recycling of intracellular components via a lysosomal pathway [2,3,4] It is a multi-step process that depends on the selective combination of autophagy-related gene (Atg) proteins involving the formation of double-membrane vesicles known as autophagosomes. These autophagosomes mature and fuse with lysosomes and their contents are degraded in an environment mediated by hydrolases [2,5,6]. Beclin-1, a Bcl-2-homology (BH)-3 domain only protein [8], is important for localization of autophagic proteins to a pre-autophagosomal structure and for mediating the nucleation process [9] It is distributed within the plasma-membrane, cytoplasm and nucleus, and has the capability to self-associate [10]. Due to the neuro-protective ability of rhEpo in different neonatal brain injury models [31,33,34,35,36], we investigated the effect of rhEpo on key autophagy activity proteins in hyperoxia-mediated neonatal brain injury
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