General Anesthesia and the Young Brain: The Importance of Novel Strategies with Alternate Mechanisms of Action

Abstract

Over the past three decades, we have been grappling with rapidly accumulating evidence that general anesthetics (GAs) may not be as innocuous for the young brain as we previously believed. The growing realization comes from hundreds of animal studies in numerous species, from nematodes to higher mammals. These studies argue that early exposure to commonly used GAs causes widespread apoptotic neurodegeneration in brain regions critical to cognition and socio-emotional development, kills a substantial number of neurons in the young brain, and, importantly, results in lasting disturbances in neuronal synaptic communication within the remaining neuronal networks. Notably, these outcomes are often associated with long-term impairments in multiple cognitive-affective domains. Not only do preclinical studies clearly demonstrate GA-induced neurotoxicity when the exposures occur in early life, but there is a growing body of clinical literature reporting similar cognitive-affective abnormalities in young children who require GAs. The need to consider alternative GAs led us to focus on synthetic neuroactive steroid analogues that have emerged as effective hypnotics, and analgesics that are apparently devoid of neurotoxic effects and long-term cognitive impairments. This would suggest that certain steroid analogues with different cellular targets and mechanisms of action may be safe alternatives to currently used GAs. Herein we summarize our current knowledge of neuroactive steroids as promising novel GAs.

Novel anesthetics in pediatric practice: is it time?

“…We have recently published an extensive summary on mechanism of action of neuroactive steroids and the lack of observable neuronal injury even after prolonged exposures in young animals [86], thus making them a potentially viable alternative to currently used general anesthetics [20]. Briefly, alphaxalone and similar neuroactive steroids, such as investigational drugs, CDNC24 [(3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol) and 3β-OH ((3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile], unlike propofol or ketamine, lack the neuroapoptogenic properties in rat pups [87,88 ▪ ].…”

Propofol attenuates kinesin-mediated axonal vesicle transport and fusion

“…General anesthetics, including propofol, impact early brain development and can cause neurodegeneration and long-lasting disruptions in synaptic communication ( Lee et al. , 2015 ; Kelz and Mashour, 2019 ; Maksimovic et al. , 2022 ).…”