Pharmacological inhibition of mitochondrial division attenuates simulated high-altitude exposure-induced cerebral edema in mice: Involvement of inhibition of the NF-κB signaling pathway in glial cells

Abstract

High-altitude cerebral edema (HACE) is the severe type of acute mountain sickness, which is still lack of effective therapy. This study investigated for the first time the protective effect of mitochondrial division inhibitor-1 (mdivi-1) against cerebral edema induced by simulated high-altitude exposure in mice. It was found that mdivi-1 effectively inhibited phosphorylation of dynamin-related protein-1 (Drp1), reduced expression of AQP4, decreased secretion of IL-6 and TNF-α, and alleviated cerebral edema in mice. In primary cultured astrocytes or microglia, mdivi-1 significantly decreased the hypoxia-induced Drp1 phosphorylation and mitochondrial fragmentation, inhibited the activation of the NF-κB signaling pathway, reduced the secretion of IL-6 and TNF-α. In addition, mdivi-1 inhibited mitochondrial reactive oxygen species (ROS) generation induced by hypoxia in both astrocytes and microglia. When astrocytes were treated with the conditioned medium of microglia exposed to hypoxia (H-MCM), the protein levels of p-Drp1, p-p65, and AQP4 as well as the mRNA levels of IL-6, TNF-α, and IL-1β in astrocytes were increased. When the mitochondrial components in H-MCM were removed, the influence of microglia on astrocytes under hypoxia was significantly alleviated. Treated with mdivi-1, the integrity of mitochondria released from microglia induced by hypoxia were significantly improved. In conclusion, pharmacological inhibition of mitochondrial division by mdivi-1 alleviated cerebral edema induced by simulated high-altitude exposure in mice. Inhibition of ROS/NF-κB signaling pathway may contribute to the protective effect of mdivi-1. Under hypoxic conditions, mdivi-1 may attenuate the activation of astrocytes by reducing the release of damaged mitochondria from microglia.