Crosstalk Between the Oxidative Stress and Glia Cells After Stroke: From Mechanism to Therapies

Abstract

Stroke is the second leading cause of global death and is characterized by high rates of mortality and disability. Oxidative stress is accompanied by other pathological processes that together lead to secondary brain damage in stroke. As the major component of the brain, glial cells play an important role in normal brain development and pathological injury processes. Multiple connections exist in the pathophysiological changes of reactive oxygen species (ROS) metabolism and glia cell activation. Astrocytes and microglia are rapidly activated after stroke, generating large amounts of ROS via mitochondrial and NADPH oxidase pathways, causing oxidative damage to the glial cells themselves and neurons. Meanwhile, ROS cause alterations in glial cell morphology and function, and mediate their role in pathological processes, such as neuroinflammation, excitotoxicity, and blood-brain barrier damage. In contrast, glial cells protect the Central Nervous System (CNS) from oxidative damage by synthesizing antioxidants and regulating the Nuclear factor E2-related factor 2 (Nrf2) pathway, among others. Although numerous previous studies have focused on the immune function of glial cells, little attention has been paid to the role of glial cells in oxidative stress. In this paper, we discuss the adverse consequences of ROS production and oxidative-antioxidant imbalance after stroke. In addition, we further describe the biological role of glial cells in oxidative stress after stroke, and we describe potential therapeutic tools based on glia cells.

Keywords: astrocyte; microglia; oxidative stress; stroke; therapies.

Figure 1

The main mechanisms of ROS production after stroke. Electrons released from the electron transport chain (ETC) react with O₂ to produce superoxide. Mitochondrial complexes, oxidases in the matrix, and NADPH oxidase are involved in the release of ROS. Ca²⁺, NO, and succinate produced by the TCA cycle are important contributing factors. $O_2^{-}$ is catalyzed by SOD to produce H₂O₂, which can be decomposed into H₂O and O₂. NO can combine with $O_2^{-}$ to form ONOO^-, causing nitrosative stress.

Figure 2

Astrocytes and microglia interact and function together during stroke. Astrocytes release Ca²⁺, S100B, and cytokines that affect the redox state of microglia. The production of H₂O₂ and NO by microglia facilitates the activation process of astroglial. Glial cells affect glutamate transport, inflammatory factor secretion, matrix protease activation, and antioxidant production via ROS, which together cause post-stroke excitotoxicity, neuroinflammation, BBB destruction, and neurogenesis.

Figure 3

The relationship between oxidative stress and the Nrf2 signaling pathway in astrocytes. ROS or compounds stimulate Nrf2 transcription into the nucleus and participate in the transcription of target genes. increased synthesis of enzymes such as HO-1, NQO1, GPx, and MRP1 counteract oxidative stress and regulate metabolism. Nrf2 is also involved in regulating inflammatory responses.