SCHEME 1.

Neuroinflammation and Oxidative Stress Cycle in Epilepsy.Initial insults such as systemic infection, traumatic brain injury (TBI), status epilepticus (SE), and genetic mutations initiate inflammatory and oxidative signaling cascades. NF-KB activation leads to the production of proinflammatory cytokines such as IL-1β, TNFα, and IL-6, which have been shown to i nduce gliosis, mitochondrial dysfunction, and glutathione (GSH) depletion. GSH depletion impairs cellular and mitochondrial antioxidant defenses, enabling aberrant oxidative signaling and damage. NAPDH Oxidase 2 (NOX2) upregulation also commonly occurs with neuroinflammation. NOX2 utilizes NADPH, which is needed for the reductive abilities of antioxidant systems like thioredoxin reductase and glutathione peroxidase, to produce superoxide (O₂ ^-)_. O₂ ^-is primarily enzymatically converted to the redox-signaling reactive H₂O₂. The increased levels of steady-state H₂O₂ leads to the activation of numerous redox-sensitive pathways that influence neuroinflammation. For example, NF-KB activation and subsequent microglia activation relies on NOX2 activity, indicating that reactive oxygen species (ROS) production perpetuates neuroinflammation. Nrf2 is also activated by ROS to increase expression of the antioxidant response element (ARE) to combat oxidative damage and neuroinflammation, making it an attractive therapeutic target. The danger-associated molecular pattern (DAMP) HMGB1 is released in response to neuronal damage, which signals through TLR4 to activate NF-KB, induce gliosis, and increase NOX2 and COX-2 expression. Reduced HMGB1 has chemoattractant properties, but adjacent cysteine residues act as a redox switch where oxidation to a disulfide form increases affinity for TLR4 and induces cytokine like properties. The NLRP3 inflammasome, which activates IL-1β, can also by activated by ROS from the mitochondria and NOX. Extracellular matrix (ECM) digesting proteinases such as matrix metalloproteinases (MMPs) are also upregulated in the neuroinflammatory environment. This can lead to the disruption of the blood brain barrier (BBB) and perineuronal nets (PNs) surrounding inhibitory parvalbumin interneurons (PVINs). MMP9 has demonstrated redox-sensitive activation, which is associated with the loss of PNs and death of PVINs. Mitochondria dysfunction can result from excessive mitochondrial ROS (mtROS) which not only accounts for metabolic alterations, but can lead to inflammation-inducing events such as astrogliosis, apoptosis, and lipid peroxidase mediated death (ferroptosis). Metabolic dysfunction, excitatory/inhibitory (E/I) imbalance, and neurodegeneration can all result from these oxidative and inflammatory processes which ultimately contribute to epileptogenesis.