Ferroptosis is involved in regulating perioperative neurocognitive disorders: emerging perspectives

Abstract

Since the twenty-first century, the development of technological advances in anesthesia and surgery has brought benefits to human health. However, the adverse neurological effects of perioperative-related factors (e.g., surgical trauma, anesthesia, etc.) as stressors cannot be ignored as well. The nervous system appears to be more “fragile” and vulnerable to damage in developing and aging individuals. Ferroptosis is a novel form of programmed cell death proposed in 2012. In recent years, the regulation of ferroptosis to treat cancer, immune system disorders, and neurodegenerative diseases have seen an unprecedented surge of interest. The association of ferroptosis with perioperative neurocognitive disorders has also received much attention. Cognitive impairment can not only affect the individual’s quality of life, but also impose a burden on the family and society. Therefore, the search for effective preventive and therapeutic methods to alleviate cognitive impairment caused by perioperative-related factors is a challenge that needs to be urgently addressed. In our review, we first briefly describe the connection between iron accumulation in neurons and impairment of brain function during development and aging. It is followed by a review of the pathways of ferroptosis, mainly including iron metabolism, amino acid metabolism, and lipid metabolism pathway. Furthermore, we analyze the connection between ferroptosis and perioperative-related factors. The surgery itself, general anesthetic drugs, and many other relevant factors in the perioperative period may affect neuronal iron homeostasis. Finally, we summarize the experimental evidence for ameliorating developmental and degenerative neurotoxicity by modulating ferroptosis. The suppression of ferroptosis seems to provide the possibility to prevent and improve perioperative neurocognitive impairment.

The effects of general anesthetics on mitochondrial structure and function in the developing brain

“…One such pathway, termed ferroptosis, is characterized by iron-dependent production of excessive lipid peroxidation and subsequent membrane damage and cell death ( 149 , 150 ). Owing to its ability to exist in different oxidation states, iron is an essential micro-element, necessitating a tightly controlled regulatory network for iron transport, metabolism, and cellular distribution ( 151 ). When these pathways are disrupted such that total cellular iron levels rise, the pro-oxidant environment induces excessive lipid peroxidation, most notably of the fatty acyl moieties on phospholipids of poly unsaturated fats, resulting plasma membrane permeabilization and lytic cell death ( 150 ).…”

Potential of Therapeutic Small Molecules in Apoptosis Regulation in the Treatment of Neurodegenerative Diseases: An Updated Review

“…On the other hand, typical biochemical characteristics of ferroptosis include GPX4 inactivation, GSH depletion, and cystine deficiency [ 95 ]. It has been demonstrated that ferroptosis plays a role in neurodegeneration [ 96 , 97 , 98 ]. It also includes dementia, astrocyte dysregulation, degeneration of myelin sheaths, failure of neuronal communication, oxidation of neurotransmitters, activation of inflammation, and cell death [ 93 , 96 , 97 , 98 ].…”

“…It has been demonstrated that ferroptosis plays a role in neurodegeneration [ 96 , 97 , 98 ]. It also includes dementia, astrocyte dysregulation, degeneration of myelin sheaths, failure of neuronal communication, oxidation of neurotransmitters, activation of inflammation, and cell death [ 93 , 96 , 97 , 98 ]. Moreover, iron or free iron overload can trigger lipid peroxidation in Schwann cells, microglia, oligodendrocytes, astrocytes, and neurons.…”

Exploring the Impact of Preoperative Sleep Fragmentation on Cognitive Function in Mice: The Role of Microglial Activation and Iron Metabolism

“…Tese disorders, previously considered distinct entities, are now recognized as interconnected conditions that can signifcantly impact patients' quality of life and long-term outcomes postsurgery [2]. As we continue to grapple with the complex etiologies and risk factors of PND, it has become evident that these conditions are not merely a product of surgical stress or anesthesia, but rather result from a multifactorial cascade involving patient's preoperative cognitive status, genetic predisposition, comorbid conditions, surgical factors, and postoperative care practices [3]. In addition to the direct impact on cognitive function, PND can lead to prolonged hospital stays, increased healthcare costs, and higher rates of morbidity and mortality [4].…”