Norepinephrine increases the level of monoamine oxidase-A and plays a role in intermittent hypoxia induced injury in SH-SY5Y cells

Abstract

Obstructive sleep apnea (OSA) is a common breathing sleep disorder prevalent all over the world. Norepinephrine (NE) levels were reportedly to be elevated in the circulatory system of OSA patients. Monoamine oxidase A (MAO-A) is important for the NE deamination and produces H2O2 as a catalytic byproduct. I hypothesized that elevated NE levels mediate upregulated MAO-A expression induced by intermittent hypoxia, resulting in the cellular injury. In SH-SY5Y cells, constitutively expressing only MAO-A not MAO-B, intermittent hypoxia induced cell death in a dose and time dependent manner, which was antagonized by MAO-A inhibitor M30 or clorgyline. In addition, clorgyline mitigated the elevated levels of inflammatory cytokines (tumor necrosis factor-α and interleukin-1β) and apoptotic markers (Bcl-2 and cleaved caspase-3) induced by intermittent hypoxia. Moreover, a significant increase in the level of expression of enzymes for the NE biosynthesis, namely dopamine -hydroxylase (DBH) and phosphorylated tyrosine hydroxylase (TH) was observed, which was partially prevented by antioxidant N-acetyl cysteine or calcium channel blocker nifedipine. Furthermore, exogenous NE administration, significantly increased the expression of MAO-A in the cells with or without concurrent treatment of intermittent hypoxia, which was blocked by NE transporter inhibitor desipramine. Blockade of MAO-A with clorgyline significantly attenuated the upregulated MAO-A expression and the deteriorated levels of oxidative stress (GSSH to GSH ratio, superoxide dismutase and catalase) induced by NE. In summary, my results suggest that the upregulation of MAO-A expression driven by elevated NE levels could be a maladaptive response to intermittent hypoxia leading to oxidative stress, inflammation and apoptosis. These results may provide a possible pathophysiological pathway of OSA-comorbid neurological disease and MAO-A could be a potential target to alleviate the impact of intermittent hypoxia.