Molecular Mechanisms of Anesthetic-Induced Neurotoxicity and Neuroprotection Bridging Experimental Models with Clinical Practice: Systematic Review

Abstract

General anesthesia is a cornerstone of modern surgical practice, yet growing evidence indicates that commonly used volatile anesthetics such as sevoflurane and isoflurane are not neurobiologically inert. Instead, they can induce mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, neuroinflammation, and synaptic dysregulation, thereby contributing to postoperative delirium and postoperative cognitive dysfunction (POCD), particularly in vulnerable populations. This narrative review aims to provide an integrative overview of the molecular mechanisms underlying anesthetic-induced neurotoxicity, evaluate emerging neuroprotective strategies, and discuss translational challenges in bridging preclinical findings with clinical outcomes. Literature published between 2000 and 2025 was systematically retrieved from PubMed, Scopus, Web of Science, and Embase. Eligible studies included experimental and clinical research on anesthetic neurotoxicity, molecular pathways, neuroprotection, and translational perspectives. Data were qualitatively analyzed and categorized into pathophysiological mechanisms, neuroprotective interventions, and translational barriers. Key mechanisms of anesthetic-induced neuronal injury include inhibition of mitochondrial complex I, reactive oxygen species generation, prolonged ER stress with CHOP activation, microglial-mediated neuroinflammation, and Alzheimer’s-like pathology characterized by tau hyperphosphorylation and amyloid-beta aggregation. Promising neuroprotective agents such as dexmedetomidine, xenon, antioxidants, and preconditioning strategies demonstrate multi-pathway protective effects but face translational limitations. Emerging biomarkers, particularly neurofilament light chain (NfL) and tau protein, show potential for objective detection of neuronal injury and perioperative risk stratification. General anesthesia poses significant risks of neurotoxicity, underscoring the need for a paradigm shift from passive harm avoidance toward proactive, biomarker-guided neuroprotection. Future directions include the integration of molecular insights, precision monitoring, and multi-modal interventions to establish brain-protective perioperative care and ensure long-term cognitive safety