Perturbation of catecholamine biosynthesis has been implicated as a cause of neuronal cell death after hypoxic-brain injury. Thus, the perturbation of oxygen homeostasis by hypoxia can affect neuronal viability resulting from the alteration of catecholamine biosynthesis that are regulated by oxygen-dependent enzymes. Previous studies have shown that the hypoxia causes the increase of hypoxia-inducible factors (HIFs) in certain areas of the brain. Although hypoxia is known to cause the intracellular acidosis, it is not clear how intracellular acidosis play the role in the activity of HIF. In the present study, cobalt chloride is used to chemically induce hypoxia in dopaminergic MN9D cells that expresses HIF-1α. Our findings shown that cobalt chloride decreases intracellular pH and increase reactive oxygen species (ROS) production that leads to MN9D cell death. Thus, these evidences suggest that the cell death may be due to an activation of HIF and perturbation of catecholamine biosynthesis. In addition, the Cl-/HCO3- exchanger inhibitor significantly increase intracellular pH, decreases reactive oxygen species (ROS), and protects MN9D cells against cobalt chloride. Similarly, ascorbic acid decreases ROS production and increases cell viability. On the other hand, the Na+/H+ exchanger and acid sensing ion channel inhibitor decreases intracellular pH and increases ROS. No cellular protection from this inhibitor against cobalt chloride were observed. Therefore, it is proposed that the mechanism of cell death is caused by an activation of HIF-1α under hypoxic condition that leads to a decrease in intracellular pH and increase of ROS production resulting in cell death. On the other hand, the neuroprotection mechanism may be due to an increase of intracellular pH that prevent an activation of HIF-1 α causing a decrease in ROS production. While it is not clearly understood how HIF-1α leads to cell death, a better understanding of the mechanism of cell death under hypoxia condition could potentially lead to the development of pharmacological agents for the protection of neuronal damage.

Effect of acidosis on the mechanism of cell death under hypoxia induced by cobalt chloride in dopaminergic MN9D cells

2019 Spring National Meeting

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