Abstract
BackgroundIntermittent hypoxia (IH) plays a critical role in sleep breathing disorder-associated hippocampus impairments, including neurocognitive deficits, irreversible memory and learning impairments. IH-induced neuronal injury in the hippocampus may result from reduced precursor cell proliferation and the relative numbers of postmitotic differentiated neurons. However, the mechanisms underlying IH-induced reactive oxygen species (ROS) generation effects on cell proliferation and neuronal differentiation remain largely unknown.ResultsROS generation significantly increased after 1–4 days of IH without increased pheochromocytoma-12 (PC12) cell death, which resulted in increased protein phosphatase 2A (PP2A) mRNA and protein levels. After 3–4 days of IH, extracellular signal-regulated kinases 1/2 (ERK1/2) protein phosphorylation decreased, which could be reversed by superoxide dismutase (SOD), 1,10-phenanthroline (Phe), the PP2A phosphorylation inhibitors, okadaic acid (OKA) and cantharidin, and the ERK phosphorylation activator nicotine (p < 0.05). In particular, the significantly reduced cell proliferation and increased proportions of cells in the G0/G1 phase after 1–4 days of IH (p < 0.05), which resulted in decreased numbers of PC12 cells, could be reversed by treatment with SOD, Phe, PP2A inhibitors and an ERK activator. In addition, the numbers of nerve growth factor (NGF)-induced PC12 cells with neurite outgrowths after 3–4 days of IH were less than those after 4 days of RA, which was also reversed by SOD, Phe, PP2A inhibitors and an ERK activator.ConclusionsOur results suggest that IH-induced ROS generation increases PP2A activation and subsequently downregulates ERK1/2 activation, which results in inhibition of PC12 cell proliferation through G0/G1 phase arrest and NGF-induced neuronal differentiation.
Highlights
Intermittent hypoxia (IH) plays a critical role in sleep breathing disorder-associated hippocampus impairments, including neurocognitive deficits, irreversible memory and learning impairments
To further clarify whether the increased mitochondrial reactive oxygen species (ROS) levels were induced by IH, superoxide dismutase (SOD) was added each day to the culture medium for 4 days (IH4 + SOD)
Lower levels of mitochondrial ROS generation were found with IH4 + SOD as compared with IH4 (p < 0.05)
Summary
Intermittent hypoxia (IH) plays a critical role in sleep breathing disorder-associated hippocampus impairments, including neurocognitive deficits, irreversible memory and learning impairments. IH has been reported to result in partially irreversible memory and learning impairments in both animals and humans [3]. ROS may play a role in inhibiting the leukemic cells proliferation [7] and the differentiation of rabbit bone marrow stromal [8] and neuroblastoma cells [9] by activating numerous signalling pathways that involve extracellular signal-regulated kinases 1/2 (ERK1/2) [10]. ERK and ERK-dependent NF-κB activation is required for oxidative stress-induced osteoblastic differentiation inhibition by primary rabbit bone marrow stromal cells and calvarial osteoblasts [8]. ERK1/2 signalling is causally linked to the transcriptional activation of those genes required for cell proliferation and differentiation [11]
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