Do We Have Viable Protective Strategies against Anesthesia-Induced Developmental Neurotoxicity?

Abstract

Since its invention, general anesthesia has been an indispensable component of modern surgery. While traditionally considered safe and beneficial in many pathological settings, hundreds of preclinical studies in various animal species have raised concerns about the detrimental and long-lasting consequences that general anesthetics may cause to the developing brain. Clinical evidence of anesthetic neurotoxicity in humans continues to mount as we continue to contemplate how to move forward. Notwithstanding the alarming evidence, millions of children are being anesthetized each year, setting the stage for substantial healthcare burdens in the future. Hence, furthering our knowledge of the molecular underpinnings of anesthesia-induced developmental neurotoxicity is crucially important and should enable us to develop protective strategies so that currently available general anesthetics could be safely used during critical stages of brain development. In this mini-review, we provide a summary of select strategies with primary focus on the mechanisms of neuroprotection and potential for clinical applicability. First, we summarize a diverse group of chemicals with the emphasis on intracellular targets and signal-transduction pathways. We then discuss epigenetic and transgenerational effects of general anesthetics and potential remedies, and also anesthesia-sparing or anesthesia-delaying approaches. Finally, we present evidence of a novel class of anesthetics with a distinct mechanism of action and a promising safety profile.

Keywords: ROS; mitochondria; neonatal anesthesia; neuroactive steroids; neuroprotection; neurotoxicity; signaling pathways.

Figure 1

Summary of key cellular targets in the pathophysiology of anesthesia-induced developmental neurotoxicity. Red arrows and crosses represent the main events by which GAs exert their deleterious effects in immature neurons. GAs deprive neurons of survival signals initiated by growth factors, transduced by two major kinase pathways. Furthermore, GAs may directly induce ROS formation, genetic and epigenetic disturbances, and mitochondrial instability leading to cytochrome c exudation and apoptosis. Black borders indicate neurotoxicity-reversal points, triggered by neuroprotective strategies discussed previously. BDNF, brain-derived neurotrophic factor; NGF, neural growth factor; PI3K, phosphatidylinositol 3 kinase; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; ERK, extracellular signal-regulated kinase; GSK-3β, glycogen synthase kinase 3 beta; ROS, reactive oxygen species; Nrf2, nuclear factor E2-related factor 2; Ac, acetylated histones; Me, methylated DNA; CBP, CREB-binding protein.