Propofol via Antioxidant Property Attenuated Hypoxia-Mediated Mitochondrial Dynamic Imbalance and Malfunction in Primary Rat Hippocampal Neurons

BACKGROUND: Hypoxia may induce mitochondrial abnormality, which is associated with a variety of clinical phenotypes in the central nervous system. Propofol is an anesthetic agent with neuroprotective property. We examined whether and how propofol protected hypoxia-induced mitochondrial abnormality in neurons. METHODS: Primary rat hippocampal neurons were exposed to propofol followed by hypoxia treatment. Neuron viability, mitochondrial morphology, mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (MMP), and adenosine triphosphate (ATP) production were measured. Mechanisms including reactive oxygen species (ROS), extracellular regulated protein kinase (ERK), protein kinase A (PKA), HIF-1α, Drp1, Fis1, Mfn1, Mfn2, and Opa1 were investigated. RESULTS: Hypoxia increased intracellular ROS production and induced mPTP opening, while reducing ATP production, MMP values, and neuron viability. Hypoxia impaired mitochondrial dynamic balance by increasing mitochondrial fragmentation. Further, hypoxia induced the translocation of HIF-1α and increased the expression of Drp1, while having no effect on Fis1 expression. In addition, hypoxia induced the phosphorylation of ERK and Drp1(ser616), while reducing the phosphorylation of PKA and Drp1(ser637). Importantly, we demonstrated all these effects were attenuated by pretreatment of neurons with 50 μM propofol, antioxidant α-tocopherol, and ROS scavenger ebselen. Besides, hypoxia, propofol, α-tocopherol, or ebselen had no effect on the expression of Mfn1, Mfn2, and Opa1. CONCLUSIONS: In rat hippocampal neurons, hypoxia induced oxidative stress, caused mitochondrial dynamic imbalance and malfunction, and reduced neuron viability. Propofol protected mitochondrial abnormality and neuron viability via antioxidant property, and the molecular mechanisms involved HIF-1α-mediated Drp1 expression and ERK/PKA-mediated Drp1 phosphorylation.