A holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies

Abstract

The year 2016 marked the 15th anniversary since anesthesia-induced developmental neurotoxicity and its resulting cognitive dysfunction were first described. Since that time, multiple scientific studies have supported these original findings and investigated possible mechanisms behind anesthesia-induced neurotoxicity. This paper reviews the existing mechanistic literature on anesthesia-induced neurotoxicity in the context of a holistic approach that emphasizes the importance of both neuronal and non-neuronal cells during early postnatal development. Sections are divided into key stages in early neural development; apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination and blood brain barrier/cerebrovasculature. In addition, the authors combine the established literature in the field of anesthesia-induced neurotoxicity with literature from other related scientific fields to speculate on the potential role of non-neuronal cells and to generate new future hypotheses for understanding anesthetic toxicity and its application to the practice of pediatric anesthesia.

The actions of volatile anesthetics: a new perspective

“…Regarding the side effects of anesthetics, it is clear that some off-target effects, for example cardiac arrhythmias and myocardial depression, stem from effects on non-neural ion channels (Zanghi & Jevtovic-Todorovic, 2017 disturbances in the development and maturation of the central nervous system may be owing to effects on glial cells as well as the effects of decreased synaptic activity on neurons (Zanghi & Jevtovic-Todorovic, 2017), some of which are potentially reversible through the application of receptor agonists (Huang et al, 2016). Regarding the most-feared issue of apoptosis in the developing brain (Ikonomidou et al, 2001;Zanghi & Jevtovic-Todorovic, 2017), the issue is less clear. Mitochondria are crucial components of the apoptotic pathway, releasing cytochrome c and other factors that direct the cell towards cell death (Boulbrima et al, 2016).…”

A systematic review and narrative synthesis on the histological and neurobehavioral long‐term effects of dexmedetomidine

“…The milestones of neurobehavioral development vary across species but the developmental progression in general is comparable. In the first weeks of life, critical neurodevelopment occurs; apoptosis, synaptogenesis, gliogenesis, and myelination, regardless of biological differences between species …”

General Anesthetic‐Induced Neurotoxicity in the Immature Brain: Reevaluating the Confounding Factors in the Preclinical Studies

“…Furthermore, GA were also found to induce various types of neurodegeneration, such as apoptosis of oligodendrocytes and neurons, microglial activation, cytoskeletal abnormalities of astrocytes, imbalanced differentiation of neural precursor cells, disruption of mitochondrial dynamics, and even damage to the blood-brain barrier. Because the neurodegenerative changes and potential injury mechanisms were thoroughly and elaborately outlined in recently published reviews [6][7][8]11], we will not repeat it in the present paper.…”

“…Among this research, a landmark study in this field showed that PND7 rats exhibited neuroapoptosis in a variety of brain regions and prolonged impairment in learning and memory after exposed to a commonly used anesthetic cocktail (N 2 O-midazolam-isoflurane) for 6 h [5]. Subsequent preclinical studies demonstrated that GA caused a vast amount of acute injury and long-term cognitive impairments in rodents [6][7][8][9][10][11][12][13] and nonhuman primates (NHP) [9,10,[14][15][16][17][18][19][20][21][22][23]. Even worse, exposure to GA in neonatal rodents produced adverse effects on the learning and memory of their offspring via epigenetic modulation [24][25][26][27].…”