Figure 2.

Double-edged sword effects of astrocyte activation. TBHQ activates Nrf2 and then regulates its downstream HO-1, HIF-1α, and VEGF. This process activates the Sigma-1 receptor, so that astrocytes become activated from inactivated, and activated astrocytes can play a role in resisting methamphetamine-induced oxidative stress. TBHQ can also increase activated astrocytes and their coverage to reduce ROS. ROS inhibits the PI3K/AKT signaling pathway. TBHQ, as an Nrf2 agonist, can also indirectly activate Nrf2 by positively regulating the PI3K/AKT signaling pathway. Sigma-1 receptor KO or Sigma-1 receptor antagonists can activate Nrf2 as well as block excessive Sigma-1 receptors, thereby preventing the overactivation of astrocytes. However, methamphetamine can induce overactivation of astrocytes. TBHQ: tert-butyl hydroquinone; Nrf2: nuclear factor E2 related factor 2; HO-1: heme oxygenase-1; HIF-1α: hypoxia-inducible factor-1α; VEGF: vascular endothelial growth factor; KO: knockout; ROS: reactive oxygen species; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B.