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.

Keywords: general anesthetics; neuroactive steroid analogues; neurotoxicity; synaptogenesis.

Figure 1

Synthesized neuroactive steroids—chemical structures. Chemical structures of synthesized steroids used in our studies: 3β-OH—(3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile; CDNC24—(3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol; alphaxalone—5α-pregnan-3α-ol-11,20-dione.

Figure 2

Summary of known and potential mechanisms of neuroactive steroids. 3β-OH inhibits postsynaptic T-channels without having a direct effect on postsynaptic GABA_A receptors. In addition to postsynaptic potentiation of GABA_A, both CDNC24 and alphaxalone presynaptically reduce spontaneous GABA release, thus decreasing GABA content in the synaptic cleft. In addition to its effect on postsynaptic GABA_A receptors and reduction in presynaptic GABA release in the synaptic cleft, alphaxalone also simultaneously blocks postsynaptic T-channels. Additionally, based on the well-known abilities of steroid compounds to pass cellular membranes, there is a possibility that the explanation for the absence of cell death in neurons lies in their direct or indirect interactions with membrane-bound, intracellular, and nuclear receptors, either as agonists or antagonists. These targets, as well other potential targets on the presynaptic terminal, remain unknown.