Seizure-Induced Oxidative Stress in Temporal Lobe Epilepsy

Figure 1

Biochemical reactions of ROS/RNS and their elimination by cellular endogenous antioxidants. Components in blue represent nonenzymatic antioxidants; green represents oxidative and antioxidant enzymes; and small red explosion sign represents generation of free radicals. NOX is the key enzymatic source of ROS. It reduces oxygen to superoxide anion and hydrogen peroxide. forms H₂O₂ which is the most reactive radical among its group that is produced via Fenton reaction. OH^• leads to lipid peroxidation by producing harmful metabolites such as MDA and 4-HNE leading to mitochondrial dysfunction and cell death. It also produces HOCl^• and PhO^• which are extremely toxic oxidants that disrupt tight junctions and increase paracellular permeability. H₂O₂ is eliminated by CAT, in peroxisomes, and GPx (location varies). At rapid rates, superoxide anions compete with NO which results in the formation of highly reactive molecule called peroxynitrite (ONOO^•), in cytoplasm, leading to increased ROS production, oxidation of DNA, RNA, and proteins, ion channel dysfunction, and loss of bioactive NO^•. Peroxynitrite inactivates Mn-SOD, thereby increasing the flux of superoxide anions available to react with NO. SOD catalyzes the reduction of superoxide anions into H₂O₂, in mitochondria in the presence of enzymes GPx and CAT; H₂O₂ gets converted into water and oxygen. Antioxidant enzymes such as GPx oxidize GSH to GSSG and GSH_red recycles GSH back from GSSG. NADPH gets reduced to NADP by GSH_red. GSH/GSSG is a commonly used biomarker of oxidative stress in biological systems. However, GPx also catalyzes H₂O₂ into H₂O by using reduced TRX_red. Antioxidant defense against toxic oxygen intermediates comprises an intricate network which is heavily influenced by nutrition (vitamins A, E, and C and fatty acids). CGS plays an important role in glutathione metabolism and acts as an antioxidant in glial cells such as astrocytes. Extracellular oxidized cysteine is reduced to cysteine by thioredoxin reductase or glutathione that helps to maintain the steady state balance between antioxidants and ROS [24, 41, 80]. ROS, reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase; SOD, superoxide dismutase (Cu/Zn—copper/zinc, Mn—manganese); CAT, catalase; , superoxide anion; H₂O₂, hydrogen peroxide; NO, nitric oxide; , peroxynitrite; HOCl, hypochlorous acid; PhO^•, phenoxy radical; OH^•, hydroxyl radical; GSH, glutathione; GSSG, oxidized glutathione; TRXox/, thioredoxin reduced and oxidized; TRX_red, thioredoxin reductase; GSH_red, glutathione reductase; GPx, glutathione peroxidase; CGS, cystine/glutamate antiporter system.