Oxidative cell death in the central nervous system: mechanisms and therapeutic strategies

Abstract

Oxidative cell death is caused by an overproduction of reactive oxygen species and an imbalance in the antioxidant defense system, leading to neuronal dysfunction and death. The harm of oxidative stress in the central nervous system (CNS) is extensive and complex, involving a variety of molecular and cellular level changes that may lead to a variety of acute and chronic brain pathologies, such as stroke, traumatic brain injury, or neurodegenerative diseases and psychological disorders. This review provides an in-depth look at the mechanisms of oxidative cell death in the central nervous system diseases. In addition, the review evaluated existing treatment strategies, including antioxidant therapy, gene therapy, and pharmacological interventions targeting specific signaling pathways, all aimed at alleviating oxidative stress and protecting nerve cells. We also discuss current advances and challenges in clinical trials, and suggest new directions for future research, including biomarker discovery, identification of potential drug targets, and exploration of new therapeutic techniques, with a view to providing more effective strategies for the treatment of CNS diseases.

Keywords: antioxidant therapy; central nervous system; neurodegenerative diseases; neuroprotection; oxidative stress.

FIGURE 1

Overview of the mechanisms of cell death induced by ROS. (A) Apoptosis: Initiated by cell shrinkage and membrane blebbing, leading to nuclear fragmentation and apoptotic body formation. (B) Necrosis: Marked by swelling of the cell and organelles, culminating in rupture of the cell membrane and release of cell contents. (C) Parthanatos: Involves chromatin condensation and DNA damage, resulting in cell atrophy, thickened nucleus, and membrane lysis. (D) Ferroptosis: Characterized by mitochondrial ridge reduction or disappearance, mitochondrial outer membrane rupture, and lipid peroxidation accumulation, leading to membranolysis. (E) Pyroptosis: Features pyrogenic corpuscles formation, cell swelling, and membranes burst, followed by nuclear pyconosis and DNA breakage. (F) Paraptosis: Shown by mitochondrial and endoplasmic reticulum swelling, resulting in vacuole formation. (G) Oxeiptosis: Represents ROS-induced caspase-independent apoptosis-like cell death, associated with mitochondrial depolarization.

FIGURE 2

Regulation of apoptosis in CNS diseases. ROS-induced mitochondrial damage leading to cytochrome C release, activating caspase-9 and initiating apoptosis. The extrinsic pathway, activated by Fas receptor and FADD, involves caspase-8 and -10 to promote cell death. The diagram highlights how ROS affect signaling pathways like MAPK and NF-kB, influencing apoptosis in CNS diseases.

FIGURE 3

Regulation of ferroptosis in CNS diseases. Ferroptosis, mediated by xCT and GSH pathway, is relevant to CNS diseases, and is linked to neurodegeneration and glioblastoma.

FIGURE 4

Mechanisms of Antioxidant Therapy in CNS Diseases. Antioxidant therapies, including the activation of antioxidant enzymes, administration of NAC, vitamins, Coenzyme Q10, MitoQ, iron chelators, and polyphenols, work to reduce ROS levels.