Molecular Mechanisms of Anesthetic Neurotoxicity: A Review of the Current Literature

Abstract

Data from epidemiologic studies and animal models have raised a concern that exposure to anesthetic agents during early postnatal life may cause lasting impairments in cognitive function. It is hypothesized that this is due to disruptions in brain development, but the mechanism underlying this toxic effect remains unknown. Ongoing research, particularly in rodents, has begun to address this question. In this review we examine currently postulated molecular mechanisms of anesthetic toxicity in the developing brain, including effects on cell death pathways, growth factor signaling systems, NMDA and GABA receptors, mitochondria, and epigenetic factors. The level of evidence for each putative mechanism is critically evaluated, and we attempt to draw connections between them where it is possible to do so. While there are many promising avenues of research, at this time no consensus can be reached as to a definitive mechanism of injury.

Anesthetics disrupt brain development via actions on the mTOR pathway

“…The mechanisms by which general anesthetics might disrupt brain development have yet to be clearly defined. Early work on this topic identified molecular evidence of upregulation of pro-apoptotic pathways by general anesthetic drugs in the developing brain [ 15–17 ], but more recent studies have cast doubt on whether cell death is the principal mechanism of damage in anesthetic neurotoxicity [ 18–20 ]. Thus, it is of interest to consider other potential mechanisms of injury, particularly those which relate developmental anesthetic neurotoxicity to better-studied disorders of brain development.…”

Anesthetic neurotoxicity: Apoptosis and autophagic cell death mediated by calcium dysregulation

“…Besides ER calcium release sites, there are several proposed targets for inhaled anesthetics mediated neurotoxicity (Jackson et al, 2016; Wang et al, 2015). Recent studies have proposed the role of p75 growth factor activation on anesthetics mediated neurotoxicity (Pearn et al, 2012).…”

BAX is necessary for neuronal death following exposure to isoflurane during the neonatal period

“…Neuroinflammation has been described in adult models of anesthesia exposure, but has not been assessed in neonatal models (39). We therefore investigated whether neuroinflammation occurs following early life exposure to isoflurane, and whether it occurs independent of neuronal death using Bax knockout mice.…”