Figure 4.

Illustration of signaling pathway modulators involved in endogenous cellular antioxidant synthesis. Extracellular stimulants such as mitophagy, ROS, and oxidative damage may lead to the activation of cell signaling pathways such as AKT, PGC-1α, mTOR, and SIRT. These signaling pathways are involved in upregulating endogenous antioxidant homeostasis by activating nuclear antioxidant response element (ARE) signaling via the activation of common transcription factors Nrf-2 and Keap1. Activation of the nuclear ARE gene upregulates mitochondrial biogenesis. Additionally, ARE gene expression activation may also leads to activation of several mitochondrial antioxidant transcription factors, thereby protein biosynthesis and protect cells against external stimuli. Increased antioxidant levels further balance redox homeostasis by decreasing cellular ROS, oxidative stress, and apoptotic cell death response together by improving the cellular antioxidant capacity and overall health of mitochondria. By activating these pathways, therapeutic compounds may be further able to offer neuroprotection following TBI and CNS diseases.